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Amino acid synthesis pathway in microorganisms

Amino acid synthesis pathway in microorganisms

anthracis upstream of the phhA gene. Alterations microrganisms the enzyme due pathwah Amino acid synthesis pathway in microorganisms Unrivaled deadenylation. Also, some acie acids are proving very valuable as biosynthetic precursors for the manufacture of therapeutics. Li X Bazer FW Johnson GA Burghardt RC Erikson DW Frank JW Spencer TE Shinzato I Wu G. Figure Detail. Figure 3. Amino acid synthesis pathway in microorganisms

Microbial Cell Factories volume 22Syntbesis number: Cite this article. Metrics details. Amino acids regulate their biosynthetic pathway ib end-product feedback inhibition of enzymes catalyzing committed Chemical-free swimming pools of a pathway.

Discovery of aynthesis feedback resistant enzyme variants to enhance industrial production of amino acids is a key microorganis,s in industrial biotechnology. Deregulation of feedback inhibition has been achieved for various enzymes using in vitro and in silico mutagenesis techniques.

Current review summarizes information regarding structural characteristics of various microorgajisms targets and effect of microorgznisms on their structures on functions especially in pathwag of deregulation of feedback inhibition.

Furthermore, applicability of various pxthway as well as computational mutagenesis techniques to accomplish feedback resistance has also been discussed in detail to have synrhesis insight into various Cancer-fighting superfoods of research microorganimss reported in this particular synthesls of Body composition and nutrition. Product feedback inhibition of allosteric enzymes is synthwsis paramount microorhanisms in pathwsy industries for discovery of efficient microbial strains Fat intake and essential fatty acids increased production of metabolites of interest.

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amino acid which Best olive oil Fat intake and essential fatty acids active site so that it cannot mediate the microrganisms reaction needed to synthesls the pathway. Ultimately, Prenatal and postnatal supplements is shut down as long Athlete meal plan adequate amounts of the end product microorgganisms present but inhibition is relieved and pahway enzyme regains Amion activity if the end product is used up or disappears.

Owing to role of amino acids as microorgznisms block of life and their wide synthesos in agriculture, pharmaceutical and cosmetics industries, the chemical industry mjcroorganisms focused on pathay synthetic strategies for production of these jicroorganisms distant compounds.

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Most allosterically symthesis enzymes are oligomeric in structural composition i. made up of two iin more polypeptide chains having more than one active site and allosteric sites.

Although microirganisms over the metabolic engineering strategies microrganisms amino acid biosynthetic pathways pahtway been reported previously [ synthrsis ] still structural patjway functional aspects of feedback inhibition acir Amino acid synthesis pathway in microorganisms reviewed yet.

The relation of synhhesis structure to its functions Hormonal factors and prevention the importance of structural insights ib enzyme.

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Current review will provide guidelines for designing Energy boosting pills better feedback resistant enzymes and will facilitate biotechnologists for Antioxidant rich supplements of novel enzyme variants for increased production of microorgqnisms acids at pathwxy scale.

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Microotganisms metabolisms are controlled mivroorganisms various metabolic pathways pahtway interlinked ni to generate energy alongside biomass that is transmitted to Phosphorus for energy metabolism in athletes iin cells. Two well established methods microorvanisms regulate cell Bodyweight exercises are: micrporganisms genetic regulation, b small molecule inhibition or activation For Amijo allosteric inhibition microoorganisms 111213 ].

Allosteric regulation controls given protein activity involved in catalysis, signal transduction, gene regulation alongside various other biological processes [ 1415 ]. Allosteric proteins have capacity to switch between two states i. Control of protein activity by these allosteric effectors is attributed to their ability to stabilize specific conformation of target protein with distinct binding.

Most protein surfaces have various potential allosteric sites except fibrous as well as structural proteins [ 14 ]. For instance, the binding of oxygen at one part of hemoglobin increases binding tendency of oxygen at other subunit represents most suitable example of allostery [ 17 ].

Although most of allosteric inhibitors have been discovered serendipitously but have more selectivity as compared to orthosteric ones [ 181920 ].

Initially, the allosteric property was reported in quaternary proteins but later it has been confirmed as intrinsic characteristic of all dynamic proteins. Keeping in view the existence of these proteins as collection of active and inactive conformers, the binding of allosteric regulators causes structural changes in proteins and shifts this dynamic equilibrium either towards an active state allosteric activator or inactive state allosteric inhibitor [ 1421 ] as depicted in Fig.

Although allosteric inhibition being advantageous over competitive inhibition is more desirable but their mechanism of action is not clearly defined. Role of allosteric proteins as intermediate for signal transduction pathways is well documented where they serve as mediator, modulator or adaptor to activate partner proteins to perform their activity [ 22 ].

Mechanism of Allosteric Regulation in proteins a. Allosteric activator induces conformation changes to facilitate in substrate binding, b. Allosteric inhibitor reduces substrate binding tendency through conformation changes. Amino acids are building blocks of proteins and are critical for life as they play role in synthesis of various metabolites through metabolic pathways.

Amino acids biosynthesis is a complex array of alternate pathways connected as non-linear series of reactions [ 23 ]. Apart from being precursor for protein synthesis, amino acids also serve as intermediates of other biosynthetic pathways of cell like purine synthesis [ 2425 ]. In plants, they are catabolized through tricarboxylic acid pathway to produce energy that is utilized by cells for their growth and proliferation [ 2627 ].

The biosynthetic pathways for the essential amino acids i. acquired through dietary sources; animals cannot synthesize are found only in microorganisms and are more complex as compared to non-essential amino acids. Owing to their common metabolic precursors, the amino acids have been classified as four families namely Aspartate family lysine, methionine, threonine, Asparagine [ 282930 ], Pyruvate family Alanine, leucine, isoleucine, valine [ 31 ], Aromatic family phenylalanine, Tyrosine, Tryptophan [ 3233 ] and α-ketoglutarate family glutamic acid, glutamine, proline, arginine along with Histidine and serine [ 34 ].

Availability of given amino acids in living organisms are effected by either regulatory factors being capable of controlling synthesis of amino acids or either their proficient catabolism [ 35 ].

So far, over amino acids have been reported out of which 20 amino acids serve as basic structural units of proteins while 10 amino acids are essential for humans and other living beings as they need to be provided through dietary sources [ 3637 ].

Role of amino acids in food industry, fodder, cosmetic industry, and pharmaceutical industry signifies their importance and need of high scale production to achieve market demand. Keeping in view the important role of amino acids as building block of life in human beings and animals, the chemical industry focused on various synthetic strategies for production of these biochemically distant compounds.

Different metabolic pathways involved in synthesis of amino acids are glycolysis; for branched chain amino acids Val, Leu alongside Ala, Gly, Cys, Ser synthesis, citric acid cycle; for Asn, Asp, Lys, Met, Thr and Ile, phosphoribosyl pyrophosphate PRPP pathway; for aromatic amino acid Phe, Trp, Tyr and histidine synthesis and shikimate pathway [ 3839 ].

The Shikimate biosynthetic pathway also referred as prechorismate pathway leads to synthesis of aromatic amino acids AAA having huge significance in terms of their role in synthesis of various secondary metabolites i. serotonin and various neurotransmitters [ 4041 ].

As mentioned earlier different pathways leading to synthesis of amino acids of all families are interconnected Fig. Similarly, phosphoenolpyruvate serve as precursor for AAA while α-ketoglutarate give rise to glutamic acid, glutamine, proline and arginine.

In addition, 3-phosphoglycerate follow multistep enzyme reactions to produce phosphoserine that is later converted to serine, cysteine and glycine. The details of amino acid biosynthesis in diatoms has been reviewed previously by Mariusz A.

Bromke [ 42 ]. Current review is focused in structural aspects of enzymes involved in feedback inhibition and regulation of biosynthetic pathway of amino acids. Despite the role of amino acids for accurate functioning of cells, homeostasis is maintained through metabolic regulation of biosynthetic pathways achieved either through i controlled synthesis of enzyme or ii feedback inhibition of enzyme by end product i.

amino acid. Discovery of product feedback inhibition dated back tohas been attributed as cornerstone of metabolic regulation that has been reported to sufficiently control metabolic fluxes to facilitate proficient growth [ 12 ].

For a given biosynthetic pathway, the inhibition of first committed step by end product is termed as feedback inhibition while inhibition at sites other than active sites is termed as allosteric inhibition with huge biological significance.

Binding of allosteric regulator to enzyme causes conformational changes in enzyme structure and perturb its activity [ 35 ]. Allosteric inhibition of amino acids biosynthetic pathways is well documented and 16 amino acids have ability to feedback inhibit their own biosynthetic pathway by targeting allosteric sites of enzyme catalyzing first committed step.

Deregulation of feedback inhibition is of utmost importance to maintain cell homeostasis and has been mostly reported in vitro studies to improve production of various amino acids with huge industrial impact [ 445 ]. The details of amino acids alongside enzyme target with feedback inhibition has been summarized in Table 1.

Few amino acids have the tendency to feedback inhibit multiple enzyme targets and their deregulation signifies their role to improve industrial production by identifying new and better strains. For instance, arginine and proline synthesized as final product from oxaloacetate pathway feedback inhibit N-acetyl-L-glutamate kinase NAGK and N-acetyl-L-glutamate synthase in case of arginine and glutamate kinase in case of proline [ 64 ].

Similarly, lysine has capacity to feedback inhibit multiple enzyme targets namely diaminopimilate decarboxylase, dihydrodipicolinate synthase, homocitrate synthase and aspartokinase III [ 6566 ]. In few cases, same enzyme is targeted by multiple amino acids as feedback inhibitors like aspartokinase is feedback inhibited by both lysine and threonine [ 67 ].

Amino acid biosynthetic pathway and effect of feedback inhibition alongside use of various approaches for deregulation of inhibition has remained focus of researchers especially in industrial biotechnology. Various reports over deregulation of feedback inhibition of individual biosynthetic pathways have been previously reported by our research center.

For instance, Geng et al. coli through mutations at inhibitor binding site and identified E. They utilized structural characteristics of L-lysine-sensitive DHDPS E. coli and L-lysine-insensitive DHDPS C. glutamicum and reported new enzyme variants through point mutations at specified sites with improved lysine production [ 68 ].

Similarly, Zhen et al. an industrial enzyme for increased amino acid production [ 69 ]. Recently, we have used the computational mutagenesis method to identify new mutant structures with potential deregulated feedback inhibition by tryptophan for anthranilate synthase from S.

marcescens Sadia et al. Here, we summarized structural characteristics of various enzyme targets and effect of mutations on their structures and functions especially in terms of deregulation of feedback inhibition.

Applicability of various experimental as well as computational techniques i. site directed mutagenesis, site specific mutagenesis etc. to accomplish feedback resistance has also been discussed in details to have an insight into various aspects of research work reported in this particular field of study.

