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LncRNA SNHG1 contributes to sorafenib resistance by activating the Akt pathway and is positively regulated by miR in hepatocellular carcinoma cells. Download references. This work was supported by the National Natural Science Foundation of China , , Jiangxi Provincial Natural Science Foundation ACB, BAB , the Training Plan for Academic and Technical Leaders of Major Disciplines in Jiangxi Province BCJ , Science and Technology Project of Jiangxi Provincial Health Commission , the Scientific Research Project of Cultivating Outstanding Young People in First Affiliated Hospital of Nanchang University YQ Jiangxi Institute of Respiratory Disease, The First Affiliated Hospital of Nanchang University, Nanchang City, , Jiangxi, China.

Jiangxi Clinical Research Center for Respiratory Diseases, Nanchang City, , Jiangxi, China. China-Japan Friendship Jiangxi Hospital, National Regional Center for Respiratory Medicine, Nanchang City, , Jiangxi, China.

School of Basic Medical Sciences, Nanchang University, Nanchang City, , Jiangxi, China. Nanchang Vocational University, Nanchang City, , Jiangxi, China.

Department of Critical Care Medicine, Medical Center of Anesthesiology and Pain, The First Affiliated Hospital of Nanchang University, Nanchang City, , Jiangxi, China.

School of Huankui Academy, Nanchang University, Nanchang City, , Jiangxi, China. Department of Burn, The First Affiliated Hospital of Nanchang University, Nanchang City, , Jiangxi, China.

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Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Skip to main content. Cumulative feedback inhibition through end product metabolites; and 4. Alterations of the enzyme due to adenylation and deadenylation.

The taut form of GS is fully active but, the removal of manganese converts the enzyme to the relaxed state. The specific conformational state occurs based on the binding of specific divalent cations and is also related to adenylation.

Glutamine and a regulatory protein called PII act together to stimulate adenylation. The regulation of proline biosynthesis can depend on the initial controlling step through negative feedback inhibition.

coli , proline allosterically inhibits Glutamate 5-kinase which catalyzes the reaction from L-glutamate to an unstable intermediate L-γ-Glutamyl phosphate.

Arginine synthesis also utilizes negative feedback as well as repression through a repressor encoded by the gene argR. The gene product of argR , ArgR an aporepressor , and arginine as a corepressor affect the operon of arginine biosynthesis. The degree of repression is determined by the concentrations of the repressor protein and corepressor level.

Phenylalanine , tyrosine , and tryptophan , the aromatic amino acids , arise from chorismate. Each one of these has its synthesis regulated from tyrosine, phenylalanine, and tryptophan, respectively. The rest of the enzymes in the common pathway conversion of DAHP to chorismate appear to be synthesized constitutively, except for shikimate kinase , which can be inhibited by shikimate through linear mixed-type inhibition.

Tyrosine and phenylalanine are biosynthesized from prephenate , which is converted to an amino acid-specific intermediate.

This process is mediated by a phenylalanine PheA or tyrosine TyrA specific chorismate mutase-prephenate dehydrogenase. PheA uses a simple dehydrogenase to convert prephenate to phenylpyruvate , while TyrA uses a NAD-dependent dehydrogenase to make 4-hydroxylphenylpyruvate.

Both PheA and TyrA are feedback inhibited by their respective amino acids. Tyrosine can also be inhibited at the transcriptional level by the TyrR repressor.

TyrR binds to the TyrR boxes on the operon near the promoter of the gene that it wants to repress. Tryptophan biosynthesis involves conversion of chorismate to anthranilate using anthranilate synthase.

This enzyme requires either glutamine as the amino group donor or ammonia itself. Anthranilate synthase is regulated by the gene products of trpE and trpG.

trpE encodes the first subunit, which binds to chorismate and moves the amino group from the donor to chorismate. trpG encodes the second subunit, which facilitates the transfer of the amino group from glutamine. Anthranilate synthase is also regulated by feedback inhibition: tryptophan is a co-repressor to the TrpR repressor.

Aspartate can be converted into lysine, asparagine, methionine and threonine. Threonine also gives rise to isoleucine. As is typical in highly branched metabolic pathways, additional regulation at each branch point of the pathway.

This type of regulatory scheme allows control over the total flux of the aspartate pathway in addition to the total flux of individual amino acids.

The aspartate pathway uses L-aspartic acid as the precursor for the biosynthesis of one fourth of the building block amino acids. The enzyme aspartokinase , which catalyzes the phosphorylation of aspartate and initiates its conversion into other amino acids, can be broken up into 3 isozymes, AK-I, II and III.

AK-I is feed-back inhibited by threonine , while AK-II and III are inhibited by lysine. As a sidenote, AK-III catalyzes the phosphorylation of aspartic acid that is the committed step in this biosynthetic pathway.

