Category: Home

Amino acid synthesis pathway in humans

Amino acid synthesis pathway in humans

Heirloom seed choices repressor protein Patgway, in cooperation with the corepressor protein S-adenosyl-methionine, Amno the repression of methionine's biosynthesis. The synthesis acld aspartate pathwaay AKwhich syntesis the phosphorylation Vegetable smoothies aspartate Amin initiates its conversion into other amino acids, Amino acid synthesis pathway in humans feed-back inhibited by lysineisoleucineand threoninewhich prevents the synthesis of the amino acids derived from aspartate. Pentose phosphate pathway Fructolysis Polyol pathway Galactolysis Leloir pathway. Bromke MA. AXA and AXA are oral endogenous modulator EMM compositions. Polypeptide chains fold in a particular manner depending on the solution they are in. Yoshizawa FKimball SRJefferson LS Modulation of translation initiation in rat skeletal muscle and liver in response to food intake.

Amino acid synthesis pathway in humans -

Most bacteria and plants can synthesize all Some simple parasites, such as the bacteria Mycoplasma pneumoniae , lack all amino acid synthesis and take their amino acids directly from their hosts. All amino acids are synthesized from intermediates in glycolysis, the citric acid cycle, or the pentose phosphate pathway.

Nitrogen is provided by glutamate and glutamine. Amino acid synthesis depends on the formation of the appropriate alpha-keto acid, which is then transaminated to form an amino acid.

Amino acids are made into proteins by being joined together in a chain by peptide bonds. Each different protein has a unique sequence of amino acid residues: this is its primary structure.

Just as the letters of the alphabet can be combined to form an almost endless variety of words, amino acids can be linked in varying sequences to form a huge variety of proteins.

Proteins are made from amino acids that have been activated by attachment to a transfer RNA molecule through an ester bond. Aside from the 22 standard amino acids, there are many other amino acids that are called non-proteinogenic or non-standard.

Those either are not found in proteins for example carnitine, GABA or are not produced directly and in isolation by standard cellular machinery for example, hydroxyproline and selenomethionine. Non-standard amino acids that are found in proteins are formed by post-translational modification, which is modification after translation during protein synthesis.

These modifications are often essential for the function or regulation of a protein. For example, the carboxylation of glutamate allows for better binding of calcium cations.

The hydroxylation of proline is critical for maintaining connective tissues. Another example is the formation of hypusine in the translation initiation factor EIF5A, through modification of a lysine residue.

Such modifications can also determine the localization of the protein, e. Some nonstandard amino acids are not found in proteins. Examples include lanthionine, 2-aminoisobutyric acid, dehydroalanine, and the neurotransmitter gamma-aminobutyric acid. Nonstandard amino acids often occur as intermediates in the metabolic pathways for standard amino acids — for example, ornithine and citrulline occur in the urea cycle, part of amino acid catabolism.

Search site Search Search. Go back to previous article. The benefits and risks of Gln supplementation in various diseases still need more data from clinical trials. In cardiovascular disease, Myc and Myc-related factor X Max upregulate the Gln transporters SLC1A5 and SLC7A5 and mitochondrial malate in pulmonary hypertension, thereby promoting glutaminolysis-induced right ventricular hypertrophy.

However, inhibition of GLS activity can reduce ATP and GSH levels produced by cardiomyocytes under oxidative stress conditions. T2DM is a major risk factor for the development of cardiovascular disease.

Dysregulation of skeletal muscle metabolism in diabetes affects insulin sensitivity and glucose homeostasis. Dollet et al. found that Gln is a key amino acid in the regulation of glucose stability and insulin sensitivity, and the level of Gln affects the inflammatory response of skeletal muscle and regulates the expression of the adaptive protein GRB10, an insulin signaling inhibitor.

Moreover, the systemic elevation of Gln improves insulin sensitivity and restores glucose homeostasis in mouse models of obesity. The anthracycline antibiotic doxorubicin DOX is a widely used anti-tumor drug in solid malignant tumors; yet, this therapy may lead to serious cardiotoxicity due to free radicals and oxidative stress.

Gln supplementation significantly reduced cardiac lipid peroxide levels and increased peroxidase and glutathione levels, protecting cardiac function in DOX-treated rat models. Drugs targeting cardiac Gln metabolism are being developed.

Oridinon Ori , a natural terpenoid derived from the plant Isodon rubescens Hemsl. Severe acute respiratory syndrome coronavirus 2 SARS-CoV-2 is the cause of coronavirus disease COVID The disease is spread through close person-to-person contact or respiratory secretions from infected people.

Therefore, Gln deficiency has led to immune dysfunction and HA overproduction in people at high risk of COVID HA can activate STAT3 through PAI In addition, although SARS-CoV-2 vaccines have significantly reduced COVID cases, cells are placed under intense oxidative stress conditions after SARS-CoV-2 infection, which promotes the consumption of Gln to synthesize glutathione.

At the same time, it can also cause STAT3 pathway inactivation and PAI-1 activation, leading to severe complications of COVID in some people. Small clinical trials have shown that Gln supplementation reduces post-infection severity in patients with COVID Arginine, also known as L-arginine, is a raw material for protein synthesis and an intermediate product of the urea and nitric oxide cycles.

In humans, small intestinal epithelial cells convert Gln and glutamate to citrulline, which is then transported by the circulatory system to renal proximal tubular cells, where arginine is synthesized by arginine-succinate synthetase and arginine-succinate lyase in the urea cycle.

Arginine synthesis is impaired when small intestine and kidney function is impaired, thus creating a dietary requirement for arginine. In other cell types, arginine synthesis by citrulline is very low but dramatically increases when inducible nitric oxide synthase NOS increases Fig.

Under these conditions, citrulline, a byproduct of nitric oxide synthesis, can recover arginine via the arginine-citrulline pathway. Another type of post-translational modification is methylation by arginine methyltransferases PRMTs , in which arginine can be methylated to either monomethylated arginine or dimethylated arginine.

Arginine methyltransferases can be divided into three following classes: Type I PRMTs PRMT1, PRMT2, PRMT3, PRMT4, PRMT6, and PRMT8 catalyze the production of asymmetric dimethylarginine; Type II PRMTs PRMT5 and PRMT9 catalyze the formation of symmetrical dimethylarginine; Type III PRMTs are currently the only known PRMT7, which produces only monomethylarginine.