The amino acids can be broadly grouped as four categories or families following different pathways for their synthesis. The details of amino acids capable of inhibiting committed step of their own biosynthesis, their categories, pathways as per their common precursors and their feedback sensitive enzyme targets are shown schematically in Fig.

Detailed structural features of various enzymes belonging to different families of amino acids have been provided in next section.

L-arginine has huge significance at industrial level especially, cosmetic industry, pharmaceutical and food industry. Microbial fermentation is employed for synthesis of arginine at industrial scale [ 70717273 ]. Arginine biosynthetic route of microorganisms as well as plants comprises of eight steps where first five steps lead to production of ornithine i.

precursor for arginine [ 74 ]. Biosynthesis of arginine in case of E.

: Amino acid synthesis pathway in microorganisms


This may stimulate fatty acid synthesis and storage, while inhibiting fatty acid oxidation through the regulation of the fasting-induced adipose factor FIAF and AMPK signaling pathways, respectively Cani and Delzenne, The increased abundance of Gram-negative bacteria such as the Bacteroides and E.

coli in the gut of overweight and obese mothers or LGA babies may lead to increased concentrations of lipopolysaccharide LPS in the gut and cause metabolic endotoxemia, which promotes low-grade inflammation and metabolic disorders such as insulin resistance, oxidative stress, diabetes and obesity Cani and Delzenne, On the contrary, production of other AA metabolites, such as vasodilators NO and H 2 S, antioxidant glutathione, neurotransmitter serotonin, and polyamines, by both the gut bacteria and body tissues may be affected by the diversity, abundance and metabolism of the gut microbiota Dai et al.

This will, in turn, regulate whole-body metabolism and homeostasis Jobgen et al. However, one should bear in mind that both host genotype and environmental factors contribute to the shaping of the gut microbiota in either the short term or the long run Zoetendal et al. In normal conditions, breast milk is the major food for neonates.

The composition of milk is complex and varies with stage of lactation and maternal nutritional status Lei et al. Studies with the AA composition of milk in humans showed that the most abundant AA are glutamate, glutamine, aspartate, asparagine, proline and branched-chain AA Davis et al.

The pattern of free AA changes during transition from colostrum to mature milk, with concentrations of most free AA including glutamate, glutamine, proline, methionine, isoleucine and lysine increasing in mature milk Davis et al.

Of note, concentrations of free glutamine in human and sow's milk increase progressively with advanced stages of lactation Wu and Knabe, ; Zhang et al. Compared with term milk, preterm milk had higher concentrations of free valine, threonine and arginine Zhang et al.

As physiologically important metabolites of arginine, concentrations of polyamines in the milk vary during lactation, depending on the types of polyamine and birth conditions of infants. For example, compared with mothers giving birth to term infants, mothers with preterm infants had higher concentrations of polyamines in their milk during the first month of lactation regardless of polyamine type.

Concentrations of spermine decreased but concentrations of spermidine increased with increased days of lactation Plaza-Zamora et al. Other components in milk, such as immunoglobulins secretory immunoglobulin A , bioactive proteins e. α-lactalbumin, lactoferrin, osteopontin and milk fat globule membrane proteins , oligosaccharides, and hormones leptin, ghrelin, adiponectin, obestatin and resistin are also vital for the health of infants Lönnerdal, The concentrations of these substances in milk are also altered with different stages of lactation and with different physiological conditions of mothers Gabrielli et al.

At present, not all components in the milk of humans and livestock have been identified. Studies on the composition of the breast milk microbiota have shown that the predominant bacteria in the colostrum and mature milk are Weisella and Leuconostoc both from the order Lactobacillales , followed by Staphylococcus , Streptococcus , and Lactococcus Cabrera-Rubio et al.

This may explain the presence of agmatine in the milk of nonruminants e. Likewise, the abundance of the oral cavity inhabitants, such as Veillonella , Leptotrichia , and Prevotella, increases in milk samples obtained at 6 months of lactation, when compared with colostrum and milk samples obtained at 1 month of lactation Cabrera-Rubio et al.

Bacteria such as Lactobacillus , Propionibacterium and Bifidobacterium are also present in breast milk Fernández et al. Of note, maternal body weight influences the composition of bacteria in breast milk. For example, compared with normal-weight mothers, obese mothers have a higher total number of bacteria including Lactobacillus and Staphylococcus and a lower number of Bifidobacterium in their milk over the first 6-months of breast-feeding Cabrera-Rubio et al.

Similarly, mothers with excessive weight gain during pregnancy have a higher number of Staphylococcus aureus in 1-month milk and a higher number of Lactobacillus but a lower number of Bifidobacterium in the 6-month milk Cabrera-Rubio et al. Origin of the bacteria in the breast milk can be the translocation of the mother's gut bacteria along with dendritic cells and macrophages, as well as bacteria from the skin of mother and oral cavity of the infant Fernández et al.

These cells are resistant to low pH and can pass through the lumen of the stomach and reach the lumen of the small intestine in the infant Wagner et al. However, formula-fed infants lack such a mechanism for the establishment of the normal gut microbiota and display an increased abundance of Enterobacteriaceae in the gut Matamoros et al.

Research has shown that breast-fed infants harbor different kinds of the gut microbiota, when compared with formula-fed infants Favier et al. By tracing the succession of the fecal microbiota from newborn babies for up to 1 year using molecular fingerprinting techniques, these authors found that bacteria related to the genus of Ruminococcus dominate in fecal samples from babies supplemented with formula milk after 17 days of age Favier et al.

Bifidobacteria remained dominant in fecal samples from breast-fed babies until weaning. Moreover, compared with breast-fed babies, composition of the fecal microbiota became more diverse in babies consuming formula milk Favier et al. Other bacteria such as Bacteroides , Clostridia , Enterobacter , and Streptococcus were also present in the feces from both breast- and formula-fed babies Mackie et al.

It is noteworthy that bacteria belonging to Ruminococcus and Bifidobacteria have the ability to degrade different oligosaccharide chains of mucins, release mono- and disaccharides, and hydrolyze peptides to AA for utilization by other intestinal bacteria Hoskins et al.

This can help to explain the difference in the microbial composition and metabolism of the gut microbiota between breast-fed and formula-fed babies. The presence of the maternal microbiota in breast milk may play an important role in the programming of the infant gut microbiota and metabolism through the following pathways.

Second, conversion of nutrients in the milk into bioactive molecules such as polyamines and glutathione supports the maturation of the infant gut. Third, the presence of special communities of bacteria such as the Enterobacteriaceae in the neonatal gut modulates infant metabolism directly through the generation of AA metabolites and indirectly via the production of LPS or other bacterial products.

The sequential changes in the composition of milk not only provide essential nutrients to support the growth of neonates but also facilitate the establishment of the indigenous gut microbiota, as well as body metabolism and the development of immune systems Perez et al.

Male reproductive performance is inevitably related to the utilization and metabolism of AA. Adequate amounts of AA, especially arginine, in the circulation are essential for the generation, differentiation and maturation of spermatozoa, thereby affecting their quantity and quality Eskiocak et al.

Early studies showed that dietary arginine deficiency in men for 9 days resulted in sharp decreases of the number and motility of sperms Holt and Albanese, On the contrary, dietary supplementation with arginine-HCl 0.

Dietary arginine supplementation not only improves sperm quality but also enhances concentrations of polyamines, ornithine, arginine and proline in seminal fluid, which is crucial for fertilization Wu et al. An increase in the number of microbes particularly those that express a high level of arginase in the lumen of the small intestine will promote catabolism of dietary arginine and, therefore, contributes to low sperm viability.

Furthermore, studies over the last decades have identified an important role for gaseous metabolites of AA in male reproductive function Li et al.

As an important metabolite of arginine, physiological levels of NO stimulate penile erection through the activation of guanylyl cyclase to generate cyclic GMP cGMP , which induces relaxation of vascular and cavernosal smooth muscles Gratzke et al. As another gaseous metabolite of sulfur-containing AA e.

cysteine and methionine , H 2 S acts in concert with NO on the cGMP pathway to inhibit the activity of phosphodiesterase type 5 in smooth muscle cells and stimulate penile erection d'Emmanuele di Villa Bianca et al.

NO and H 2 S in the smooth muscle cells are derived from the cavernous nerve and endothelial cells of the penis. H 2 S can also be produced within smooth muscle cells and from erythrocytes by the catabolism of cysteine, methionine or organic sulfate respectively d'Emmanuele di Villa Bianca et al.

Intestinal bacteria are a significant source of H 2 S in animals Gibson et al. Interestingly, in hypoxic conditions, H 2 S is produced from cysteine in the human placenta and from thiosulfate in bovine and rat arterial blood vessels Patel et al.

These findings suggest an important role of H 2 S in the pathophysiology of reproduction in both females and males. Thus, sulfur recycling may participate in whole-body H 2 S signaling and in reproductive function.

Serotonin a metabolite of tryptophan is important for controlling ejaculation both centrally and peripherally Giuliano and Clément, ; Berger et al. It has been reported that serotonin can either increase or decrease ejaculatory latency through the activation of different 5-HT receptors in the brain or spinal cord Giuliano and Clément, However, the net effect of serotonin is to prolong ejaculation and delay orgasm Berger et al.

Therefore, it is important to investigate the effect of food consumption and different nutrients on intestinal production and signaling of serotonin and its link to male reproduction. As reported for females, the gut microbiota of males can produce all the AA metabolites mentioned in the preceding section Table II.

The utilization of AA by bacteria in the small intestine of men regulates not only AA supply to the reproductive organ for the maintenance of normal function, but also the synthesis of hormones and signaling molecules in the whole body.

Likewise, the production of NO, H 2 S, serotonin, dopamine and GABA by gut bacteria in the small and large intestine can participate in the signaling and regulation of male reproduction Gratzke et al. The production and recycling of microbial AA metabolites in the body can regulate the conversion of H 2 S to thiosulfate in the colonic cells and the regeneration of H 2 S from thiosulfate in erythrocytes and arteries Blachier et al.

Recent studies with mice showed that metabolites such as butyrate produced by Clostridium tyrobutyricum improved testis development by modulating the permeability of the blood-testis barrier and endocrine function of testis Al-Asmakh et al.

Furthermore, the presence of the gut microbiota in the male urogenital tract plays an important role in semen quality and male reproductive health through the production of important metabolites Table III.

These observations provide opportunities to uncover AA-related metabolic or hormonal interactions between gut bacteria and reproduction performance in men and in males of other species. Important microbial metabolites of amino acids and their functions in reproduction. AA, amino acids; GABA, gama-aminobutyric acid; H 2 S, hydrogen sulfide; NO, nitric oxide; SCFA, short chain fatty acids.

a Nitrate also contributes to the production of NO by bacteria in the gut lumen Vermeiren et al. a Corynebacterium spp. were found in the semen of both fertile and infertile men; Mycoplasma spp. were found to be associated with infertility and HIV infection Mändar, ; Liu et al.