Aspartate kinase becomes downregulated by the presence of threonine or lysine. Lysine is synthesized from aspartate via the diaminopimelate DAP pathway. The initial two stages of the DAP pathway are catalyzed by aspartokinase and aspartate semialdehyde dehydrogenase.

These enzymes play a key role in the biosynthesis of lysine , threonine , and methionine. Transcription of aspartokinase genes is regulated by concentrations of the subsequently produced amino acids, lysine, threonine, and methionine.

The higher these amino acids concentrations, the less the gene is transcribed. ThrA and LysC are also feed-back inhibited by threonine and lysine. Finally, DAP decarboxylase LysA mediates the last step of the lysine synthesis and is common for all studied bacterial species.

The formation of aspartate kinase AK , which catalyzes the phosphorylation of aspartate and initiates its conversion into other amino acids, is also inhibited by both lysine and threonine , which prevents the formation of the amino acids derived from aspartate.

Additionally, high lysine concentrations inhibit the activity of dihydrodipicolinate synthase DHPS. So, in addition to inhibiting the first enzyme of the aspartate families biosynthetic pathway, lysine also inhibits the activity of the first enzyme after the branch point, i.

the enzyme that is specific for lysine's own synthesis. The biosynthesis of asparagine originates with aspartate using a transaminase enzyme. The enzyme asparagine synthetase produces asparagine, AMP , glutamate, and pyrophosphate from aspartate, glutamine , and ATP.

In the asparagine synthetase reaction, ATP is used to activate aspartate, forming β-aspartyl-AMP. Glutamine donates an ammonium group, which reacts with β-aspartyl-AMP to form asparagine and free AMP. Two asparagine synthetases are found in bacteria.

Both are referred to as the AsnC protein. They are coded for by the genes AsnA and AsnB. AsnC is autogenously regulated, which is where the product of a structural gene regulates the expression of the operon in which the genes reside.

The stimulating effect of AsnC on AsnA transcription is downregulated by asparagine. However, the autoregulation of AsnC is not affected by asparagine. Biosynthesis by the transsulfuration pathway starts with aspartic acid.

Relevant enzymes include aspartokinase , aspartate-semialdehyde dehydrogenase , homoserine dehydrogenase , homoserine O-transsuccinylase , cystathionine-γ-synthase , Cystathionine-β-lyase in mammals, this step is performed by homocysteine methyltransferase or betaine—homocysteine S-methyltransferase.

Methionine biosynthesis is subject to tight regulation. The repressor protein MetJ, in cooperation with the corepressor protein S-adenosyl-methionine, mediates the repression of methionine's biosynthesis.

The regulator MetR is required for MetE and MetH gene expression and functions as a transactivator of transcription for these genes.

MetR transcriptional activity is regulated by homocystein, which is the metabolic precursor of methionine. It is also known that vitamin B12 can repress MetE gene expression, which is mediated by the MetH holoenzyme.

In plants and microorganisms, threonine is synthesized from aspartic acid via α-aspartyl-semialdehyde and homoserine. Homoserine undergoes O -phosphorylation; this phosphate ester undergoes hydrolysis concomitant with relocation of the OH group.

The biosynthesis of threonine is regulated via allosteric regulation of its precursor, homoserine , by structurally altering the enzyme homoserine dehydrogenase. This reaction occurs at a key branch point in the pathway, with the substrate homoserine serving as the precursor for the biosynthesis of lysine, methionine, threonin and isoleucine.

High levels of threonine result in low levels of homoserine synthesis. The synthesis of aspartate kinase AK , which catalyzes the phosphorylation of aspartate and initiates its conversion into other amino acids, is feed-back inhibited by lysine , isoleucine , and threonine , which prevents the synthesis of the amino acids derived from aspartate.

So, in addition to inhibiting the first enzyme of the aspartate families biosynthetic pathway, threonine also inhibits the activity of the first enzyme after the branch point, i.

the enzyme that is specific for threonine's own synthesis. In plants and microorganisms, isoleucine is biosynthesized from pyruvic acid and alpha-ketoglutarate. Enzymes involved in this biosynthesis include acetolactate synthase also known as acetohydroxy acid synthase , acetohydroxy acid isomeroreductase , dihydroxyacid dehydratase , and valine aminotransferase.

In terms of regulation, the enzymes threonine deaminase, dihydroxy acid dehydrase, and transaminase are controlled by end-product regulation. the presence of isoleucine will downregulate threonine biosynthesis.