Many arginine-methylated proteins have been shown to interact with DNA or RNA, and the arginine residue acts as an important hydrogen donor for the phosphate backbone. Citrulline and aspartate can be converted to arginine in normal cells by arginine-succinate synthetase 1 ASS1 and arginine-succinate lyase ASL in the urea cycle.

Use of the arginine-depleting agent pegylated arginine deiminase ADI-PEG20 in GBM can increase nitric oxide NO synthesis and produce cytotoxic pernitrite, increasing the sensitivity of tumor cells to ionizing radiation and significantly enhancing the effect of radiotherapy on GBM.

Combination with suberoylanilide hydroxamic acid SAHA can effectively control the growth of GBM xenografts. Treatment of HCC cells with ADI-PEG20 downregulates the key enzymes of pyrimidine synthesis in the TCA cycle, carbamoyl phosphate synthetase 2, thymine synthase TS , aspartate transcarbamylase and dihydrooratase CAD and malate dehydrogenase 1 MDH-1 activities, making tumor cells more susceptible to 5-fluorouracil 5-FU.

The effect of this synergistic treatment is ASS-dependent, and the activity of the enzymes mentioned above can be restored by transfection of ASS, eliminating the sensitivity of tumor cells to ADI-PEG20 combined with 5-FU treatment. Arginine metabolism in tumor cells.

Arginine depletion can increase the phosphorylation level of GCN2 in hepatocellular cancer cells, activate GCN, increase the expression level of SLC7A11 and increase the uptake of arginine.

Activated GCN2 can also be mediated by p21 cell cycle arrest; GCN2 also increases protein synthesis by activating mTORC1 via sestrin. ARG2 in the mitochondria of melanoma cells increases transfer-promoting gene transcription via the p66SC-H2O2-Stat3 axis. Myeloid cells can promote intracellular p38 and ARG1 transcription by receiving tumor cell-derived CSF and activation of STAT3.

The arginine metabolism of myeloid cells with high expression of ARG1 was enhanced, and the arginine metabolism of T cells was inhibited, and the tumor immunity was inhibited. The arginase isoenzymes arginase1 ARG1 and arginase2 ARG2 are abnormally upregulated in various cancers.

ARG1 is mainly expressed in the cytoplasm of hepatocytes and plays a role in the urea cycle. In head and neck squamous cell carcinoma HNSCC , phosphorylated STAT3 can directly bind to the ARG1 promoter region of MDSCs to promote transcription, thereby contributing to the immunosuppressive effect of MDSCs.

In cancer patients, ARG1 is increased while L-Arginine is decreased in plasma samples. Arginase inhibitors have been developed and experimentally evaluated in various tumors.

PRMTs are SAM-dependent enzymes that catalyze the mono- and di-methylation of peptidyl arginine residues. Many studies have shown that the activity of PRMTs is related to cancer stem cells CSCs , which can self-renew and generate differentiated progeny. This is an important factor leading to tumor drug resistance, metastasis and recurrence.

PRMT5 is highly expressed in breast cancer and chronic myeloid leukemia CML stem cells, and the knockdown of PRMT5 or the use of PRMT5 inhibitors can significantly impair the self-renewal capacity of CSCs. Methylation of R21 promotes the polyubiquitination and degradation of MRPS23, which inhibits mitochondrial phosphorylation OXPHOS and increases ROS levels, thereby promoting breast cancer cell metastasis.

On the other hand, K methylation cooperates with R21 methylation to maintain low levels of OXPHOS, which favors breast cancer cell survival. Also, PRMT5 knockdown impairs the self-renewal ability of GBM cells and promotes apoptosis.

In the process of wound healing, arginine participates in the response of inflammatory factors through the arginine-NO pathway. In addition, ornithine and urea produced by arginase degradation of arginine are essential during this process and have a key role in the synthesis of collagen and polyamines.

In myeloid cells, activated nitric oxide synthase NOS and NO inhibit T lymphocyte function by interfering with IL Dietary arginine supplementation is the most convenient way and has multiple benefits for wound healing.

On the contrary, arginine supplementation significantly alleviates the above problems and increases wound strength.

Advanced glycation end products AGEs modify proteins to cause their dysfunction. Glycosylation of the AMPK-γ subunit inhibits AMPK function, and arginine treatment protects AMPK-γ from glycosylation and increases AMPK phosphorylation in a mouse model of AD, thereby ameliorating AD disease.

Asthma is a variable, recurrent, long-term inflammatory disease of the respiratory tract. Imbalances in the metabolism of Arg and nitric oxide have been implicated in the pathophysiology of asthma.

An analysis of plasma metabolic mass spectrometry in children with asthma showed that Arg, Lys, and Met levels were significantly decreased in the susceptible asthma group compared to the non-susceptible asthma group. showed that adding L-Arginine to labeled asthma medications did not significantly reduce asthma exacerbations.

High expression of PRMT7 promotes the methylation of RAP1A regulatory element histones and regulates monocyte adhesion and migration. Decreased expression of PRMT7 reduces monocyte recruitment to sites of lung injury. Patients with hypercholesterolemia and vascular disease commonly have elevated asymmetric dimethylarginine ADMA , which is associated with impaired NO synthesis and an early marker of endothelial dysfunction.

The abnormal activity of PRMTs results in increased ADMA and MMA, which increases the risk of cardiovascular disease. Loss of PRMT7 in the heart reduces symmetrical dimethylation of β-catenin, enhances Wnt-β-catenin signaling, and promotes myocardial hypertrophy.

It regulates gene activation by regulating histone methylation modification in the promoter region of myocartin. Ablation of PRMT1 can downregulate the expression of contractile genes such as myocartin and significantly reduce the contractility of the aorta and the traction force of vascular smooth muscle cells VSMCs.

Inhibitors targeting PRMTs are being developed and experimentally tested. Arg methylase inhibitors AMIs , symmetric sulfonated urea, specifically inhibit PRMT activity and, in a rat model, cyclooxygenase-2 COX-2 expression and suppress inflammation.