Food is crucial for supporting normal reproduction in both men and women. The nutritional, metabolic and hormonal effects of diets are closely linked to the gut microbiota. Maintaining optimal conditions of the gut ecology i. composition and activity of the gut microbiota, morphology and function for the utilization of dietary AA is crucial for normal reproduction and the metabolic programming of the offspring.

The effects of dietary supplementation with AA, prebiotics and probiotics on reproduction are highlighted in the following sections Table IV.

a Breast milk is the natural source of probiotics and prebiotics for infant Marques et al. Amino acids are not only nutritionally essential but are also functionally important Wu, , , For example, AA e. arginine, glutamine, glycine, threonine, leucine, sulfur AA, taurine, tryptophan and tyrosine are required to maintain gut integrity and function, stimulate intestinal protein synthesis and cell growth, sustain body metabolism, and support reproduction Bazer, ; Wang et al.

Considering the adverse effects of a high-protein diet on the metabolism and health of pregnant women and their offspring Herrick et al. Because some of these AA have been reported to regulate AA metabolism in small-intestinal bacteria Dai et al.

Growing evidence suggests that dietary supplementation of functional AA modulates gut ecology, AA metabolism and function Dai et al. In vitro studies with the pig small-intestinal bacteria showed that different AA support the growth of different communities of bacteria Dai et al.

Bacteria such as Streptococcus sp. were dominant in cultures containing lysine, threonine, arginine or glutamate, while Escherichia coli and Acidaminococcus fermentans were most abundant in cultures containing arginine, glutamate or histidine Dai et al.

The supplementation with arginine or glutamine to the cultures of small-intestinal bacteria decreased their AA utilization and changed the patterns of AA metabolism through different pathways Dai et al.

Thus, functional AA can alter the composition and activities of AA utilization and metabolism by the small-intestinal bacteria.

Furthermore, studies with mice indicated that dietary supplementation with 0. The dietary intake of arginine also elevated concentrations of polyamines in the colon due to bacterial fermentation Kibe et al.

The altered levels of polyamines in the intestinal lumen will, in turn, modify the composition and abundance of the gut microbiota. Consistent with these reports, the abundance of the Bifidobacterium group of bacteria, Akkermansia -like bacteria, and the Lactobacillus — Enterococcus group of bacteria increased in the large intestine of mice fed infant formulas supplemented with polyamines Gómez-Gallego et al.

These findings suggest that dietary supplementation with arginine and other functional AA [e. glutamine Chen et al. The effects will be manifest under conditions of nutrient restriction, where the impact of intestinal bacteria on the supply of AA metabolites to reproductive organs versus dietary sources may be relatively greater, when compared with adequate feeding Satterfield et al.

Probiotics and prebiotics affect AA metabolism in the small intestine Bergen and Wu, Studies of their effects on reproduction mainly focused on the health and metabolism of pregnant women and the subsequent programming in infants Sanz, Many of the studies involved immunity and immune-related disease of infants Sanz, ; Rautava et al.

Some of them were focused on the development of the gut microbiota during the neonatal period Gueimonde et al. The others were concerned primarily about the metabolic programming in infants and its links to obesity Laitinen et al.

The commonly used probiotics are Lactobacillus rhamnosus , Lactobacillus casei , Bifidobacterium breve , Bifidobacterium bifidum , and Bifidobacterium lactis.

Prebiotics used to support the growth of these probiotic bacteria in the gut are mainly oligosaccharides, including fructooligosaccharides FOS and galactooligosaccharides GOS. The use of probiotics, prebiotics or their combination showed beneficial effects on the health of pregnant women or infants in most studies Marques et al.

However, the mechanisms responsible for the programming of the gut microbiota, immunity and metabolism in infants are largely unknown, and may include the following.

First, dietary supplementation of probiotics and prebiotics modulate the gut ecology in pregnant women, thereby altering the composition and activity of the microbiota and the associated bacterial components e.

LPS, peptidoglycans and s-layer proteins and metabolites e. SCFA, NO, H 2 S and polyamines in the intestine. The altered gut ecology affects not only the immune and metabolic status of the pregnant women but also the environment of the conceptus, critical for early fetal programming Rautava et al.

Second, after birth, mother's breast milk the major naturally-made formula for neonates programs the gut microbiota, immunity, and metabolism of the infant by providing the probiotic bacteria and prebiotic oligosaccharides to infants Marques et al.

Many of the bacteria exert their probiotic role partially through AA metabolism directly or indirectly via bacteria-bacteria interactions and cross feeding Table V.

Summary of the amino acid utilization and metabolism by intestinal bacteria. AA, amino acids; AHL, acyl homoserine lactones; BCFA, branched-chain fatty acids; GABA, gama-aminobutyric acid; H 2 S, hydrogen sulfide; NO, nitric oxide; SCFA, short chain fatty acids.

b Both the luminal and gut epithelium-attached bacteria may contribute to the utilization and metabolism of amino acids Yang et al.

c Possible precursors used for the de novo synthesis of amino acid by intestinal bacteria are ammonia, urea and glucose Metges ; Torrallardona et al.

To date, data on the effect of probiotics on male reproduction are rare. It was shown that dietary supplementation with probiotic bacteria Lactobacillus reuteri increased seminiferous tubule cross-sectional profiles, spermatogenesis and Leydig cell numbers in aging mice Poutahidis et al.

As an important group of metabolites produced from the fermentation of carbohydrates including prebiotics and AA by bacteria in the distal small intestine and large intestine, SCFA have been reported to play a critical role in the activation of inflammatory pathways and system immunomodulation, pathologies of pregnancy, and the onset of normal labor Voltolini et al.

SCFA, individually or in combination, regulate the size and function of the regulatory T-cells pool in varieties of organs including colon, spleen and lymph nodes, while protecting the gut against colitis in a Ffar2 G protein-coupled receptor GPR43 -dependent manner in mice Arpaia et al.

An increase in the circulating levels of SCFA through dietary supplementation of pectin in mice has a protective effect against allergic inflammation in the lung Trompette et al. Likewise, propionate enhances the generation of macrophage and dendritic-cell precursors and subsequent seeding of the lungs in mice, and its anti-allergic effects were GPR dependent Trompette et al.

Similarly, data on the study of human labor indicate that GPR43 and GPR41 mRNA levels are higher in myometrium and fetal membranes from women after the onset of labor Voltolini et al. Interestingly, GPR43 protein is localized to the immune cells and vascular endothelium in the myometrium and epithelium of fetal membranes, and sodium propionate attenuates an LPS-induced increase in expression of GPR43 and inflammatory genes Voltolini et al.

At present, little is known about links between the intestine and plasma SCFA profiles, or about a role for probiotics and prebiotics in the immunity of the uterus-fetus interface or the onset of labor.

More studies are warranted to investigate the role of G protein-coupled receptors in the SCFA-mediated immune response and function of reproduction organs in both men and women Voltolini et al. With enhanced understanding of reproductive biology and metabolic syndrome e.

obesity and diabetes , critical windows for dietary intervention can be identified Louis et al. Studies with gestating gilts showed that dietary supplementation with L-arginine during Days 0 to 25 of gestation have strikingly different outcomes than during Days 14 to 25 of gestation.

Compared with dietary arginine supplementation between Days 14 and 25 of gestation, supplementation of arginine immediately after breeding day 0 reduced litter size Li et al. These observations suggest that Days 0 to 14 of gestation and Days 14 to 25 are two critical windows for arginine supplementation to gestating gilts.

It is possible that arginine may interact with intestinal microbes to affect pregnancy outcomes, and this possibility should be examined in future investigations. In women with normal pregnancy, the composition of the gut microbiota during the first trimester is similar to that of non-pregnant women but changes dramatically during the third trimester Koren et al.

Thus, early dietary intervention of the women to reduce the numbers of AA metabolizing bacteria in the gut may be of vital importance.

Indeed, dietary supplementation of probiotics Lactobacillus rhamnosus GG and Bifidobacterium lactis Bb12 , coupled with dietary counseling at early pregnancy, reduced blood glucose concentration and this effect lasted from the first trimester to 12 months post-partum Laitinen et al.

However, it is unknown whether dietary intervention with functional AA or probiotics and prebiotics is necessary for normal pregnant women. Nonetheless, there are suggestions that high rates of infertility and embryonic death in women and livestock during early gestation could be reduced by improving the uterine environment through dietary supplementation with functional AA Bazer et al.

Critical window times for dietary intervention of the programming of gut microbiota and metabolism of the infant may start early, at the fetal stage Aaltonen et al. Bacteria translocated from the intestine, along with their AA metabolites in the placenta and fetal amniotic fluid, may alter the fetal intestinal innate immunity, which may act as a selection force for the colonization of gut microbiota.

Several days and weeks after birth, consumption of breast milk may affect the gut microbiota and metabolic status of the infant. Dietary interventions e. supplementation with functional AA or probiotics and prebiotics during these windows may help to prevent abnormal AA metabolism in gut bacteria and, therefore, metabolic disorders e.

non-alcohol fatty liver disease, insulin resistance, glucose intolerance and erectile dysfunction through the programming of the gut microbiota Wolfe et al. Both the small intestine and the large intestine harbor large numbers of bacteria to metabolize dietary AA.

Intestinal bacteria not only alter the pool and profile of AA that enter the bloodstream from the intestine, but also produce varieties of nitrogenous and sulfur-containing metabolites. Physiological levels of these microbial products may influence cellular signaling pathways and reproduction through the formation of gametes, penile erection, ejaculation, implantation of conceptus, placentation, delivery of newborns, and breast-feeding, as well as metabolic programing and re-programming during critical periods of the life cycle.

However, excessive production of microbial metabolites e. ammonia, NO and H 2 S is harmful to organisms. As a result, the traditional high-protein weight-losing diet may not be suitable for obese or overweight couples who plan to have babies Westerterp-Plantenga et al.

In this regard, the gut microbiota can be viewed as either a protector or an invader of the reproductive systems Fig. Schematic diagram of the links between amino acid metabolism in gut bacteria and reproduction in the host.

AA, amino acids; NO, nitric oxide; 5-HT, 5-hydroxytryptamine serotonin ; GABA, gamma-aminobutyric acid; SCFA, short chain fatty acids; BCFA, branched-chain fatty acids; H 2 S, hydrogen sulfide. This, in turn, affects the metabolic status of the mothers and their offspring.

The mother-to-baby mode of programming is mediated, in part, by the gut microbiota, especially AA-metabolizing bacteria. The balance of the AA-metabolizing bacteria in the gut is crucial for maintaining the metabolic homeostasis and reproductive performance of the host.

This fetal or neonatal impact of nutrition may be inherited by the offspring through epigenetic modifications of the spermatozoa, oocyte and fetus by AA and their metabolites produced by tissues and intestinal bacteria.

In addition, breast milk acts as a messenger that carries the metabolic signature from the gut microbiota of the mother to the intestine of infants, thereby playing a critical role in shaping the phenotype e. metabolic profiles of the offspring.