High concentrations of isoleucine also result in the downregulation of aspartate's conversion into the aspartyl-phosphate intermediate, hence halting further biosynthesis of lysine , methionine , threonine , and isoleucine.

coli , the biosynthesis begins with phosphorylation of 5-phosphoribosyl-pyrophosphate PRPP , catalyzed by ATP-phosphoribosyl transferase. Phosphoribosyl-ATP converts to phosphoribosyl-AMP PRAMP. His4 then catalyzes the formation of phosphoribosylformiminoAICAR-phosphate, which is then converted to phosphoribulosylformimino-AICAR-P by the His6 gene product.

After, His3 forms imidazole acetol-phosphate releasing water. His5 then makes L -histidinol-phosphate, which is then hydrolyzed by His2 making histidinol. His4 catalyzes the oxidation of L -histidinol to form L -histidinal, an amino aldehyde.

Cell Communication and Signaling volume Amino acid metabolism regulationRegulationn number: 87 Cite this article. Metrics details. Metabolic reprogramming is one of metabokism main characteristics of cancer cells and plays pivotal Amino acid metabolism regulation Nutritional support for injury prevention the proliferation metabolismm survival revulation cancer cells. Amino Anti-viral treatments is one of the key nutrients for cancer cells and many studies have focused on the regulation of amino acid metabolism, including the genetic alteration, epigenetic modification, transcription, translation and post-translational modification of key enzymes in amino acid metabolism. Long non-coding RNAs lncRNAs are composed of a heterogeneous group of RNAs with transcripts of more than nucleotides in length. LncRNAs can bind to biological molecules such as DNA, RNA and protein, regulating the transcription, translation and post-translational modification of target genes. Now, the functions of lncRNAs in cancer metabolism have aroused great research interest and significant progress has been made. Amino acids play several Caloric intake and food labels roles metabopism plants, from acod the building blocks of proteins Regulatiion being essential metabolites interacting ackd many branches aciid metabolism. They are also important molecules that shuttle organic regukation Amino acid metabolism regulation the plant. Acis of this anxiety management techniques role in nitrogen metabolism, amino acid biosynthesis, ketabolism, and transport are tightly regulated to meet meatbolism in response to nitrogen and carbon availability. While much is known about the feedback regulation of the branched biosynthesis pathways by the amino acids themselves, the regulation mechanisms at the transcriptional, post-transcriptional, and protein levels remain to be identified. This review focuses mainly on the current state of our understanding of the regulation of the enzymes and transporters at the transcript level. Current results describing the effect of transcription factors and protein modifications lead to a fragmental picture that hints at multiple, complex levels of regulation that control and coordinate transport and enzyme activities. It also appears that amino acid metabolism, amino acid transport, and stress signal integration can influence each other in a so-far unpredictable fashion.

Amino acid metabolism regulation -

In recent years, the interaction between tumor cell metabolism and immunity has become the focus of our understanding of tumor immune evasion. Many studies have found that changes in amino acid metabolism can affect both tumor and T cells in the TME, leading to tumor immune escape Fig.

In response to this finding, strategies targeting amino acids to enhance tumor immunotherapy have been proposed. A preclinical study has found that blocking CTLA-4 in conjunction with the inhibition of indoleamine 2, 3-dioxygenase IDO , a key enzyme in tryptophan metabolism, significantly enhanced the antitumor effect of anti-CTLA-4 antibodies [ 19 ].

In addition, inhibitors of IDO combined with CAR-T cells can restore the control of IDO-positive tumors [ 20 ]. Therefore, combination immunotherapy with targeted amino acid metabolism is a promising strategy to enhance immunotherapy. Schematic diagram summarizing the bridge between amino acid metabolism and T cell.

A In the TME, T cells compete with tumor cells for amino acids. B Amino acid metabolism mainly affects T cell immunity through three aspects, including amino acid depletion caused by nutrient competition, toxic metabolites and crosstalk with glucose metabolism and lipid metabolism.

C Amino acid metabolism can affect glucose metabolism and lipid metabolism. On the one hand, amino acids regulate the activity of enzymes related to glucose metabolism or glucose transport. On the other hand, the intermediates of amino acid metabolism can directly act as substrates for glucose metabolism or lipid metabolism.

Abbreviations: TME, tumor microenvironment; ONOO-, peroxynitrite; IL-2R, IL-2 receptor; PTMs, post-translational modifications; TCA cycle, tricarboxylic acid cycle; α-KG, α-ketoglutarate; OXPHOS, oxidative phosphorylation; GLUT, glucose transporter; PKM2, pyruvate kinase isozymes M2; PEP, phosphoenolpyruvate; LDH-A, lactate dehydrogenase A; IDO1, indoleamine 2, 3-dioxygenase 1.