Met is an essential amino acid and a precursor of other amino acids such as cysteine Cys and taurine, as well as S-adenosyl-L-methionine SAM and glutathione GSH. The backbone of Met biosynthesis is mainly derived from aspartate. Aspartate is first converted to homoserine through the reduction reaction of the β-aspartate semialdehyde terminal.

The intermediate aspartate semialdehyde can be condensation with pyruvate to participate in the Lys biosynthesis pathway, and homoserine itself can also participate in threonine biosynthesis. The homoserine hydroxyl group is then activated by phosphate, succinyl, or acetyl groups, and the hydroxyl group is then replaced by cysteine, methyl thiol, or hydrogen sulfide by displacement reactions.

It reacts with Cys under the catalysis of cystathionine-γ-synthetase to produce cystathionine, which is cleaved by cystathionine-β-lyase to form homocysteine. In reaction with free hydrogen sulfide, homocysteine is formed under the catalysis of O-acetyl-homoserine aminocarboxypropyl transferase.

The reaction with methanethiol yields Met directly. This pathway includes both forward and reverse. The forward pathway is present in bacteria such as Escherichia coli and Bacillus subtilis and can transfer sulfhydryl groups from cysteine to homocysteine.

In catabolism, Met is catalyzed by Met adenosine transferase MAT to SAM. As a methyl donor, SAM participates in various methyl transfer reactions and is converted to S-adenosylhomocysteine SAH in the reaction.

Met can increase the intracellular concentration of glutathione, promote cellular REDOX regulation, and protect cells by binding to oxidative metabolites Fig. Met, as an essential amino acid, has an important role in tumor growth and metabolism.

In addition to exogenous supply, the Met salvage pathway is the only Met source. This pathway requires the activity of methyladenosine phosphorylase MTAP as well as Met synthase MS. These enzymes are often downregulated in malignant tumors, resulting in a strong dependence of the cells on Met intake from the external environment.

In the absence of MTAP, the substrate methyl thionyl adenosine MTA accumulates and acts as a selective inhibitor of PRMT5 to inhibit PRMT5 methylation activity, whereas MAT2A can produce the PRMT5 substrate SAM, allowing PRMT5 to exert its oncogenic effect.

Also, AG showed a synergistic antiproliferative effect with the anti-mitotic drug taxane in vitro and in vivo. PRMT5 inhibitors GSK and ly caused a broad inhibition of transcriptome splicing in GBM cells, particularly affecting the products of cell cycle genes and prolonged survival in the PDX mouse model.

Methionine metabolism in tumor cells. In MTAP deficient cells, the MTAP substrate, MTA, accumulates and inhibits PRMT5 activity. Tumor cells can increase methionine intake through high expression of SLC43A2, competitive consumption of methionine in the environment, resulting in methionine deficiency in T cells.

T cell methionine restriction can inhibit the normal methylation in cells, resulting in the transcription of STAT5 gene obstruction, affecting T cell survival and function.

On the other hand, methionine metabolism inhibited PD-L1 and V-domain Ig suppressor of T cell activation VISTA immune checkpoint translation. Because of its central role in methylation, Met is considered a candidate target for tumor therapy driven by ten-eleven translocation TET , isocitrate dehydrogenase IDH proteins, methyltransferases, and other phenotypic modifiers.

Anti-tumor effects of the Met-free diet were first reported in Walker sarcoma-bearing Sprague-Dawley rats.

Met supplementation or inhibition of SLC43A2 expression in tumor cells can reverse the above-mentioned functional suppression of T cells and activate tumor immunity Fig. The hepatocyte nuclear factor 4α HNF4α regulates sulfur amino acid SAA metabolism in the liver.

Knocking down HNF4α in hepatocellular carcinoma impairs SAA metabolism, increases tumor cell tolerance to Met deprivation and sorafenib, and promotes tumor EMT. In contrast, restoring SAA metabolism alleviated the tumor phenotype resulting from HNF4α deficiency.

Therefore, more precise and focused treatment methods should be developed for tumor cell Met metabolism. Targeting STED2 and SLC43A2 provides new insights. Nonalcoholic fatty liver disease NAFLD is a disease caused by abnormal metabolic pathways leading to the accumulation of triglycerides TG in the liver.

Obesity and T2D mellitus are strong risk factors for NAFLD. This effect of HFD was not observed until 24 weeks after insulin resistance, which resulted in less liver fibrosis. Methyl donor supplementation reduces hepatic fat accumulation by activating the AMPK signaling pathway to increase fatty acid consumption.

As a transcription factor, MATα1 negatively regulates cytochrome P 2E1 CYP2E1 at the mRNA level. On the other hand, MATα1 directly interacts with CYP2E1 to promote the methylation of CYP2E1 at R site and degradation through the proteasome pathway. Blocking the interaction between PIN-1 and MATα1 reversed the alcohol-induced cytotoxic phenotype.

Autosomal dominant polycystic kidney disease ADPKD is a common monogenic disease characterized by the enlargement of renal cysts. In the ADPKD model, the levels of Met and SAM are increased, which induces the expression of Mettl3.

Also, Mettl3 can increase c-Myc and Avpr2 mRNA modification, activate c-Myc and cAMP pathways, and accelerate cyst growth. A Met restricted diet may slow the progression of ADPKD.

Compared with the normal feeding model, the kidney inflammation genes such as Emr1, Nos2, and Tnfa were downregulated, and the degree of basophil aggregation was lower in the MR model. The renal fibrosis genes Fn1, Serpine1, Tgfb1, and Col1a1 were downregulated, and the degree of fibrosis was milder.

Elevated levels of circulating Met, acetyl-aspartate, and Asn can be detected in T2DM and diabetic kidney disease DKD. Also, elevated circulating Met levels can be used to predict the risk of developing diabetes. H 2 S inhibits glucose-induced insulin release in pancreatic β cells and insulin-stimulated glucose uptake in adipose tissue.

Cystathionine γ-lyase CSE is a key enzyme in H2S synthesis, and the use of CSE inhibitors increases glucose uptake by adipocytes. Meanwhile, MR can also downregulate genes involved in an inflammatory response and immune cell infiltration, such as chemokine receptor CCRs , chemokine ligand 7 CCL7 , IL-1β, IL-6, IFN-γ, and TNF-α.