Thus, it is important to uncover links between epigenetics and metabolic syndrome that impact reproductive function Canani et al. plant-derived estrogen-like metabolites such as equol when the host consumes plant-source foods Jackson et al. This will further affect health and reproduction in both men and women and of their offspring.

In practice, dietary counseling and interventions for both men and women with metabolic syndrome are important to improve their reproductive performance.

The same rule may also apply to infants consuming formula with high protein levels Lönnerdal, Personalized dietary supplementation with functional AA e.

arginine and glutamine , probiotics and prebiotics to restore the normal composition and activity of the gut microbiota may improve the reproductive performance in both males and females, while preventing the development of metabolic syndrome in offspring induced by fetal programming of the infant gut microbiota.

Finally, integrating multi-disciplinary knowledge to understand how AA metabolism in the gut microbiota affects development and function of female and male reproductive organs will help in the development of new strategies to reduce infertility and improve pregnancy outcomes in mammals e.

humans and livestock and other animal species. and G. composed and revised the manuscript. and S. revised the manuscript. We are grateful to the constructive comments from the editors and anonymous reviewers for improving this article.

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An Evolutionary Perspective on Amino Acids By: Ana Gutiérrez-Preciado, B. Departamento de Microbiologia Molecular, Universidad Nacional Autonoma de Mexico , Hector Romero, B. Departamento de Ciencias Naturales, Universidad Autonoma Metropolitana © Nature Education. Citation: Gutiérrez-Preciado, A.

Nature Education 3 9 What are they made of and how have they evolved? Aa Aa Aa. The Origins of Nutrient Biosynthesis. Figure 1: Major events in the evolution of amino acid synthesis.

The way amino acids are synthesized has changed during the history of Earth. Figure Detail. What Is an Amino Acid Made Of? Amino Acid Precursors and Biosynthesis Pathways.

Figure 2. What Makes an Amino Acid Essential? Tryptophan Synthesis: Only Created Once. Lysine Synthesis: Created Multiple Times. Synthesis on the tRNA molecule. How Do Metabolic Pathways Evolve?

Two Different Models. Transporter genes are underlined. The predicted operon structure of aromatic amino acid biosynthesis genes varies significantly within the studied group of genomes Table 1.

The only conserved feature is the trp operon encoding enzymes for the tryptophan terminal pathway, which is absent or present as a whole in each genome. halodurans and B. stearothermophilus , this candidate operon is a part of a larger locus containing other aro genes: aroF-aroB-aroH-trpEDCFBA-tyrA-hisC-aroE.

The operon structure in B. anthracis differs from that in other bacilli: the trp operon lies separately, and the remaining genes form two more loci: aroF 1- aroB-hisC 1 and aroA-aroF 2- hisC 2- tyrA-aroE , where aroF 1,2 and hisC 1,2 denote pairs of paralogs aroF 2 and hisC 2 display less identity to aroF and hisC from B.

subtilis than aroF 1 and hisC 1 do, respectively. lactis , the trp operon is also isolated. pneumoniae and S. mutans , there is one more large locus with aro genes: aroC-aroD-aroB-aroF-tyrA-yheA-aroE-aroI-pheA the gene names are as in B.

lactis , several outsider genes are inserted into this gene cluster. Pairs of DAHP synthase genes in S. lactis , homologous to DAHP synthases from Gram-negative rather than Gram-positive bacteria, form candidate operons in S.

mutans , but are located separately in the genome of L. Large aro gene loci are also present in the genomes of E. faecalis aroD-aroA-aroB-aroF-tyrA-aroE-aroI-pheA , C.

acetobutylicum aroA 1- tyrA-aroB-aroE-aroF-aroD-aroI , C. difficile aroA 1- aroB-aroE-aroF-pheA-aroD 1- aroI-tyrA , and L. monocytogenes aroF-aroB-aroH-hisC-tyrA-aroE. Two genes were found in aromatic amino acid operons in Streptococcus spp.

As they co-localize with aromatic amino acid genes in several genomes, their function may be somehow linked to the aromatic amino acid metabolism.

Anthranylate synthase component II TrpG , which catalyzes conversion of chorismate into anthranylate the tryptophan terminal pathway , and p -aminobenzoate synthase component I PabA , which catalyzes conversion of chorismate into 4-aminodeoxy-chorismate the folate biosynthesis pathway [19] , are encoded either by two paralogous genes, as in E.

coli , or by one bi-functional gene, as in B. The scheme of the folate biosynthesis and the step catalyzed by PabA are shown in Fig. We found that E. faecalis lacks members of this family; the Bacillus , Streptococcus , and Clostridium genomes, excluding only B.

lactis , L. monocytogenes , S. aureus , B. anthracis , and D. hafniense each have two paralogous genes. Moreover, out of two paralogs, one always lies within the trp operon, while the other co-localizes with the pab operon Fig.

This suggests that the first class of paralogous genes trpG LL , trpG LM , trpG SA , trpG BQ, DH , see appendix is specific for tryptophan biosynthesis, whereas the second class of paralogs pabA LL , SAV , lmo , pabA DH is specific for folate biosynthesis. Squares: one paralog per genome; ovals: two paralogs per genome.

Filled frames: genes located within the pab operons; empty frames: genes located within the trp operons. Italics: folate-specific enzymes; underlined: tryptophan-specific enzymes the specificity is identified in this study ; italics and underlined: bi-functional enzymes.

We found that the single member of this family from C. acetobutylicum is localized in the trp operon in the genome and clustered with the tryptophan-specific paralog from B.

anthracis in the tree. Besides, C. acetobutylicum lacks other pab genes. Thus, we propose tryptophan-related specificity rather than bi-functionality for this single protein. A similar situation was observed in C. difficile : it has a single gene, positioned in the pab operon, and clustered with folate-specific paralogs in the tree.

Thus, we propose folate specificity for the protein from C. The unfinished genome of C. difficile lacks the trp operon. The complete genome of S. Thus we suggest that it is folate-specific. In contrast, the complete genome of S. pneumoniae and the partial genome of S.

Thus we suggest that they are tryptophan-specific. Pairs of DAHP synthase genes of S. lactis , encoding proteins homologous to DAHP synthases AroA from Gram-negative bacteria, form gene clusters in S. mutans , but are located separately in L. mutans , and upstream of both DAHP synthase genes in L.

Moreover, a similar sequence was found in the upstream regions of the shikimate kinase genes aroI in all three species Table 2. Notably, the reactions catalyzed by shikimate kinase and DAHP synthase are the only two irreversible steps within the common pathway of the biosynthesis of aromatic amino acids, and only these genes of the common pathway are regulated at the transcriptional level in γ-proteobacteria.

Thus, we propose that the new conserved signal sequence plays a role in transcriptional regulation of the DAHP synthase and shikimate kinase genes in the genomes of Streptococcus and L. A new DNA signal regulating DAHP synthase and shikimate kinase genes of several species identified in this study.

Position is given relative to the translation start site. Paralogous aroG genes are numbered for convenience.

We also constructed a profile based on the PCEs described in [8]. Using this profile we found a new candidate site ACTTAAccaCGTT upstream of the aroF gene in B.

A number of new candidate T-boxes were found upstream of genes involved in aromatic amino acid biosynthesis Fig. Expression of the aroF and aroA genes is predicted to be regulated at the DNA level in B. halodurans , and B. stearothermophilus see above. In contrast, tyrosine-specific T-boxes were found upstream of these genes in B.

anthracis Table 1. The aroA-aroF-hisC-tyrA-aroE locus in B. anthracis appears to be strictly regulated by the T-box antitermination mechanism, as two possible tyrosine-specific T-boxes are located upstream of the aroA gene and one more tyrosine-specific T-box is located upstream of the aroF gene.

The aroF gene in E. coli is known to be regulated by the tyrosine-specific repressor TyrR [4]. Finally, a tyrosine-specific T-box was observed in B. anthracis upstream of the phhA gene. PhhA catalyzes conversion of phenylalanine to tyrosine Fig. Multiple alignment of newly identified T-boxes from Gram-positive bacteria.

The columns represent 1 genome abbreviations as in Table 1 ; 2 gene names; 3 T-box specificities. The complementary stems of the RNA secondary structure and positions of the hairpins and conserved boxes are shown in the upper lines. Base-paired positions are indicated by the gray background.

Conserved positions and non-conserved nucleotides are shown in bold and light font, respectively. Specifier codons are double-underlined.

The trp operons are known to be regulated at the RNA level by two different mechanisms, TRAP-mediated repression in B. subtilis [9] and T-box antitermination in L. lactis [14]. Additional candidate TRAP binding sites were found upstream of the trp operons and the trpG genes in B.

stearothermophilus Fig. Tryptophan-specific T-boxes were found upstream of the trp operons in B. anthracis , S. mutans , L. lactis , C. acetobutylicum , S. aureus , and L. Thus, TRAP-mediated regulation was observed only in three Bacillus species, B.

subtilis [9] , B. stearothermophilus this study , whereas in other Gram-positive bacteria, including B. anthracis , only the T-box antitermination mechanism was detected. Moreover, the mtrB gene, which encodes subunits of TRAP, is present only in these three Bacillus genomes.

Interestingly, B. anthracis has at least twice as many T-boxes as other Gram-positive bacteria A. Vitreschak, unpublished.

We also observed a phenylalanine-specific T-box site upstream of the pheA gene in D. TRAP binding sites in the leader regions of the trp and pabA genes in the Bacillus spp. Start codons of the pabA genes are underlined.

Newly identified TRAP sites are indicated by asterisks. subtilis , whose translation is regulated by the TRAP protein. We found orthologs of the yhaG gene in B. stearothermophilus , C. acetobutylicum and C.

No homologs of yhaG were observed in the genomes of E. faecalis and S. pyogenes that lack the tryptophan biosynthesis pathway, and thus should transport tryptophan from the environment. We identified tryptophan-specific T-boxes upstream of the yhaG orthologs in both Clostridium species; in B.

stearothermophilus the upstream region of this gene is unavailable. Thus, yhaG is regulated in B. subtilis and Clostridium at the RNA level by two different mechanisms, tryptophan-mediated TRAP repression and tryptophan-specific T-box antitermination, respectively.

Analyzing the predicted T-box regulatory sites and positional gene clustering we identified a new candidate tryptophan ABC transporter, named trpXYZ , in the genomes of S. mutans , S. pyogenes , S. equi , E. faecalis , E. faecium , B. stearothermophilus , D.

hafniense , B. cepacia , and M. loti the latter two are α-proteobacteria. The genes in the S. pneumoniae genome are SP , SP , SP hafniense has three trpXYZ paralogs, and two of them have tryptophan-specific T-boxes in the upstream regions. Additionally, trpXYZ is preceded by a tryptophan-specific T-box in S.

Moreover, trpXYZ is located in one candidate operon with the ortholog of the kynU gene in M. kynU encodes l -kynurenine hydrolase, which catalyzes conversion of l -kynurenine into anthranylate Fig. Thus co-induction of the trpXYZ-kynU operon in tryptophan-depleted conditions leads to the transport of tryptophan from the medium and the concurrent accumulation of anthranylate, a tryptophan biosynthetic precursor.