Given that the relationship between amino acid metabolism and T cells has not been thoroughly reviewed, we describe the crosstalk between amino acid metabolism and the immunosuppressive microenvironment as well as the feasibility and limitations of targeted amino acid metabolism therapy and combination therapy, which will contribute to the development of new cancer treatment strategies.

In tumor tissues, owing to the high concentration of growth factors, the activation of key intracellular signaling molecules, such as c-Myc [ 21 ] and E2F [ 22 ] increases the expression of amino acid transporters, leading to the high uptake of amino acids by tumor cells and the depletion of amino acids.

Nutrient limitation in the TME provides an environment in which immune, stromal, and cancer cells must compete for nutrients for biosynthesis, bioenergy, and effector functions. Immune cells are often not adapted to nutrient competition, which is the main mechanism regulating antitumor immunity [ 23 ].

T cells have received the most attention as the main tumor killer. The deleterious effects of arginine starvation on human T cells were first described in [ 24 ].

Arginine consumption has been found to lead to the inhibition of T cell activation under phytohemagglutinin stimulation. An increasing number of studies have shown that complex and diverse mechanisms are involved in the effects of amino acid starvation and T-cell immunity Fig.

Nutrient competition affects T cells through a variety of mechanisms. Nutrient competition leads to amino acid depletion, which inhibits mTOR and activates GCN2, alters PD-1 expression, and affects epigenetic and post-translational modifications. Together, these pathways affect T cell protein translation, growth, proliferation, differentiation, activation, and effector function.

Abbreviations: 4E-BP1, EIF4E-binding protein; S6K1, p70 S6 kinase; eIF2α, eukaryotic initiation factor 2; cdk4, cyclin-dependent kinase 4; NT, nitration of tyrosine; ONOO-, peroxynitrite; mPGES1, microsomal prostaglandin E synthetase 1; UDP-GlcNAc, uridine diphosphate n-acetyl glucosamine; IL-3R, IL-3 receptor; GlcNP, glucosaminephosphate; Ac, acetyl; T, Thymine; Me, methyl; C, Cytosine; SAM, S-adenosyl methionine; α-KG, α-ketoglutarate.

Nutrient deficiency is a selective stress that shapes the evolution of most cellular processes [ 25 ]. Because amino acids play a crucial role in maintaining cellular homeostasis, different species have developed different mechanisms to detect amino acid abundance over the course of evolution.

Eukaryotic cells are equipped with nutrient sensors such as mTOR, a conserved serine-threonine kinase that is activated when amino acids are abundant and regulates various anabolic processes required for growth [ 26 ].

Through binding with protein binding partners, mTOR can form mTOR complex 1 mTORC1 or mTOR complex 2 mTORC2 [ 27 ]. In conclusion, as the core component of mTORC1 and mTORC2, mTOR plays a key role in amino acid metabolism and immunity [ 33 ].

Not all amino acids can regulate mTOR activity; only leucine, arginine, lysine, glutamine, methionine, and tryptophan can regulate mTOR activity [ 34 , 35 , 36 , 37 , 38 ]. Inhibition of mTOR affects protein translation, cell proliferation, differentiation, effector functions, and many other factors.

Protein translation is regulated by mTOR through two independent mechanisms: inactivation of the EIF4E-binding protein 4E-BP1 and activation of p70 S6 kinase S6K1 [ 39 ].

Polyamine metabolism is affected by mTOR by influencing ODC translation, which plays an important role in T cell activation and differentiation [ 41 ]. T cell proliferation is regulated by mTOR through two pathways. On the one hand, inhibition of mTOR activity impairs the activation of the c-Myc signaling pathway, leading to metabolic stress and defective T cell proliferation [ 42 ].

On the other hand, mTOR forms an intracellular complex with the serine-threonine kinase aurora B and survivin from the costimulatory molecule CD28, which is responsible for allowing the G1-S transition in antigen-stimulated T cells [ 43 ]. Inhibition of mTOR promotes differentiation of T cells into immunosuppressive Tregs.

One Study has shown that mTOR inhibition promotes Treg production via Rag and Rheb GTPases [ 35 ]. In conclusion, mTOR inhibition induced by amino acid deprivation shifts the balance between Th1 and Treg production toward the Treg phenotype.

GCN2 is another eukaryotic amino acid sensor that, unlike mTOR, directly senses the depletion of individual essential or nonessential amino acids in cells by binding to uncharged cognate tRNAs [ 45 ].

In eukaryotes, the GCN2 and mTOR pathways are major regulatory switches that determine protein synthesis in response to fluctuations in amino acid levels [ 26 ].

In contrast to the mTOR regulatory mechanism, the absence of any amino acids activates GCN2 kinase activity [ 36 ].

As eukaryotic amino acid sensors, GCN2 and mTOR have similar effects on T cell function. GCN2 also regulates protein translation, proliferation, differentiation, and effector functions of T cells.