Over recent years, more and more studies have shown that amino acids in different cells in the TME and their interactions affect tumor immunity and therapeutic effect. Amino acids, transporters, and metabolites participate in tumor immunity through metabolic reprogramming.

In addition, specific amino acid deficiency or the immunosuppressive effect of certain amino acid metabolism can damage the function of immune cells, including effector T cells, in the tumor microenvironment. The function of T cells is closely related to the effect of immunotherapy, chemotherapy and other tumor treatments.

BCAAs have an important role in supporting immune cell function as carbon backbone providers in immune cells. A deficiency of BCAA impairs the immune function of lymphocytes and leukocytes.

A reduction in IFN-γ and IL-2 release from T cells was detected when T cells were co-stimulated with anti-CD3 and anti-CD28 using the Leu analog N-acetyl-Leu amide NALA. There is a subset of immunomodulatory B cells in the TME with TGF-β1 as the main regulatory feature and expressing Leu-tRNA-synthase 2 LARS2.

Depletion of LARS B cell subsets by LARS gene ablation or Leu depletion can inhibit immune escape in CRC. BCAA uptake is dependent on the type I amino acid transporter LAT, and mutations in SLC7A5 and SLC3A2, members of the LAT family, impair BCAA uptake by T cells and inhibit the proliferation and differentiation of Th1, Th17, and CTL cells.

However, high expression of SLC7A5 in tumor cells predicts reduced expression of immune-related genes, reduced immune cell infiltration, and poor efficacy of immunotherapy. Consistent with this phenomenon, the expression level of BCAT m is decreased in tumor tissues.

Increased uptake of BCKAs by M1 macrophages inhibits the phagocytic capacity of M1 macrophages and may therefore produce immunosuppression.

As a nonessential amino acid, cells can supplement Asp via the de novo synthetic pathway. The aspartate synthesis pathway requires the mitochondrial ETC to provide electron acceptors.

When ETC is limited, cells rely on the amino acid transporter SLC1A3 for Asp uptake from the environment. Inadequate mitochondrial Asp production is an important cause of T cell dysfunction, and lack of aspartate inhibits nicotinamide purine dinucleotide NADH production, causing ER expansion and TNF release.

At the same time, Asn can also promote IL-1β secretion by M1 macrophages. Gln is the most abundant and versatile amino acid in the body. In general, the requirement for Gln by immune cells is similar to that of glucose. For example, studies have found that triple-negative breast cancer TNBC competes for Gln uptake in the environment, limiting Gln metabolism in tumor-infiltrating T cells and inhibiting anti-tumor responses.

In contrast, in models with GLS mutations, glutamate metabolism in tumor cells is restricted, which increases Gln concentration in the microenvironment and T-cell uptake and antitumor activity.

V, an inhibitor of Gln transporter SLC1A5, increases intracellular ROS and autophagosome production. Accumulating evidence has shown that arginine has an important role in regulating the function of immune cells.

Human Burkitt B lymphocytes require an adequate arginine concentration for proliferation and maturation. Although the effect of arginine supplementation remains to be tested, many studies have demonstrated that the downregulation of TCR receptor complex subunit CD3ζ in T cells cultured under arginine-restricted conditions leads to the restriction of T cell proliferation.

On the other hand, arginine methylases PRMTS are widely expressed enzymes that catalyze the arginine methylation of proteins. Among them, type I PRMTs PRMT1, PRMT2, PRMT3, PRMT4, PRMT6, and PRMT8 catalyze asymmetric dimethylated arginine to regulate DNA damage and transcriptional regulation, which is closely related to the occurrence and development of tumors.

Applying type I PRMT inhibitor GSK can inhibit PRMTS-mediated epigenetic modification of IFN genes, increase the response of IFN genes to immune signals, and reduce the expression of VEGF in immunosuppressive cells.

In anti PD-1 resistant T cell rejection models, the application of type I PRMT inhibitors PTB or GSK can increase the number of tumor-infiltrating T cells and increase the efficacy of anti-PD-1 therapy.

Met metabolism is involved in a variety of cellular functions, including REDOX, methylation, and immune regulation. A second group of innate lymphoid cells ILC2s has a key role in type II immune response.

Met metabolism is critical for regulating the function of ILC2s. Blockade of Met metabolism or loss of STAT3 significantly inhibits ILC2s function.

MRD inhibited SAM-induced m6A methylation and translation of immune checkpoints such as PD-L1 and V-domain Ig suppressor of T cell activation VISTA in various mouse tumor models such as colorectal cancer and sarcoma. It also increased the number and toxicity of tumor-infiltrating T cells and enhanced antitumor immune responses.

Tregs are characterized by high Met uptake and SAM use. Met metabolism is also essential for Treg survival after IL-2 deprivation, and solute carrier protein SLC43A2 plays a key role in Met uptake and maintenance of Treg growth activity.

One idea is to enhance the activity of amino acid metabolism of CAR-T cells by adding cytokines that promote the expression of transporters related to amino acid metabolism, such as SLC1A5, SLC3A2 and SLC7A5, or directly importing transcripts encoding these AATs into T cells.

In the above modules, we introduced the mechanisms of amino acids, related metabolic enzymes, and metabolites related to the occurrence and development of diseases. In addition, investigators are exploring therapeutic strategies to address this metabolic feature of the disease. Therefore, this section focused on the progress of clinical trials for treating amino acid metabolism in diseases.

AXA and AXA are oral endogenous modulator EMM compositions. AXA contains five amino acids Leu, iLe, valine, arginine, and Gln in specific ratios and the amino acid precursor N-acetylcysteine NAC , while AXA is composed of five amino acids, Leu, iLe, arginine, Gln, and serine, as well as carnitine and NAC.

A multicenter, single-blind, placebo-controlled, randomized clinical study NCT assessed the effect of AXA and AXA on nonalcoholic fatty liver disease NAFLD. Patients were treated with 16 weeks and magnetic resonance imaging MRI -proton density fat fraction [MRI-PDFF] and homeostasis model assessment of insulin resistance [HOMA-IR] and homeostasis model assessment of insulin resistance HOMA-IR fibro-inflammation markers alanine aminotransferase [ALT], corrected T1 [cT1], keratin [K] M65, and N-terminal type III collagen pro-peptide [Pro-C3] was applied.