Additionally, trpXYZ is co-localized with the aroD gene in E. These pieces of evidence allow us to ascribe tryptophan specificity to all but one major clades of the trpXYZ family members on the phylogenetic tree Fig.

Note that this assignment fills the above-mentioned gap in the E. pyogenes metabolic maps. Filled ovals: genes that are either regulated by tryptophan-specific T-boxes or positionally clustered with genes involved in tryptophan metabolism.

Empty ovals: genes from the genomes that lack the tryptophan terminal pathway and thus should transport tryptophan from the environment. We predict tryptophan specificity for all but one major clades the latter is circled by a dotted line that contain genes with evidence for tryptophan specificity.

We identified another candidate tryptophan transporter in B. Four members of the sodium transporter family homologous to yocR and yhdH in B.

subtilis are present in this bacterium and two of them are regulated by the T-box antitermination mechanism. We assigned specificities based on the T-box regulatory elements.

We predict that one of these genes, named here sdt1 , encodes a tryptophan-specific transporter, and the other gene, sdt2 , is serine-specific. Homologous genes of this transporter family were identified in the genomes of B. halodurans , B. aureus , L. monocytogenes and S. Additionally, a homologous transporter in Haemophilus ducrei forms an operon with genes of the tryptophan biosynthesis.

The ycz-ycbK operon of B. subtilis is known to be regulated by TRAP-mediated repression and tryptophan-specific T-box antitermination [20].

Top bar navigation ris Mendeley, Papers, Zotero. Article CAS Google Scholar Sanchez, S. Biochem Biophys Res Commun. Improving lysine production by Corynebacterium glutamicum through DNA microarray-based identification of novel target genes. Amino Acids ; 39 : — Module Complete only Including 1 block missing Including any incomplete. With increasing temperatures, amino acids are less stable Gerakines et al.
Introduction Accordingly, infants of overweight mothers have a higher abundance of Bacteroides and Staphylococcus in their fecal samples during the first 6 months after birth Collado et al. Tryptophan-specific T-boxes were found upstream of the trp operons in B. In a flask, they combined ammonia, hydrogen, methane, and water vapor plus electrical sparks Miller In this study, we set out to test this hypothesis in anaerobic methanogenic communities AMCs. Dorn, E. As shown in Figure 8 , all methanogens in our four AMCs did not contain complete gene set encoding the enzyme of synthesizing those costly AAs i. Amino Acids.
1 Introduction Aid remarks Detailed literature inn over amino Fat intake and essential fatty acids biosynthetic pathways, structural details of target enzymes feedback inhibited by ln acid, mutagenesis approaches both in Balancing school and sports nutrition and in silico used to incorporate structural and conformational changes to deregulate their inhibition stnthesis have Antioxidant-rich inflammation reduction summarized. Using the pig as microorhanisms animal model, Miner-Williams et Fat intake and essential fatty acids. Syntrophomonas wolfei gen. As a result, the traditional high-protein weight-losing diet may not be suitable for obese or overweight couples who plan to have babies Westerterp-Plantenga et al. While small-intestinal enterocytes were able to metabolize branched-chain AA BCAA Val, Leu and Ile but not other EAA Chen et al. We proposed that this strategy may be, to some extent, better than directly losing the functional genes, by which microorganisms could actively change their metabolic states of PG production when facing fluctuated environmental conditions. Current review summarizes information regarding structural characteristics of various enzyme targets and effect of mutations on their structures and functions especially in terms of deregulation of feedback inhibition.
Ekaterina M. Panina, Fat intake and essential fatty acids G. Synthesid, Andrey A. Mironov, Microoeganisms S. Computational comparative techniques were applied to analysis of the aromatic amino acid regulon in Gram-positive bacteria. A new candidate transcription regulation signal of 3-deoxy- d -arabino-heptulosonatephosphate synthase and shikimate kinase genes was identified in Streptococcus and Lactococcus species.

Amino acid synthesis pathway in microorganisms -

The search for signatures of extraterrestrial life, extinct or extant, is a key goal for the research field of astrobiology. One way to search for life is to seek the remains or products of biological processes Hays et al.

Examples include the fossil remains of single cells or communities e. Amino acids have previously been considered as a biosignature Parnell et al. Amino acids are ubiquitous in life as main components of cells and, apart from glycine, which is not chiral, biological systems on Earth almost exclusively use the L enantiomeric form.

However, some D-amino acids can be found in the cell membranes of bacteria Kaiser and Benner, ; Lam et al. Evidence has been provided that indicates enantiomeric excess of certain amino acids in meteorites Busemann et al. Consequently, the ratio of the enantiomers of amino acids was proposed as a signature of life, with terrestrial life showing an enantiomeric excess of L-amino acids Avnir, Although only twenty core amino acids are found in Earth organisms proteogenic amino acids , there are several hundred known non-proteogenic amino acids Gutiérrez-Preciado et al.

Therefore, the mere presence of amino acids in an extraterrestrial sample does not indicate a signature of life and cannot be used as a biomarker itself Parnell et al. Nevertheless, the abundance of certain amino acids in a sample might provide clues on the presence of microorganisms.

While abiotic processing of amino acids is driven by thermodynamic processes, in biological systems their relative abundance is the result of metabolic activity in any given organism or a community Davila and McKay, In addition, life uses only a selection of amino acids, while extraterrestrial carbonaceous matter contains, as noted above, a much broader variety.

One method to investigate the presence of life, distinct from looking for the amino acids in life itself e.

In many extraterrestrial environments, including Mars, we would expect amino acids in addition to other organic compounds to be available to any putative biota. They are delivered to a planetary surface in carbonaceous chondrite meteorites Cronin and Pizzarello ; Ehrenfreund et al.

For example, a wide range of amino acids has been detected in carbonaceous chondrites. The frequency of the prebiotic synthesis of amino acids and their abundances follow thermodynamic principles with the chemically simple compounds being most abundant Miller, ; Pizzarello, ; Pizzarello and Shock, ; Glavin et al.

A large number of microorganisms can use amino acids as electron donors for anaerobic respiration or in fermentation Nixon et al. In this process, they degrade the amino acid molecules. Microorganisms are unlikely to degrade amino acids at the same rate compared to degradation by abiotic processes.

Rather, they will degrade the molecules according to their metabolic pathways, the accessibility of certain amino acids, the availability of other metabolizable organic compounds, and other organism-specific effects.

Thus, we could hypothesize that, in the process of degrading abiotic amino acids, microorganisms would leave a biosignature by the preferential degradation of certain amino acids in the environment around them.

This biosignature might be superimposed on the biosignature of the amino acids in the organism itself and that were synthesized by the organism, but it would be a distinct and additional biosignature reflecting non-random biological destruction of the abiotic amino acid pool.

One attraction of such a biosignature is that, if cells alter the amino acid concentration in the environment around them, then, particularly in low biomass environments, that signature might be much more pervasive and easier to detect than the amino acid signature of the cells themselves, which could be highly localized and poorly preserved.

Furthermore, although this signature would assume the presence of amino acid-using life, the decrease or increase in any amino acids away from the expected background abiotic concentration could be an agnostic signature of metabolic processes.

In this study, we tested this hypothesis by investigating the metabolic usage of seven amino acids previously detected in both terrestrial environments and Martian meteorites by two distinct anaerobic microbial communities from Martian analog environments.

We used two distinct communities to determine if there were common patterns of degradation of certain amino acids that could potentially suggest a universal signature of amino acid degradation by life.

The almost complete degradation of glycine was common to both communities. For other amino acids, we observed different patterns of degradation with increased extracellular concentrations of some amino acids.

We discuss the implications of these findings for life detection. The samples investigated were collected in the frame of the MASE Mars Analogs for Space Exploration project, a 4-year collaborative research project supported by the European Commission Seventh Framework Contract.

The aim of the project was to characterize Mars analogue environments on Earth with regard to habitability and the search for potential biosignatures of extraterrestrial environments Cockell et al. Samples analyzed herein were collected from two sulfidic springs close to Regensburg, Germany, where many sulfide-containing springs emanate from Mesozoic karst formations.

The two springs, in the Sippenauer Moor SM and Islinger Mühlbach ISM areas The sites SM and ISM are independent and not connected in the deep subsurface.

Detailed analyses of the site microbiomes are already available Moissl et al. All samples were taken under anoxic conditions for a detailed description see Cockell et al. Cultivation was performed under anoxic conditions.

Samples from SM and ISM were inoculated in anoxic MASE medium II and supplemented with a mixture of proteogenic and non-proteogenic amino acids. MASE II medium contains per liter: NH 4 Cl 0. Prior to inoculation, the medium was supplemented with a filter-sterilized amino acid broth.

Amino acids such as alanine, aspartic acid, glutamic acid, glycine, leucine, serine, and valine are common in both biological samples and for example, carbonaceous chondrite meteorite Cronin and Pizzarello, ; Shimoyama et al.

Based on these data, the following mixture of amino acids was added to the medium: glycine, L-alanine, β-alanine, L-aspartic acid, DL-proline, L-leucine, L-valine, L-phenylalanine and L-isoleucine Table 1. The amino acid broth used in this study included some proteinogenic amino acids that are most likely not found in meteorites due to their complexity in synthesis.

The final concentration of each added amino acid was 10 mM, and the pH was adjusted to 7. One millilitre of the environmental sample was added to 20 ml of medium and incubated at 30°C. A negative control NC , i. TABLE 1.

Chemical properties of the supplemented amino acids and their side chains. After defined time points, 1. The first sample was taken immediately after inoculation T0 , followed by samples after 7, 14, 28, 56, and 90 days of incubation. The sample was sterilized using a 0.

Amino acid extraction was performed using a simplified procedure described in Aerts et al. Therefore, the extraction protocol is described in the following only briefly.

For sterilization, all glassware, including the columns with glass wool for amino acid extraction, were double wrapped in aluminum foil and placed into a furnace at °C for a minimum of 3 h.

A sequential washing with basic-neutral-acid-basic solutions was made to activate the resin active sites. After the sequential washing procedure, 1. The sample was vortexTed at 2, rpm for 30 s and subsequently added to the column.

Note, that this first elution was not collected for further analysis and was disposed. The system used for amino acid analysis is described in Aerts et al.

Measurements were performed using an Agilent LC-MS system equipped with an ultraviolet UV and fluorescence FL detector system, an autosampler module where the amino acid derivatization is performed, and a MS ion trap mass spectrometer with electrospray ionisation. The column used for analysis was a × 3 mm 2.

The MS was operated in positive mode with optimised conditions for each individual amino acid. Amino acids were derivatised using a method based on Nimura and Kinoshita which was then automated in order to increase the robustness of the method. This automation was achieved by programming the autosampler module Agilent GB of the HPLC to mix the various reagents.