The effect of GCN2 activation is mainly mediated by phosphorylation of the downstream target eukaryotic initiation factor 2 eIF2α. Amino acid depletion triggers signaling through GCN2 kinase and inhibits cyclin D3 [ 46 ] and cyclin-dependent kinase 4 CDK4 through eIF2α phosphorylation, leading to reduced Rb protein phosphorylation, low E2F1 expression, and cell cycle arrest [ 47 , 48 ].

Furthermore, phosphorylated eIF2α fails to bind to methionyl tRNA, which blocks the translation initiation of most mRNAs [ 52 ], but selectively enhances the translation of a few transcripts, such as activating transcription factor 4 ATF4 [ 36 ].

Specifically for T cells, ATF4 promotes metabolism reprogramming of T cells, including upregulation of glycolysis, oxidative phosphorylation, and glutaminolysis, thus providing substrates and energy for anabolism [ 53 ]. The increase in ATF4 translation has a protective effect on T cells and partially neutralizes the adverse effects of amino acid depletion on T cells to a certain extent.

In conclusion, GCN2 appears to promote formation and immunosuppressive activity of Tregs, as well as inhibit effector T cells. PD-1 and PD-L1 are extensively studied immune checkpoints. PD-1 is expressed on T cells, and its cognate ligand PD-L1 is expressed on target cells such as cancer cells.

Binding of PD-1 to PD-L1 leads to inhibition of TCR-related signaling molecules, resulting in T cell depletion and protection of target tissues from T cell-mediated damage [ 57 ]. Under glutamine restriction, the level of intracellular glutathione GSH decreased, which led to the upregulation of PD-L1 in tumor cells, and then inhibited T cell activity [ 60 ].

The relationship between glutamine and PD-L1 is also demonstrated by the fact that upregulated PD-L1 can return to normal levels after glutamine recovery [ 61 ]. In addition, multiple amino acid deletions inhibit mTOR activity and Akt phosphorylation, leading to Forkhead box O FOXO transcription factor activation and upregulation of PD-1 expression in Tregs.

Subsequently, PD-1 binds to the ligand, activates the lipid phosphatase phosphatase with tensin homology PTEN in Tregs, inhibits phosphatidylinositol 3-kinase PI3K activity, and blocks phosphorylation at another Akt activation site to maintain Akt inhibition, forming a feedback loop [ 64 ].

This initiates a stable state of self-sustaining inhibition in Tregs, which is maintained by the circulation between PD-1 and Akt, leading to the sustained suppression of antitumor immunity. In conclusion, amino acid depletion can lead to the upregulation of PD-L1 and PD-1 thereby inhibiting antitumor immunity.

To prevent aberrant signaling that may adversely affect cell homeostasis, protein expression and activity must be strictly regulated. These regulatory mechanisms include epigenetic modifications of the genome and PTMs of proteins that determine the translational ability of transcripts and function of proteins, respectively.

The core of epigenetics is the modification of histones and nucleic acids, which together regulate chromatin structure and gene expression, and produce genetic phenotypic changes without altering the DNA sequence [ 65 ].

Downstream of epigenetics is an additional level of regulation called PTM, which allows for the most refined and dynamic control of protein biology, including localization, conformation, interaction, and activation [ 66 ].

Amino acids are involved in a variety of epigenetic processes and PTMs associated with T-cell immunity Table 1. The main epigenetic modifications involved in amino acid metabolism are methylation, demethylation, and acetylation.

The methylation of DNA and histones is dependent on methionine because its metabolite S-adenosyl methionine SAM is a universal methyl donor [ 37 ].

Proline plays a role in epigenetic regulation by inducing specific histone methylation patterns [ 67 ]. DNA methylation can be reversed by removal of oxidized methylated bases by Tet proteins, a process that requires α-ketoglutaric acid α-KG [ 68 ].

α-KG is a TCA cycle intermediate, and glutamine is the main source of α-KG when glucose is scarce [ 73 ]. A recent study found that glutamine depletion is accompanied by a decrease in α-KG, which inhibits histone demethylation [ 74 ].

Histone acetyltransferases use acetyl-CoA to provide acetyl groups for acetylation. Glutamine and branch chain amino acids can be metabolized to produce acetyl-CoA [ 37 ]. The absence of these amino acids affects important cellular signaling pathways.

PTMs involving amino acids include hypusination, nitrosylation, O-GlcNAcylation, and glycosylation. These modifications modulate immune processes through various mechanisms, including regulating the activity of enzymes or signaling molecules, altering protein interactions, determining subcellular localization, and controlling protein translation.