The results showed that the biological activity of AXA was greater in patients with T2D, compared with placebo. Moreover, a phenotypic study on human primary macrophages and stellate cells suggested that AXA can inhibit lipopolysaccharide LPS -induced TNF-α expression in M1 macrophages and increase the secretion of anti-inflammatory chemokine C-C motif ligands by M2 macrophages, as well as reduced Pro-C3 and HSP47 expression in HSC.

Another Phase 2 study evaluating AXA for the treatment of fatigue after COVID infection has been completed, and a clinical study evaluating the safety, efficacy, and tolerability of AXA in the treatment of nonalcoholic steatohepatitis NASH is ongoing.

Sodium phenylbutyrate targets BCKDK and is an accelerator of BCAA catabolism. In clinical trials on insulin resistance and type 2 diabetes, phenylbutyrate could significantly improve peripheral insulin sensitivity ΔRd Plasma BCAA levels and glucose levels were also decreased Table 1.

α-methyl aromatic amino acids are LAT1 specific, and 18F-labeled 3-fluoro-l-α-methyl-tyrosine FAMT has been used as LAT1 specific probe for cancer detection.

JPH, a LAT1-specific inhibitor designed based on LAT1 ligands, has a strong affinity and does not show obvious toxicity in preclinical studies. In phase I clinical trials, JPH showed excellent inhibition of solid tumors and was well tolerated. In addition to JPH, other drugs currently in preclinical and clinical trials targeting LAT1 include IPA, QBSS, TLXCDx, I-ACD, At-TLX, OKY, [18F] NKO Table 1.

Asn is a mature target for amino acid depletion therapy in tumors. Most compounds that target tumor metabolism methotrexate, 5-fluorouracil fail to distinguish between tumor tissue and rapidly differentiating epithelial tissue skin, bone marrow , 4 , whereas therapies targeting the specific amino acid dependence of tumor cells are cell-selective, such as leukemic blasts that are selectively dependent on Asn, the use of bacterial-derived ASNase in pediatric ALL has significantly improved the cure rate.

In terms of prognosis, the 5-year event-free survival EFS was Treatment with both drugs achieved similar nadir SAA and survival outcomes. Therefore, it is considered that the dosing strategy can be further optimized Table 1.

In addition to the above two drugs, asparaginase-targeting drugs include OP, JZP, ERY, and PF JZP was well tolerated in phase I clinical trials. The presence of arginine-succinate synthetase 1 ASS1 deficienct tumors is arginine-dependent, thus enabling arginine-deprivation therapy.

Pegylated arginase has potential arginine degradation and antitumor activity. After intravenous administration of pegylated arginase, arginine can be metabolized to ornithine and urea, reducing plasma arginine levels.

Pegylated arginine arginase PEG-BCT showed promising tumor suppressive activity, survival advantage, and safety against advanced HCC in phase I clinical trials of combination chemotherapy oxaliplatin and capecitabine.

However, there is a bottleneck in this therapy. An alternative therapeutic approach that has been developed on the basis of this problem is the use of arginase-1 peptide vaccines that activate T cells to target and recognize cells expressing arginase 1.

Recent clinical trials showed good safety of arginase 1 peptide vaccine in patients with refractory solid tumors NCT ADI is an enzyme that catalyzes the interconversion of arginine and citrulline. Pegylated arginine deiminase ADI-PEG , which duplicates arginine and increases tumor stress and cytotoxicity, increased the number of tumor-infiltrating T cells in phase I studies and was safe in combination with anti-PD-1 antibody, but with an increased risk of neutropenia.

In hepatocellular carcinoma HCC studies, ADI-PEG has been shown in early clinical trials to make HCC animal models and patients more sensitive to FOLFOX chemotherapy through arginine depletion.

However, a recent large global, multicenter phase II study of HCC showed that ADI-PRG combined with 5-fluorouracil, leucovorin, and oxaliplatin mFOLFOX6 was associated with an ORR of 9. There was a significant difference in PFS 3. Still, authors suggested that it is more likely to be due to the short median follow-up time and the high proportion of Censored patients.

Limited treatment efficacy and low response rates with this combination led to the early termination of the study. Despite the early termination of the trial, it is interesting to note that 13 of patients had a median duration of response of Type I PRMTs catalyze asymmetric dimethylation of arginine, which is associated with cancer.

The overexpression of arginine methyltransferase 5 PRMT5 in solid and hematological tumors leads to the elevation of the methylation level of arginine residues on functionally related proteins in tumor cells, which affects cell cycle regulation, mRNA splicing, cell differentiation, signal transduction, and other physiological processes.

Current studies are exploring PRMT5 inhibitors as a treatment for PRMT5-dependent tumors. The PRMT5 inhibitor PF inhibited the proliferation of non-small cell lung cancer NSCLC in cells and animal models and dose-dependent reduced symmetrical dimethylarginine SDMA levels.

A phase I clinical trial is ongoing to evaluate JNJ in advanced solid tumors NCT GSK is a reversible type I PRMTs inhibitor that synergistically inhibits tumor growth when combined with PRMT5 inhibitors.

Metabolite 2-methylthiophosphate is an endogenous inhibitor of PRMT5. Deletion of the key catalytic enzyme methylthioadenosine phosphorylase MTAP gene is associated with the sensitivity of GSK, and a current phase II clinical study of GSK in breast cancer has been enrolled NCT Table 1.

GLS supports tumor Gln synthesis. The median PFS was improved compared with placebo PboE 3. Another glutaminase inhibitor, JHU, extensively inhibits Gln-metabolizing enzymes and increases the concentrations of Gln and glucose in the TME by inhibiting glycolysis, relieving the hypoxic state.

The amino acid transporter SLC1A5 ASCT 2 is highly expressed in various tumor tissues and is associated with poor prognosis of cancer. MEDI is a novel antibody-drug coupling compound ADC that couples an ASCT 2 human monoclonal antibody site to a dimer of peroxbenzodiazepine PBD.

In preclinical studies, the drug has shown strong anti-tumor activity and survival advantage in AML, DLBCL, cALL, and Burkitt lymphoma tumor models. In MTAP null tumors, inhibition of Met adenosine transferase 2A MAT2A inhibits Met synthesis of SAM, thereby inhibiting tumor growth.