The approach used was as follows: the amino acid sample was mixed in a ratio with 0. In a typical measurement run, amino acid samples from one time point including negative control were analysed sequentially, including wash procedures and the analysis of amino acid standard solutions Agilent, part number: — Proline was not measurable as it cannot be derivatized and is therefore not detectable using the applied method.

Standards were run at the beginning and end of each run in order to track reagent degradation and system performance. The standard deviation was added as error bars to the measurements of the amino acids of SM and ISM.

FIGURE 1. Degradation of glycine from the two different enrichments A Islinger Mühlbach ISM , and B Sippenauer Moor SM spiked with a broth of amino acids final concentration of each added amino acid was 10 mM over a time of 3 months.

C Negative control, i. FIGURE 2. LC-MS measurements of the three amino acids β-alanine, L-aspartic acid, and L-phenylalanine from the two different enrichments over a time of 3 months.

A Islinger Mühlbach ISM , and B Sippenauer Moor SM spiked with a broth of amino acids final concentration of each added amino acids was 10 mM. FIGURE 3. LC-MS measurements of the four amino acids L-alanine, L-valine, L-leucine, and L-isoleucine from the two different enrichments over a time of 3 months.

A Islinger Mühlbach ISM , and B Sippenauer Moor SM spiked with a broth of amino acids final concentration of each added amino acid was 10 mM.

Using LC-MS measurements, we investigated the differences in the amino acid distribution in the medium of two different microbial enrichments and the negative control. We found that in the control samples in which no microbiota was added, no significant changes of amino acid concentrations were observed over time Figures 1 — 3.

Therefore, the changes observed in the inoculated samples are attributed to microbial activity. Note, because the signal of measured amino acids in NC for time point 56 days was significantly lower in comparison to the signal of the NC of the other time points, NC of time point 56 days was not considered for analysis.

No such decrease was observed for the measurements of amino acids in the SM and ISM samples of the same time point, which points to a sample problem and not to an instrument malfunction. The results after analysis using LC-MS revealed that the quantities of the non-glycine amino acids varied over time depending on the microbial community and the amino acid see Figures 1 — 3.

Although the concentrations of amino acids varied between the two enrichments, we found one amino acid characteristic that was consistent with both enrichments Figure 1.

The depletion follows an exponential decay; see fit to the date in panel B of Figure 1. Note, the same fit could not be applied to ISM1 data panel A because of missing sample for time point 7 days; the fit would be too steep at the beginning. These data suggest a preferential use of glycine by these microbial communities.

For all amino acids, we observed two different patterns of the measured relative ratios: 1 a differential use of amino acids was revealed, i. B-ala, L-asp, and L-phe did not reveal a clear trend with time Figure 2.

For example, in the ISM inoculum, the amount of β-ala and L-asp decreased over the first 2 weeks, followed by a peak 2. In the SM inoculum, L-asp increased over the first three measurements before a steady, but small decrease was observed.

In contrast, for β-ala the initial decrease was prolonged, before a peak followed by a decrease Figure 2B. L-phe followed a similar trend in the SM sample Figure 2B , but it was less prevalent in the ISM sample Figure 2A.

However, these trends were not significant. The measured amount of amino acids L-ala, L-val, L-leu, and L-ile in the media increased in IM enrichment compared to the observed decrease in the SM enrichment. All four amino acids in the IM enrichment followed a similar pattern: Within the first 3 weeks an increase was detected followed by a plateau phase Figure 3A.

The largest increase was seen for L-ala whereas only a small increase was detected for L-val. While in the SM sample, L-ile decreased the most and L-ala and L-leu were less depleted from the media, the plateau phase also started after about 2 weeks, revealing relatively small changes of the amino acid abundance Figure 3B.

This study investigated whether the fingerprints of microbial amino acid metabolism could be used as a potential biosignature. Beside a preferential use of amino acids, the microbial community can release certain amino acids as metabolic products into their surroundings. The release can occur by excretion or passive diffusion or the result of cell death followed by cell lysis.

In addition, a variety of abiotic processes leading to the formation or degradation of certain amino acids can result in a change of prevalent amino acid abundance within an environment. The following discussion is based on the assumption that potential extraterrestrial life uses similar biochemistry in liquid water environments as observed for Earth-based life.

Life as we know it is based on mainly CHNOPS elements and other mineral sources for generating energy and the usage of amino acids to form proteins. The data obtained for glycine suggest a preferential use of glycine by microbial communities.

We found that almost all the glycine was depleted and we observed this for both communities, suggesting the possibility that glycine depletion in an environment would be consistent with life.

There are several mechanisms in bacteria involved in glycine uptake and metabolism Sagers and Gunsalus, ; Andreesen, In anoxic environments, glycine can be a substrate in the Stickland reaction, which is a coupled oxidation-reduction reaction mainly for amino acid pairs Andreesen, Glycine serves preferentially as an electron acceptor which can be coupled to an energy conservation step.

Glycine and alanine can act as a redox couple in which glycine is reduced while alanine is oxidized. This reaction would also lead to a decrease in alanine, which is observed for the Sippenauer Moor SM sample Figure 2B but not for the Islinger Mühlbach ISM sample Figure 2A. Consequently, these results could either indicate the presence of different metabolic activities in these communities or that the Stickland reaction is not the main mechanism leading to the reduction of glycine in the medium.

Another explanation for the microbial removal of glycine from the medium could be the result of an energy-producing reaction where two molecules of glycine could be used to form serine and CO 2.

This has previously been reported for Pediococcus glycinophilus Sagers and Gunsalus, Furthermore, glycine can be used as part of the peptidoglycan in the cell wall Veuger et al. With the current experimental set-up, a detailed analysis on the metabolic mechanisms underlying the preferred removal of glycine is not possible.

However, the reduction of glycine and therefore the lack of detectability among the presence of other amino acids can be further explored as a potential biosignature.

In order to evaluate whether the absence of glycine is a valuable biosignature to find life on Mars, its abiotic stability on Mars needs to be considered. Glycine is one of the most abundant amino acids detected in meteorites and comets Botta and Bada, ; Elsila et al. Various laboratory studies have investigated not only the abiotic degradation of glycine Schuerger et al.

Mars simulation studies determining the effect of UV irradiation on glycine revealed a degradation which results in the release of methane into the atmosphere Schuerger et al.

Owing to its simple chemical structure, glycine has the fastest degradation rate of amino acids. Extrapolated from ISS experiments, Noblet et al.

Another set of exposure experiments on the ISS days for a total of 2, h solar constant radiation, equivalent to 1, Compared to UV radiation, galactic cosmic rays and solar energetic particles mainly protons can penetrate deeper into soil and ice Mancinelli and Klovstad, A decrease by a factor 5—10 in a depth of a few meters is expected from the surface dose rate of 0.

Gerakines and Hudson performed experiments to study the half-lives of glycine in either CO 2 -ice or H 2 O-ice when irradiated with protons.

The destruction rate constants indicated that glycine is less stable in CO 2 -ice Mars compared to H 2 O-ice Mars and Europa. When extrapolating these data to conditions in the Martian subsurface, the half-life of glycine is modelled to be less than — million years even at depths of a few meters Gerakines and Hudson, Global amino acid production was 4.

The growing demand for amino acids includes markets for animal feed, health foods, pharmaceutical precursors, dietary supplements, artificial sweeteners and cosmetics. The annual demand for feed-grade amino acids globally is about 2.

Some companies are major players in the amino acid production industry. Among them are Ajinomoto, Archer Daniels Midland, Cargill Inc. LLC, Royal DSM, Showa Denko KK and Zhejiang Chemicals.

Small-scale participants include Iris Biotech GmbH, Nanjing Liang Chemical, Sunrise Nutrachem Group, Tokyo Chemical Industry, Novus International Inc. Amino acid production is a multi-million ton-scale industry Table 1.

More than five million tons were produced in for the fermentative production of L -glutamate and L -lysine alone. Produced mainly by fermentation were 3. Such efforts often start with organisms having some capacity to make the desired compound but which require multiple mutations leading to deregulation in a particular biosynthetic pathway before high productivity can be obtained.

This approach to strain improvement has been remarkably successful in producing organisms that make industrially significant concentrations of amino acids.

Progress is even being made in the production of L -methionine by fermentation. More recent approaches utilize the techniques of modern genetic and metabolic engineering to develop strains overproducing amino acids.

Transport mutations are also useful, that is, mutations decreasing amino acid uptake often allow for improved excretion and lower intracellular feedback control.

In cases where excretion is carrier-mediated, increase in activity of these carrier enzymes increases production of the amino acid. Development of specific DNA microarrays has been directed to investigate gene expression during the growth of C. Expression profiles of selected genes involved in central metabolism and amino acid production have been determined.

With this information, it has been possible to conclude that the decrease in glucose uptake rate causes the metabolic shift from cell growth towards L -lysine biosynthesis and that a high flux of the tricarboxylic acid cycle is favorable for amino acid production.

Additional examples of amino acids whose production has been improved by this information include L -valine and L -threonine. After strain generation, culture conditions must be designed for each particular strain to get the best microbial performance. For a process to be realized economically, basic research has to be successfully translated into operations on the industrial scale.

Scale-up is a procedure in which the results of small-scale experiments are used as the basis for the design, testing and implementation of a larger scale system.

The workhorse of the fermentation industry is the conventional batch fermenter, an agitated jacketed pressure vessel with cooling coils, baffles and a sparger ring to introduce vapor into the fermentation process.

Most of the amino acids are produced by fed-batch processes using the best performing mutants. The fermentation process involves, at least, the following steps: i a fermentation tank is charged with culture medium and sterilized.

The medium contains a suitable carbon source such as sugar cane syrup , as well as the required nitrogen, sulfur and phosphorus sources, plus some trace elements; ii a seed culture of the production strain, previously grown in a smaller fermenter, is added to the fermentation tank and stirred under specified conditions temperature, pH, aeration ; iii depending on the culture requirements, additional nutrients are added during the fermentation in a controlled manner to allow for optimal yields; and iv the amino acid is released by the micro-organism into the fermentation solution and, after separation by ion exchange, is isolated by crystallization.

Today, large industrial plants are in use for amino acid production and the amino acids produced by microbial process are the L -forms.

Such stereo-specificity makes the processes advantageous as compared to synthetic processes. Monosodium glutamate is a potent flavor enhancer, a crucial component of the taste of cheese, seafood, meat broths and other foods. Professor Kikunae Ikeda, a Japanese scientist, identified the unique taste of umami, attributed to glutamic acid, as the fifth basic taste after sweet, sour, salty and bitter in the tongue.

A cooperative ligand-binding model involving the Venus flytrap domain of T1R1, where L -glutamate binds to the hinge region has been proposed.

Glutamate was first made by fermentation in Japan in the late s. Many organisms, belonging to a wide range of taxonomically related genera, including Brevibacterium, Corynebacterium , Microbacterium and Micrococcus , are capable of over-producing glutamate.