Hypusine is a modified lysine formed by the reaction of lysine with spermidine [ 75 ]. SAM generated from methionine can be further transformed into spermidine, and hypusination mediated by it occurs only on the translation initiation factor eukaryotic initiation factor 5A eIF5A [ 69 ].

As a highly conserved protein, eIF5A is required for the elongation of the translation of specific mRNA transcripts and affects protein expression in a variety of immune cells [ 76 ].

Glucose and glutamine can be metabolized to uridine diphosphate n-acetyl glucosamine UDP-GlcNAc , a substrate for O-GlcNAcylation. O-GlcNAcylation is one of the most abundant PTMs [ 38 ]. Many signaling molecules regulated by O-GlcNAcylation are fundamental to T cell survival and biological function, such as c-Myc, NFAT, and NF-κB [ 38 , 79 , 80 ].

Among them, c-Myc plays a crucial role in the clonal expansion and effector function of T cells [ 81 ], whereas NFAT [ 82 ] and NF-κB [ 83 ] signal transduction are key regulators of T-cell activation. Glutamine is required for N-linked glycosylation and is essential for protein stability and function.

Aberrant glycosylation has been observed to affect cell proliferation and growth, as in the IL-3 receptor, where abnormal branching of the sugar chain leads to altered downstream signaling [ 71 ].

The depletion of amino acids leads to the weakening of glycosylation of proteins and lipids, thus affecting the function of many proteins. There is increasing recognition that in addition to synthesizing proteins and peptides, some amino acids can act as signaling molecules and regulate key metabolic pathways that are necessary for immunity [ 84 ].

When amino acids are depleted, these biological processes can be directly inhibited, resulting in a disordered cell structure and function. Amino acids are involved in the synthesis of many substances such as nucleotides, SAM, and GSH.

Methionine is mainly involved in SAM synthesis and regulates epigenetic inheritance. Serine and glutamine are also involved in nucleotide synthesis.

GSH is the most abundant antioxidant, and is synthesized from glycine, glutamate, and cysteine. Cysteine is a rate-limiting substrate of GSH synthesis [ 37 ]. GSH deficiency increases reactive oxygen species ROS and disrupts intracellular redox homeostasis, thereby affecting cell survival and function.

Because of the different degrees of oxidative stress in Tregs and Th17 cells, GSH deficiency can promote Treg differentiation and inhibit Th17 differentiation, resulting in an imbalance between Treg and Th17 differentiation [ 88 ].

Amino acid deficiency can directly affect the expression levels of genes and downstream proteins that are closely related to the function of T cells. One previous study showed that T cells exhibit glutamine-dependent expression of cell surface activation markers CD25, CD45RO, and CD71, as well as IFN-γ and TNF-α production [ 89 ].

Besides this, glutamine deficiency in hepatocellular carcinoma upregulates the expression of LAG3 and induces functional failure of γδT cells, which are involved in mediating antitumor responses and are associated with positive prognosis [ 90 ].

Immune cell proliferation and function occur through activation of key enzymes and proteins. Amino acid deficiency or some amino acid metabolizing enzymes can also directly affect the activity of these proteins or enzymes.

Glutamine depletion leads to decreased activity of extracellular signal-regulated kinase ERK and c-Jun amino-terminal kinase JNK kinases, which further results in inhibited transcription of proliferation-related genes [ 91 ].

Arginine deprivation reduces F-actin content and CD2 and CD3 accumulation in T cell immune synapses by impinging on cofilin dephosphorylation, ultimately reducing proliferation and cytokine synthesis [ 92 ]. High consumption of amino acids by tumor cells is accompanied by the production of toxic metabolites, which have been shown to exert inhibitory effects on T cell immunity.

This ultimately leads to the biosynthesis of the cofactor nicotinamide adenine dinucleotide NAD [ 95 ]. This metabolic pathway produces metabolites, including Kyn, 3-hydroxykynurenine 3-HK , 3-hydroxyanthranilic acid 3-HAA , and quinolinic acid, all of which are collectively known as kynurenines.

Among them, Kyn is the most widely studied protein associated with antitumor immunity. Tryptophan is catalyzed to Kyn by IDO1, IDO2, or tryptophan 2, 3-dioxygenase TDO , and is the rate-limiting enzyme in this process [ 96 ].

Because IDO1 has the highest expression level and activity, many studies have identified IDO1 as a major cause of tryptophan depletion [ 97 , 98 ]. On the one hand, Kyn can directly produce toxic effects on immune cells, inhibit the proliferation of T cells and induce their apoptosis. By arresting the cell cycle in the middle of the G1 phase, Kyn selectively inhibits proliferation of activated T cells, whereas resting T cells are unaffected and subsequently activate normally [ 99 ].