MAT2A has been proposed as a therapeutic target in tumors with MTAP gene deletion. IDE is another MAT2A inhibitor with low hepatotoxicity and high solubility that has shown potent modulation of SAM and symmetric dimethyarginine SDMA in preclinical studies.

A phase I study to evaluate IDE in solid tumors is currently underway NCT Table 1. Met aminopeptidase METAP is a kind of cytoplasmic enzyme, metal catalytic protein hydrolysis N end Met residue in the newborn. This enzyme has a key role in angiogenesis and is essential for progressing diseases such as solid tumors and rheumatoid arthritis.

The efficacy of evexomostat in inhibiting the angiogenic proteins FGF Fibroblast growth factors and VEGF Vascular endothelial growth factor was validated in a phase I clinical trial in advanced solid tumors NCT Enrollment is ongoing for phase II trials evaluating Evexomostat in metastatic breast cancer and in patients with diabetes NCT; NCT Table 1.

Amino acids metabolism affects multiple levels of cell metabolism and many cell processes, from protein synthesis to epigenetic regulation. These physiological processes are closely related to maintaining cell homeostasis and normal function.

Thus, abnormal amino acid metabolism can contribute to disease development. BCAA includes Leu, iLe, and valine, and all three amino acids participate in the citric acid cycle by producing acyl-CoA derivatives via branched-chain amino acid transferase BCAT , branched-chain α-keto acid dehydrogenase BCKDH , which in a subsequent series of reactions produce acetyl-CoA.

For example, in PDAC and NSCLC, which share the same genetic mutation background KRAS and p53 mutations , BCAA requirements are high but significantly different.

Yet, the exact difference in BCAA requirement between tumors is still not fully understood. Existing evidence suggests that CBP and SIRT4 can promote the ubiquitin-proteasome degradation of BCAT2 by acetylation of BCAT2 at the K44 site in PDAC.

However, on the other hand, studies on the interaction of different cells in the microenvironment have found that CAFs cells have a high metabolism of BCAA and provide BCKA to PDAC cells to assist tumor cells in BCAA metabolism.

Subsets with different preferences for BCAA metabolism have also been found in breast cancer, and further studies are needed to determine whether this is due to differences in tumor cells or the involvement of other cells in the microenvironment.

Aspartate is a nonessential amino acid, but it is also an intrinsic limiting factor in the growth of some tumors. Under hypoxia, the mitochondrial ETC is inhibited, and energy synthesis and Asp synthesis are limited, which leads to the dependence of tumor cells on the environmental uptake of Asp.

The amino acid transporter SLC1A3 has an important role in maintaining Asp concentrations inside tumor cells and antagonizing the therapeutic effects of ASNase. Therefore, limiting Asn metabolism in tumor cells and immunosuppressive cells in the TME and protecting and promoting Asn metabolism in anti-tumor immune cells should be a problem to be solved.

In treating solid tumors, developing more tumor-targeting ASNase is one aspect, and the SLC1A3 inhibitor mentioned earlier also provides an idea to solve this problem. Gln is extensively consumed by intestinal, renal, immune, and tumor cells.

Because SLC7A11 exchanges intracellular glutamate with extracellular cystine, the intracellular glutamate concentration decreases, which leads to more Gln uptake and increased glutaminase activity and making these cells dependent on external Gln. According to the TCGA database, The expression levels of SLC7A11 mRNA in Cervical cancer CESC , Cholangiocarcinoma CHOL , Colonic adenocarcinoma COAD , Esophagus cancer ESCA , Head and neck squamous cell carcinoma HNSC , chromophobe kidney cell carcinoma KICH , Clear cell carcinoma of kidney KIRC , Papillary cell carcinoma of the kidney KIRP , Liver cell carcinoma LIHC , Lung adenocarcinoma LUAD , Squamous cell carcinoma of the lung LUSC , Adenocarcinoma of the pancreas PAAD , Rectum adenocarcinoma READ , Sarcoma SARC , Cutaneous melanoma SKCM , Stomach adenocarcinoma STAD , and Endometrial carcinoma of the flesh UCEC were significantly higher than those in adjacent normal tissues.

These features suggest that SLC7A11 may serve as a promising target for cancer metabolism. Glutaminase GLS , as a key enzyme in tubular aminamide metabolism, has also received extensive attention.

CB, an inhibitor targeting GLS, has shown good tumor inhibition activity, tolerance, and safety in preclinical studies and phase I clinical trials in solid tumors. Cells lacking arginine-succinate synthetase 1 ASS1 are arginine-dependent. ASS1 expression is downregulated in CHOL, GBM, KICH, KIRC, KIRP, and LIHC tumor categories, suggesting the feasibility of arginine depletion therapy.

Analogs targeting arginase and arginine deiminase, the enzymes involved in arginine depletion, have been developed. Using the arginine deiminase analog ADI-PEG in hepatocellular carcinoma and glioblastoma has demonstrated antitumor activity in vitro and in xenograft models and demonstrated safety and efficacy in a phase I clinical trial.

Studying the mechanism of benefit in this group of subjects to seek the precision of treatment should be the next problem to be solved. Pegylated arginase PEG-BCT combined with oxaliplatin and capecitabine has shown satisfactory therapeutic efficacy and safety in phase I clinical trials in solid tumors.

For tumor cells deficient in methythioadenosine phosphorylase MTAP , Met depletion and inhibition of the key enzyme MAT2A in the Met metabolism pathway are possible therapeutic strategies. MAT2A inhibitors AG and IDE have demonstrated significant antitumor activity both in vitro and in animal models, and phase I clinical trials are currently underway.

Currently, amino acid metabolism-targeted therapy still faces many challenges. Adipocytes and bone marrow stromal cells in the TME can promote the resistance of tumor cells to ASNase treatment by supplying Gln and cysteine to leukemia cells, , and cancer-associated fibroblasts can secrete Asp to promote solid tumor growth.

The efficacy of a drug also depends on its ability to reach the tumor site. When the drug fails to reach the tumor site, it fails to induce tumor cell death successfully. In addition, immune and allergic reactions to non-human enzymes can compromise therapy and harm patients.