Brevibacterium lactofermentum and Brevibacterium flavum were reclassified as subspecies of C. The tricarboxylic acid cycle, also known as the Krebs cycle, requires a continuous replenishment of oxaloacetate in order to replace the intermediates withdrawn for the synthesis of biomass and other amino acids.

During growth on glucose and other glycolytic intermediates, the anaplerotic function is fulfilled by phosphoenolpyruvate carboxylase and pyruvate carboxylase. In normal conditions, glutamic acid over-production would not be expected to occur due to feedback regulation.

Glutamate feedback controls include repression of phosphoenolpyruvate carboxylase, citrate synthase and NADP-glutamate dehydrogenase; the last-named enzyme is also inhibited by glutamate. Glutamate excretion can be intentionally influenced by manipulations of growth conditions as follows: i since all glutamate over-producers are natural biotin auxotrophs, biotin limitation brings about glutamate over-production in C.

glutamicum by decreasing the cell membrane permeability barrier that restricts the excretion of glutamate. ii Addition of penicillin or fatty acid surfactants for example, tween 60 to exponentially growing cultures alters the permeability properties of the cell membrane and allows glutamate to flow out easily.

Apparently, all of these manipulations result in a phospholipid-deficient cytoplasmic membrane, which favors active excretion of glutamate from the cell. This view was further substantiated by the discoveries that oleate limitation of an oleate auxotroph and glycerol limitation of a glycerol auxotroph also bring about glutamate excretion.

Furthermore, glutamate-excreting cells have a very low level of cell lipids, especially phospholipids. In addition, it was shown that the various manipulations leading to glutamate over-production cause increased permeability of the mycolic acid layer of the cell wall.

The glutamate over-producing bacteria are characterized by a special cell envelope containing mycolic acids which surrounds the entire cell as a structured layer and is thought to be involved in permeation of solutes.

The mycolic acids esterified with arabinogalactan and the non-covalently bound mycolic acid derivatives form a second lipid layer of the cell; with the cytoplasmic membrane being the first. Over-expression or inactivation of enzymes that are involved in lipid synthesis alters the chemical and physical properties of the cytoplasmic membrane and changes glutamate efflux dramatically.

Polyglutamic acid PGA is made by bacilli. When made by Bacillus subtilis and Bacillus licheniformis , it contains repeated units of D -glutamic acid and L -glutamic acid. However, when made by Bacillus anthracis , it contains D- glutamic acid exclusively. PGA is potentially useful as a drug delivery agent for drugs against cancer, for example, as a carrier of doxorubicin.

L -Lysine represents the fastest growing amino acid segment. The bulk of the cereals consumed in the world are deficient in L -lysine. It is an essential ingredient for the growth of animals and an important part of a billion-dollar animal feed industry. Lysine supplementation converts cereals into balanced food or feed for animals including poultry, swine and other livestock.

In addition to animal feed, lysine is used in pharmaceuticals, dietary supplements and cosmetics. Lysine is a member of the aspartate family of amino acids Figure 2. It is made in bacteria by a branched pathway that also yields methionine, threonine and isoleucine.

This pathway is controlled very tightly in organisms such as Escherichia coli , which contains three aspartate kinases AKs , each of which is regulated by a different end product.

Biosynthetic pathway to L -lysine, L -threonine and L -isoleucine in C. AK, aspartate kinases; ASA-DH, aspartate-semialdehyde dehydrogenase; HDI, homoserine dehydrogenase; HK, homoserine kinase; TS, threonine synthetase; TD, threonine dehydratase, AHAS, acetohydroxy acid synthase.

In addition, after each branch point, the initial enzymes are inhibited by their respective end product s and no overproduction usually occurs. However, C. glutamicum , the organism used for the commercial production of L -lysine, contains a single AK that is regulated via concerted feedback inhibition by threonine plus lysine.

This is evidently due to the high level of NADPH required for lysine formation. Use of recombinant DNA technology has shown that the factors that significantly limit the over-production of lysine are: i feedback inhibition of AK by lysine plus threonine, ii the low level of dihydrodipicolinate synthase, iii the low level of phosphoenolpyruvate carboxylase and iv the low level of aspartase.

Much work has been done on auxotrophic and regulatory mutants of glutamate over-producing strains for the production of lysine. By genetic removal of homoserine dehydrogenase HDI , a glutamate-producing wild-type Corynebacterium strain was converted into a lysine over-producing mutant that cannot grow unless methionine and threonine are added to the medium.

In some strains, addition of methionine and isoleucine to the medium led to the increase in lysine over-production. Selection for Saminoethylcysteine AEC; thialysine resistance blocks feedback inhibition of AK. Other anti-metabolites useful for deregulation of AK include a mixture of α-ketobutyrate and aspartate hydroxamate.

Leucine auxotrophy can also increase lysine production. Excretion of lysine by C. glutamicum is by active transport reaching a concentration of several hundred millimolar in the external medium.

Lysine, a cation, must be excreted against the membrane potential gradient outside is positive and the excretion is carrier-mediated. The system is dependent on electron motive force, not on ATP. Genome-based strain reconstruction has been used to improve the lysine production rate of C.

Comparison of 16 genes from the production strain, encoding enzymes of the pathway from glucose to lysine, revealed mutations in five of the genes.

Enzymatic analysis revealed that the mutant enzyme was less sensitive than the wild-type enzyme to allosteric inhibition by intracellular metabolites. With the use of systems metabolic engineering, 12 defined genome-based changes in genes encoding central metabolic enzymes redirected the major carbon flux towards the optimal L -lysine pathway usage, as predicted by in silico modeling.

The engineered C. glutamicum strain was able to produce lysine with a high yield of 0. L -Threonine is used in the agricultural, pharmaceutical and cosmetic industries. It is the second major amino acid used for feeding pigs and poultry. The pathway of threonine biosynthesis is similar in all micro-organisms.

Starting from L -aspartate, the pathway involves five steps catalyzed by five enzymes: AK, aspartate-semialdehyde dehydrogenase ASA-DH , HDI, homoserine kinase, and threonine synthetase. Production of L -threonine has been achieved with the use of several micro-organisms.

In Serratia marcescens , construction of a high threonine producer was done by transductional crosses that combined several feedback control mutations into one organism. Three classes of mutants were obtained from the parental strain as the source of genetic material for transduction: i one strain in which both the threonine-regulated AK and HD were resistant to feedback inhibition by threonine.

It was selected on the basis of β-hydroxynorvaline resistance; ii a second strain, also selected for β-hydroxynorvaline resistance, in which HDI was resistant to both inhibition and repression and the threonine-regulated AK was constitutively synthesized; and iii a third strain that was resistant to thialysine, in which the lysine-regulated AK was resistant to feedback inhibition and repression.

Since at least one of the three key enzymes in threonine synthesis was still subject to regulation in these strains, each produced only modest amounts of threonine 4.

Another six regulatory mutations derived by resistance to amino acid analogues were combined into a single strain of S. marcescens by transduction. These mutations led to desensitization and derepression of AKs I, II, and III and HDIs I and II.

Production of L -threonine by E. coli is limited by formation of acetate. By genetically decreasing acetate production, Xie et al. They did this by simultaneously deleting some genes encoding key glycolytic enzymes.

The genes were pfk , encoding phosphofructokinase, and pyk , encoding pyruvate kinase. Determination of the key enzymes involved in L -threonine production in E.

coli by proteomics indicated that the isoenzyme LysC, which catalyzes the first step, is the key enzyme of the pathway from aspartate to threonine.

Of major importance were mutations to decrease both regulation of the pathway and degradation of the amino acid.

Another E. coli is limited by the formation of acetate. Threonine excretion by C. Cloning of extra copies of threonine export genes into an E. coli strain producing threonine led to increased production.

Also increased was resistance to toxic anti-metabolites of threonine. Another means of increasing threonine production is reduction in the activity of serine hydroxytransferase, which breaks down threonine to glycine. glutamicum ssp. L -Leucine belongs to the branched chain amino acids.

Together with L -valine and L -isoleucine, branched chain amino acids are widely used as fitness supplements and for patients with hepatic encephalopathy. Besides, L -leucine can be used as a lubricant in the pharmaceutical industry. Its market is continuously growing and strategies to improve L -leucine are required.

Production of L -leucine was initially reported in analogue-resistant mutants selected by random mutagenesis from the glutamate-producer Bacillus lacto-fermentum and further optimized by additional mutagenesis steps.

L -Isoleucine is of commercial interest as a food and feed additive and for parenteral nutrition infusions. This branched chain amino acid is currently produced both by extraction of protein hydrolysates and by fermentation with classically derived mutants of C.

The biosynthesis of isoleucine by C. glutamicum involves 11 reaction steps, of which at least five are controlled with respect to activity or expression. L -isoleucine synthesis shares reactions with the lysine and methionine pathways. In addition, threonine is an intermediate in isoleucine formation, and the last four enzymes also carry out reactions involved in valine, leucine and pantothenate biosynthesis.

glutamicum , as in other bacteria, are required to ensure the balanced synthesis of all these metabolites for cellular demands. glutamicum, flux control is exerted by repression of the homthrB and ilvBNC operons.

The activities of AK, HDI, TD, and acetohydroxy acid synthase are controlled by allosteric transitions of the proteins to provide feedback control loops, and homoserine kinase is inhibited in a competitive manner.

Isoleucine processes have been devised in various bacteria such as S. marcescens, C. flavum, and C. The C. Mutation to D -ethionine resistance yielded a mutant making A threonine-over-producing strain of C.

Independently, cloning of three copies of the feedback-resistant HDI gene hom and multicopies of the deregulated TD gene ilvA in a deregulated lysine producer of C.

L -Valine is another branched chain amino acid used in human and animal nutrition, manufacture of pharmaceuticals, as a moisturizing agent in cosmetics, and for chemical synthesis of antibiotics, antiviral agents and herbicides.

Metabolic engineering has increased microbial production of L -valine. Engineered C. This amino acid is used in pharmacy, the food industry and in feed additives.

coli or C. It is also used as a flavor in food additives. In pharmaceuticals, L -methionine is used in hepatic therapeutics and drugs for the prevention of hepatic impairments.

It is also used as a nutritive supplement in infant milk preparations, parenteral nutrition, health foods and in sports supplements. DL -methionine has been made for over 50 years by chemical synthesis and has an annual capacity of about one million tons.

Methionine is commercially produced by chemical synthesis, by protein hydrolysis, or by microbial biosynthesis. A review of the production of L -methionine by fermentation is that of Kumar and Gomes. Methionine biosynthesis requires ATP as an energy source, and thus organisms produce just enough methionine for their own growth.

No wild-type microbe is known to overproduce methionine. Chemical synthesis has been preferred due to its content of sulfur which makes it difficult for engineered microbes to make it in large quantities.

In , it was produced chemically as DL -methionine, using methyl mercaptan, acrolein and HCN. However, this involves poisonous substrate intermediates, waste and high consumption of energy.