This inhibitory effect on T cell proliferation is concentration-dependent [ ]. Simultaneously, Kyn can lead to changes in the intracellular redox balance and induce cell apoptosis through ROS production [ ].

On the other hand, Kyn, as an endogenous aryl hydrocarbon receptor AhR agonist, contributes to immunosuppression of the TME and supports tumor immune escape. In Th17 cells, AhR activation promotes downstream IL production and differentiation [ ].

In addition, activated AhR controls the transcriptional program associated with tolerant DCs [ ], which in turn inhibits T-cell immune activity. Of note, many in vitro experiments have used much higher concentrations of Kyn than the actual in vivo concentrations.

The concentration of Kyn in human tumors is only in the low micromolar range, well below the 1 mM required to induce T cell apoptosis in vitro [ ], which calls into question its clinical significance.

However, treatment of mice with specific Kyn-depleting enzymes improved tumor growth and enhanced immunotherapy, suggesting that in vivo concentrations of Kyn-depleting enzymes may still be clinically relevant [ 98 ].

Further in vivo experiments are needed to verify the specific effects of Kyn. Other products of the Kyn metabolic pathway, such as 3-HAA and 3-HK, also have immunosuppressive effects.

In addition, 3-HAA stimulated TGF-β production and promoted Treg formation [ ]. Notably, 3-HAA can induce selective apoptosis of Th1 cells by promoting the release of cytochrome C and activation of caspase 8 [ , ] and mediate apoptosis via ROS production [ ]. On the one hand, arginine produces ornithine through the urea cycle, and ornithine is used to synthesize polyamines, which are important for T cell growth [ 37 ].

NO can block T cell function by interfering with the IL-2 receptor signaling pathway, thereby preventing the activation of multiple signaling molecules, including STAT5, Erk, and Akt [ ].

As mentioned in Sect. In addition, owing to its strong oxidizing effect, it can inhibit the activation-induced protein tyrosine phosphorylation or through nitration, inhibit a component of the mitochondrial permeability transition pore causing the release of cytochrome C and other death promoting factors, resulting in T cell apoptosis induction [ ].

In addition, cancer cells with abnormal glutamate decarboxylase 1 expression can use glutamine to synthesize gamma-aminobutyric acid GABA [ ]. A main function of GABA is as an important neurotransmitter; in tumor tissues, GABA can activate the GABAB receptor and inhibit the activity of GSK-3β, resulting in enhanced β-catenin signaling [ ].

In conclusion, amino acid metabolism plays a significant negative regulatory role in T cell immunity. On the one hand, amino acid depletion inhibits immune cell function in many aspects; on the other hand, some toxic metabolites accumulate in the TME, further inhibiting T cell immunity and causing immune tolerance.

Different subgroups of T cells depend on different metabolic pathways and the metabolism of T cells in different states is not the same. Compared to resting T cells, after activation, glycolysis, pentose phosphorylation, and glutamine decomposition increased and fatty acid oxidation decreased in T cells [ ].

Specifically for glucose metabolism, activated T cells show a relatively reduced dependence on oxidative phosphorylation OXPHOS and an increased need for glycolysis [ ]. Thus, a normal and desirable metabolic state is essential for T cells to function.

Amino acid metabolism can regulate the metabolism of other nutrients such as fat and sugar, ultimately leading to changes in the overall metabolism of T cells and inhibition of function.

Amino acid metabolism has the most significant effect on glucose metabolism. Metabolized amino acids can be converted into substrates in the glucose metabolic pathway to regulate glucose metabolism directly.

The process can also regulate the enzyme activity of the glucose metabolic pathway and glucose transporters to have an indirect impact on glucose metabolism.

A direct effect is achieved through the TCA cycle. Amino acids such as alanine, tryptophan, and serine can be converted to pyruvate, which partly promotes glycolysis and produces lactic acid for quick energy production [ ].

Indirect regulation is a complex process. Many amino acids regulate sugar metabolism. Serine is an allosteric activator of pyruvate kinase isozymes M2 PKM2 and supports aerobic glycolysis and lactic acid production by binding and activating PKM2 [ ], which is essential for T cell function.

Leucine and isoleucine were found to boost glucose uptake by increasing cell-surface glucose transporters [ ]. In addition, leucine can be converted to acetyl-CoA, which can acetylate and activate mTORC1, further enhancing glycolysis [ ].

The increase in arginine concentration promoted gluconeogenesis and the TCA cycle, whereas downregulated glucose transporters and glycolytic enzymes. These changes promote T cell OXPHOS and downregulate T cell activation-dependent glycolysis [ ].

In addition, the tryptophan-metabolizing enzyme, IDO1, induces p53 expression and then inhibits glucose transporters and glycolysis [ ]. At the same time, IDO1 inhibits lactate production by decreasing lactate dehydrogenase A LDH-A levels [ ].