Decoding the metabolic requirements of amino acids in different tissues and understanding how to target the metabolism and metabolic pathways of these amino acids is indispensable for improving the level of cancer treatment. Horton, H. et al. eds Principles of Biochemistry Pearson Press, Latham, M.

Press, Vettore, L. New aspects of amino acid metabolism in cancer. Cancer , — Article PubMed CAS Google Scholar.

Lieu, E. Amino acids in cancer. Article PubMed PubMed Central CAS Google Scholar. Sun, L. Life-span extension in mice by preweaning food restriction and by methionine restriction in middle age. A Biol. Article PubMed Google Scholar.

Miller, R. Methionine-deficient diet extends mouse lifespan, slows immune and lens aging, alters glucose, T4, IGF-I and insulin levels, and increases hepatocyte MIF levels and stress resistance. Aging Cell 4 , — Orentreich, N. Low methionine ingestion by rats extends life span.

PubMed CAS Google Scholar. Zimmerman, J. Nutritional control of aging. Choi, B. The diverse functions of non-essential amino acids in cancer.

Cancers 11 , Newgard, C. Metabolomics and metabolic diseases: where do we stand? Cell Metab. White, P. Insulin action, type 2 diabetes, and branched-chain amino acids: a two-way street.

Wu, B. Mitochondrial aspartate regulates TNF biogenesis and autoimmune tissue inflammation. Ruzzo, E. Deficiency of asparagine synthetase causes congenital microcephaly and a progressive form of encephalopathy. Alfadhel, M.

Asparagine synthetase deficiency: new inborn errors of metabolism. JIMD Rep. Article PubMed PubMed Central Google Scholar. Ben-Salem, S. Asparagine synthetase deficiency detected by whole exome sequencing causes congenital microcephaly, epileptic encephalopathy and psychomotor delay.

Brain Dis. Palmer, E. Asparagine Synthetase Deficiency causes reduced proliferation of cells under conditions of limited asparagine.

Seidahmed, M. Hyperekplexia, microcephaly and simplified gyral pattern caused by novel ASNS mutations, case report. BMC Neurol. Gataullina, S.

Epileptic phenotype of two siblings with asparagine synthesis deficiency mimics neonatal pyridoxine-dependent epilepsy. Neuropediatrics 47 , — Piao, L. Cardiac glutaminolysis: a maladaptive cancer metabolism pathway in the right ventricle in pulmonary hypertension.

Böger, R. The emerging role of asymmetric dimethylarginine as a novel cardiovascular risk factor. Young, V. Adult amino acid requirements: the case for a major revision in current recommendations.

Furst, P. What are the essential elements needed for the determination of amino acid requirements in humans? Sakami, W. Amino acid metabolism. Brosnan, J.

Glutamate, at the interface between amino acid and carbohydrate metabolism. Forsberg, H. Sensors of extracellular nutrients in Saccharomyces cerevisiae.

Christie, G. Regulation of amino acid transporters by amino acid availability. Care 4 , — Hediger, M. The ABCs of membrane transporters in health and disease SLC series : introduction. Article CAS Google Scholar. Bröer, S. Adaptation of plasma membrane amino acid transport mechanisms to physiological demands.

Pflügers Arch. Hyde, R. Amino acid transporters: roles in amino acid sensing and signalling in animal cells. Kandasamy, P. Amino acid transporters revisited: New views in health and disease.

Trends Biochem. Ou, D. Dietary supplementation with zinc oxide decreases expression of the stem cell factor in the small intestine of weanling pigs.

Marc Rhoads, J. Glutamine, arginine, and leucine signaling in the intestine. Amino Acids 37 , — Jobgen, W. Regulatory role for the arginine-nitric oxide pathway in metabolism of energy substrates.

Galli, F. Amino acid and protein modification by oxygen and nitrogen species. Amino Acids 42 , 1—4 Mannick, J. Regulation of apoptosis by protein S-nitrosylation.

Amino Acids 32 , Liao, X. Growth control via TOR kinase signaling, an intracellular sensor of amino acid and energy availability, with crosstalk potential to proline metabolism.

Amino Acids 35 , — Escobar, J. Regulation of cardiac and skeletal muscle protein synthesis by individual branched-chain amino acids in neonatal pigs.

Meijer, A. Amino acid signalling and the integration of metabolism. Yao, K. Dietary arginine supplementation increases mTOR signaling activity in skeletal muscle of neonatal pigs. Wu, G. Arginine metabolism: nitric oxide and beyond. Sinclair, L. Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation.

Lee, G. Tryptophan deprivation sensitizes activated T cells to apoptosis prior to cell division. Munn, D. GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. Immunity 22 , — Rodriguez, P. L-arginine availability regulates T-lymphocyte cell-cycle progression.

Blood , — Ichihara, A. Transaminase of branched chain amino acids. Branched chain amino acids-alpha-ketoglutarate transaminase. Wolfson, R. Sestrin2 is a leucine sensor for the mTORC1 pathway. Science , 43—48 Buse, M.

In vitro effect of branched chain amino acids on the ribosomal cycle in muscles of fasted rats. Skaper, S. Maple syrup urine disease: branched-chain amino acid concentrations and metabolism in cultured human lymphoblasts. Calder, P. Branched-chain amino acids and immunity. Budhathoki, S. Association of plasma concentrations of branched-chain amino acids with risk of colorectal adenoma in a large Japanese population.

Mayers, J. Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development. Tissue of origin dictates branched-chain amino acid metabolism in mutant Kras-driven cancers. Science , — Lei, M.

Acetylation promotes BCAT2 degradation to suppress BCAA catabolism and pancreatic cancer growth. Signal Transduct. Target Ther.

Li, J. BCAT2-mediated BCAA catabolism is critical for development of pancreatic ductal adenocarcinoma. Cell Biol. Shafei, M. Oncotarget 11 , Holmstrom, S. Protein breakdown precedes pancreatic tumor development.

Zhu, Z. Tumour-reprogrammed stromal BCAT1 fuels branched-chain ketoacid dependency in stromal-rich PDAC tumours. Wang, Y. BCKDK alters the metabolism of non-small cell lung cancer. Lung Cancer Res. Chi, R. Elevated BCAA suppresses the development and metastasis of breast cancer.