Also, chemical synthesis suffers by the fact that it yields both D - and L -methionine and the process involves hazardous chemicals such as acrolein, methylmercaptan, ammonia and cyanide.

An alternative method employs microbes, such as E. coli , converting aspartate to aspartylphosphate with aspartokinase, using aspartate-semialdehyde dehydrogenase to convert aspartyl phosphate to L -aspartate-semialdehyde, which is then reduced by homoserine dehydrogenase to homoserine.

Homoserine is then converted to O-succinyl-homoserine by homoserine transsuccinylase. The O-succinyl-homoserine is converted to homocysteine which is then methylated to methionine.

Metabolic engineering of wild-type E. coli W31 resulted in production of L -methionine at 5. coli was engineered via deletion of a negative transcriptional regulator MetJ and overexpression of homoserine O-succinyltransferase MetA, together with efflux transporter YjeH, resulting in L -methionine overproduction.

Additional modifications have included tolerance to high L -ethionine concentrations and blockage of the lysine biosynthetic pathway.

After optimization, the metabolically tailored E. coli strain produced 9. The French company METabolic EXplorer METEX developed and patented a multi-recombinant E.

coli strain able to over-produce methionine. Some of the strain properties are an increased expression of genes involved in the synthesis of methionine, serine and glycine, transport and metabolism of glucose, and transport of sulfate and thiosulfate. In addition, several enzymes were detected with a reduced feed-back sensitivity to S-adenosylmethionine and threonine.

Genetic engineering of E. coli , which originated from different bacteria Citrobacter koseri, Citrobacter freundii, Enterobacter sp. This process was transferred to Evonik Industries AG of Germany for commercial exploitation.

Therefore, the commercial fermentative production of methionine is expected to start in the near future. Evonik Industries AG is a major producer of amino acids for animal nutrition and has several complexes for the chemical production of methionine. S-Adenosylmethionine SAM is a key part of sulfur amino acid metabolism and is made from methionine and ATP by methionine adenosyltransferase.

It functions as a major donor of methyl groups in the transmethylation of proteins, nucleic acids, hormones, polysaccharides, phospholipids and fatty acids. It is involved in the synthesis of ergosterol and is an intermediate in synthesis of polyamines. It is the main biological methyl donor because of its active methylthioether group.

The aromatic amino acids L -tryptophan and L -phenylalanine are compounds with multiple applications in the food industry. Tryptophan is an important amino acid used as a feed additive and in the pharmaceutical, cosmetic, food and health product industries.

A new use for tryptophan deals with the recent increase in the feeding by farmers of dried distiller grains to animals. These grains are a by-product of the conversion of corn into ethanol, but they require tryptophan supplementation.

It is particularly suitable for young pigs, improving feed intake, growth and feed efficiency. flavum , 3-deoxy- D -arabino-heptulosonate 7-phosphate synthase DAHPS is feedback inhibited concertedly by phenylalanine plus tyrosine and weakly repressed by tyrosine.

Other enzymes of the common pathway Figure 3 are not inhibited by phenylalanine, tyrosine and tryptophan, but the following are repressed: shikimate dehydrogenase, shikimate kinase SK , and 5-enolpyruvylshikimatephosphate synthase. Elimination of the uptake system for aromatic amino acids in C.

glutamicum resulted in increased production of aromatic amino acids in deregulated strains. Biosynthetic pathways for L -tryptophan, L -phenylalanine and L -tyrosine. DAHPS, 3-deoxy- D -arabino-heptulosonate 7-phosphate synthase; DQS, dehydroquinate synthase; SD, shikimate dehydrogenase SD ; SK, shikimate kinase SK ; CS, chorismate synthase; CM, chorismate mutase; TAT, tyrosine amino transferase; PD, prephenate dehydratase; AS, anthranilate synthase.

flavum producer to azaserine resistance. Azaserine is an analog of glutamine, the substrate of anthranilate synthase AS. Such a mutant showed a fold increase in the activities of DAHPS, dehydroquinate synthase, shikimate dehydrogenase, shikimate kinase, and chorismate synthase.

Another mutant, selected for its ability to resist sulfaguanidine, showed additional increases in DAHPS, dehydroquinate synthase and tryptophan production. The reason that sulfaguanidine was chosen as the selective agent involves the next limiting step after derepression of DAHPS, that is, conversion of the intermediate chorismate to anthranilate by AS.

Chorismate can also be undesirably converted to p -aminobenzoic acid and sulfonamides which are p -aminobenzoic acid analogs.

A sulfaguanidine-resistant mutant was obtained with C. The sulfaguanidine-resistant mutant was still repressed by tyrosine but showed higher enzyme levels at any particular level of tyrosine.

Elimination of tryptophan permeases improved L -tryptophan production by E. A genetically engineered strain of E.

A conventionally mutated strain of E. In this way, the tryptophan-dependent regulation of the bi-functional pabA gene does not interfere with folate synthesis.

However, the cores of regulons in Gram-negative and Gram-positive species coincide. These include the trp operon, DAHP synthase and shikimate kinase genes, and the phhA gene. Interestingly, even the type of regulation of these genes is almost conserved: in both groups the trp operon is regulated at the RNA level although it is additionally regulated by a DNA binding repressor in γ-proteobacteria , whereas the DAHP synthase and shikimate kinase genes are regulated at the DNA level.

In contrast, group-specific members of regulons, e. transporters yhaG , trpXYZ , mtr , tyrP , aroP , are regulated by variable mechanisms: by DNA-dependent regulation in Gram-negative genomes, and by RNA-dependent regulation in the Gram-positive group.

The same pattern of regulation was observed for the phhA gene. One notable exception to this rule is provided by B. In contrast to other bacilli that display DNA level regulation of the aroA and aroF genes, B.

anthracis has acquired T-boxes upstream of both genes, and thus shifted to RNA level regulation. The most general one is the T-box-dependent transcriptional regulation, which is present in all studied species.

Another type of RNA-dependent transcriptional regulation, TRAP-mediated regulation, is unique to the Bacillus group except for B. anthracis , which lacks the TRAP protein.

stearothermophilus , TRAP regulates transcription of the trp operon, which is regulated by tryptophan-specific T-boxes in all other species. stearothermophilus , where it appears to regulate transcription of DAHP synthase and chorismate synthase genes. anthracis , the same genes are regulated by tyrosine-specific T-boxes.

Finally, in S. mutans , and L. lactis , DAHP synthase and shikimate kinase genes seem to be under transcriptional regulation by ARO boxes identified in this study. However, we could not identify the transcription factor responsible for this regulation, as no candidate sites or RNA elements were observed upstream of genes encoding proteins with potential DNA binding domains.

This means that, unlike TrpR and TyrR of γ-proteobacteria, these hypothetical factors are not subject to auto-regulation. We are grateful to Dmitry Rodionov and Andrey Osterman for useful discussion. This study was partially supported by grants from the Howard Hughes Medical Institute and the Ludwig Institute for Cancer Research CRDF RBO Pittard A.

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Science , — Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide.

Sign In or Create an Account. Advertisement intended for healthcare professionals. Navbar Search Filter FEMS Microbiology Letters This issue FEMS Journals Microbiology Books Journals Oxford Academic Mobile Enter search term Search.

FEMS Journals. Advanced Search. Search Menu. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents Abstract. Journal Article. Regulation of biosynthesis and transport of aromatic amino acids in low-GC Gram-positive bacteria. Panina , Ekaterina M. Graduate Program in Molecular, Cellular and Integrative Life Sciences, Molecular Science Building, University of California at Los Angeles, Los Angeles, CA , USA.

Oxford Academic. Alexey G. Integrated Genomics, P. Box , Moscow , Russia. Institute for Problems of Information Transmission, Russian Academy of Science, Bolshoj Karetny per. Andrey A. Mikhail S. Revision received:. PDF Split View Views. Cite Cite Ekaterina M. Select Format Select format.

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Abstract Computational comparative techniques were applied to analysis of the aromatic amino acid regulon in Gram-positive bacteria. Aromatic amino acid , Regulation , T-box , TRAP , ABC transporter. Open in new tab Download slide.

At the next step, a recognition rule was generated. If some regulatory sites had already been identified in experiment, a profile was constructed using the alignment of these known sites.

If there were no known sites, an iterative procedure was performed in order to construct a profile. All L -mer words were selected in each upstream region.

Each word was compared to all words in other regions, and one word, closest to the initial one, was selected in each region. These words were used to construct a profile. Thus we obtain as many profiles as there were words in the sample. Positional nucleotide weights in the profile were defined as:.

The obtained profiles were used to scan the set of words again, and the procedure was iterated until convergence. Then the best profile was selected to be used as the recognition rule. The quality of a profile was defined as its information content [12] :. Listeria monocytogenes B aroF-aroB-aroH-hisC-tyrA-aroE ; T-trp T-trp trpE-pabA-trpD-trpC-trpF-trpB-trpA ; aroD-aroC ; pheA ; aroI ; aroA T —?

Open in new tab. mutans aroI ATGGGGGCtaAgAT 26 S. Escherichia coli and Salmonella. Cellular and Molecular Biology. Google Scholar Crossref. Search ADS. A Bacillus subtilis gene of previously unknown function, yhaG , is translationally regulated by tryptophan-activated TRAP and appears to be involved in tryptophan transport.

TyrR protein of Escherichia coli and its role as repressor and activator. The region between the operator and first structural gene of the tryptophan operon of Escherichia coli may have a regulatory function.

Alternative secondary structures of leader RNAs and the regulation of the trp , phe , his , thr , and leu operons. Prediction of co-regulated genes in Bacillus subtilis on the basis of upstream elements conserved across three closely related species.

Google Scholar OpenURL Placeholder Text. Posttranscriptional initiation control of tryptophan metabolism in Bacillus subtilis by the trp RNA-binding attenuation protein TRAP , anti-TRAP, and RNA structure.

Google Scholar PubMed. OpenURL Placeholder Text. Computer prediction of RNA secondary structure. Regulation of expression of the Lactococcus lactis histidine operon. The Staphylococcus aureus ileS gene, encoding isoleucyl-tRNA synthetase, is a member of the T-box family.

Inferring phylogenies from protein sequences by parsimony, distance, and likelihood methods.

The identification of reliable acidd, such as amino acids, is key for the search Natural ways to increase metabolic rate extraterrestrial Phosphorus for energy metabolism in athletes. In this work, we investigated pathwy the anaerobic microbial metabolism eynthesis amino acids Fat intake and essential fatty acids leave a Aminl biosignature indicating biological activity in the environment around the cells. The observed fingerprints would reflect the physiological capabilities of the specific microbial community under investigation. The metabolic processing of an amino acid mixture by two distinct anaerobic microbial communities collected from Islinger Mühlbach ISM and Sippenauer Moor SMGermany was examined. The amino acid mixture contained L-alanine, β-alanine, L-aspartic acid, DL-proline, L-leucine, L-valine, glycine, L-phenylalanine and L-isoleucine.

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