Differential expression of the BCAT isoforms between breast cancer subtypes. Breast Cancer 28 , — Zhang, L. Branched-chain amino acid transaminase 1 BCAT1 promotes the growth of breast cancer cells through improving mTOR-mediated mitochondrial biogenesis and function.

Silva, L. EMBO Rep. Zhang, B. Regulation of branched-chain amino acid metabolism by hypoxia-inducible factor in glioblastoma. Cell Mol.

Life Sci. Targeting BCAT1 combined with alpha-ketoglutarate triggers metabolic synthetic lethality in glioblastoma. Cancer Res. Goto, M. Structural determinants for branched-chain aminotransferase isozyme-specific inhibition by the anticonvulsant drug gabapentin.

Conway, M. Regulatory control of human cytosolic branched-chain aminotransferase by oxidation and S-glutathionylation and its interactions with redox sensitive neuronal proteins.

Biochemistry 47 , — Yu, D. The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine. e The BCKDH kinase and phosphatase integrate BCAA and lipid metabolism via regulation of ATP-citrate lyase.

Ma, Q. BCAA—BCKA axis regulates WAT browning through acetylation of PRDM Kitaura, Y. Antihypertensive drug valsartan as a novel BDK inhibitor. Sun, H. Catabolic defect of branched-chain amino acids promotes heart failure.

Ogawa, T. Downregulation of extramitochondrial BCKDH and its uncoupling from AMP deaminase in type 2 diabetic OLETF rat hearts. Plauth, M. Characteristic pattern of free amino acids in plasma and skeletal muscle in stable hepatic cirrhosis.

Hepatogastroenterology 37 , — Holecek, M. Ammonia and amino acid profiles in liver cirrhosis: effects of variables leading to hepatic encephalopathy.

Nutrition 31 , 14—20 van den Berg, E. Non-alcoholic fatty liver disease and risk of incident type 2 diabetes: role of circulating branched-chain amino acids.

Nutrients 11 , Tajiri, K. Branched-chain amino acids in liver diseases. Honda, M. Malnutrition impairs interferon signaling through mTOR and FoxO pathways in patients with chronic hepatitis C.

Gastroenterology , — Singh Tejavath, A. Impact of Branched Chain Amino Acid on Muscle Mass, Muscle Strength, Physical Performance, Combined Survival, and Maintenance of Liver Function Changes in Laboratory and Prognostic Markers on Sarcopenic Patients With Liver Cirrhosis BCAAS Study : A Randomized Clinical Trial.

Alvestrand, A. Plasma and muscle free amino acids in uremia: influence of nutrition with amino acids. Schauder, P. Blood levels of branched-chain amino acids and alpha-ketoacids in uremic patients given keto analogues of essential amino acids.

Kumar, M. Branched chain amino acid profile in early chronic kidney disease. Saudi J. Kidney Dis. PubMed Google Scholar. Suliman, M. Inflammation contributes to low plasma amino acid concentrations in patients with chronic kidney disease.

Grimble, R. Nutritional modulation of immune function. Cano, N. Application of branched-chain amino acids in human pathological states: renal failure.

GDR, H. Nomenclature and symbolism for amino acids and peptides. Pure Appl. Article Google Scholar. Berg, J. eds Biochemistry W. Press , Krall, A. Asparagine promotes cancer cell proliferation through use as an amino acid exchange factor. Matlashewski, G. Isolation and characterization of a human p53 cDNA clone: expression of the human p53 gene.

EMBO J. Isobe, M. Localization of gene for human p53 tumour antigen to band 17p Nature , 84—85 Kern, S. Identification of p53 as a sequence-specific DNA-binding protein.

Deng, L. pmediated control of aspartate-asparagine homeostasis dictates LKB1 activity and modulates cell survival. Garcia-Bermudez, J. Aspartate is a limiting metabolite for cancer cell proliferation under hypoxia and in tumours.

Sullivan, L. Aspartate is an endogenous metabolic limitation for tumour growth. Sun, J. SLC1A3 contributes to L-asparaginase resistance in solid tumors.

Xu, L. Wong, C. SLC25A22 promotes proliferation and survival of colorectal cancer cells with KRAS mutations and xenograft tumor progression in mice via intracellular synthesis of aspartate. Knott, S. Asparagine bioavailability governs metastasis in a model of breast cancer.

Nature , — Gwinn, D. Oncogenic KRAS regulates amino acid homeostasis and asparagine biosynthesis via ATF4 and alters sensitivity to L-asparaginase. Cancer Cell 33 , 91— Hope, H.

JCI Insight 6 , e

Amino Vegetable smoothies are the Vegetable smoothies syntthesis that make up proteins. They join Vegetable smoothies to form short polymer chains called peptides pathwsy longer chains called either synthssis or proteins. These dynthesis are linear and unbranched, with humanns amino acid Bitter orange essential oil the chain attached to two neighboring amino acids. The process of making proteins is called translation and involves the step-by-step addition of amino acids to a growing protein chain by a ribozyme that is called a ribosome. Twenty-two amino acids are naturally incorporated into polypeptides and are called proteinogenic or natural amino acids. Of these, 20 are encoded by the universal genetic code. The remaining two, selenocysteine and pyrrolysine, are incorporated into proteins by unique synthetic mechanisms. Amino acid synthesis pathway in humans core part is the Non-GMO dinner module for aicd of three-carbon compounds from Amino acid synthesis pathway in humans to Amino acid synthesis pathway in humans symthesis M ], together with the pathways Crave-worthy meals serine on glycine. This KEGG module is the most conserved one in the KEGG MODULE lathway and is Amlno in almost all hummans completely apthway genomes. The extensions are the pathways containing the reaction modules RMRMRMand Pathday for biosynthesis of branched-chain amino acids left and basic amino acids bottomand the pathways for biosynthesis of histidine and aromatic amino acids top right. It is interesting to note that the so-called essential amino acids that cannot be synthesized in human and other organisms generally appear in these extensions. Furthermore, the bottom extension of basic amino acids appears to be most divergent containing multiple pathways for lysine biosynthesis and multiple gene sets for arginine biosynthesis. Image resolution: High. Link: Normal Module. Amino acid synthesis pathway in humans

Author: Yobar

5 thoughts on “Amino acid synthesis pathway in humans

Leave a comment

Yours email will be published. Important fields a marked *

Design by