Also through the downregulation of glutaminase 2 GLS2 , IDO1 blocks the supply of glutamate, a substrate for the TCA cycle, making T cells more starved [ ]. These changes ultimately inhibited T cell proliferation. In addition to affecting glucose metabolism, amino acids regulate lipid metabolism.

Glutamine metabolism produces α-KG, which is involved in fatty acid synthesis. Inhibition of glutamine uptake has been shown to reduce fatty acid synthesis and basal oxygen consumption [ ].

Serine and glycine are necessary precursors for the synthesis of lipids [ ], which are essential for cell growth, because the rapid proliferation of activated T cells relies on lipids to provide cell membranes.

Considering the important role of amino acids in tumors and the significant differences in amino acid requirements between tumor and T cells, targeted amino acid metabolism is reasonable for tumor therapy.

Various targeted amino acid therapy strategies have been proposed, including 1 depletion of extracellular amino acid pools to inhibit amino acid uptake, 2 inhibition of amino acid transporters to reduce intracellular amino acid transport, 3 use of amino acid antagonists or amino acid-metabolizing enzyme inhibitors to inhibit amino acid metabolism, and 4 decomposition of toxic metabolites or inhibition of their downstream pathways Fig.

Among these, based on the first strategy, asparaginase has been successfully used in the treatment of ALL. In addition, a variety of drugs, such as the inhibitors of arginase, PEG-Arg I BCT [ ] and ADI-PEG20 [ ], are currently in phase III clinical trials and are expected to achieve clinical conversion soon.

The mechanism diagram illustrates targets for targeted amino acid metabolism and immunotherapy. Amino acid degrading enzymes can deplete extracellular amino acid pools.

Amino acid transport inhibitors inhibit amino acid transport into cells. Amino acid antagonists and inhibitors of amino acid metabolizing enzymes can inhibit amino acid metabolism and exert biological functions. Kyn degrading enzyme and AhR antagonist inhibit the toxic effects of Kyn on T cells from upstream and downstream, respectively.

mTOR or GCN2 inhibitors can enhance efficacy in combination with drugs that target amino acid metabolism. The use of amino acid metabolism in ICB or CAR-T therapy can enhance immunotherapy efficacy.

Abbreviations: ARG, arginase; iNOS, inducible nitric oxide synthase; PTEN, phosphatqase and tensin homologue; PI3K, phosphatidylinositolkinase; ONOO-, peroxynitrite; ICB, immune checkpoint block; CAR, chimeric antigen receptor.

Following the revelation of the complex relationship between amino acid metabolism and T cells, strategies for combining targeted amino acid metabolism with immunotherapy, including ICB and adoptive cell therapy, have been proposed Fig. Enhanced immunotherapy can be achieved in combination with the above amino acid-targeting agents or by reshaping the amino acid metabolism in CAR-T cells.

To date, these studies have been conducted extensively, with several combination strategies already in clinical trials. Because amino acids are critical, it is no surprise that cancer cells are highly dependent on the external supply of amino acids to maintain amino acid homeostasis. In contrast, owing to the increased nutritional requirements, tumor cells express higher levels of amino acid transporters and have higher amino acid metabolic activity than normal cells [ ].

Thus, limiting the availability of amino acids should have specific adverse effects on tumor cells, whereas normal cells should remain mostly unaffected. Therefore, amino acid starvation therapy proposed on this basis is an attractive treatment option.

Targeting amino acid metabolism in tumor cells is expected to disrupt the intracellular metabolic balance and tumor cytoskeleton, inhibit tumor cells, and relieve the inhibitory effect of amino acid depletion on T cells.

Leukemia cells are highly dependent on extracellular asparagine because of a deficiency in asparagine synthase, the only enzyme capable of asparagine synthesis [ ].

L-asparaginase, which directly targets asparagine metabolism, has been successfully used in chemotherapy for ALL [ 72 ]. The successful application of asparaginase demonstrates the feasibility of targeting amino acid metabolism and is expected to promote the clinical transformation of metabolic enzyme-based amino acid deprivation therapy.

Similar to dependence of leukemia cells on exogenous asparagine, some solid tumors, including melanoma and hepatocellular carcinoma, depend on extracellular arginine for survival owing to the lack of de novo synthesis of arginine [ ].

Therefore, two polyethylene glycol PEG -conjugated arginine decomposers have been developed to deplete the extracellular arginine pool.

PEG functional modification can reduce its immunogenicity, prolong its blood circulation time and half-life in vivo, and improve its antitumor effect in vivo. PEG-Arg I BCT can convert arginine to ornithine, resulting in rapid depletion of extracellular and intracellular arginine libraries and reduced proliferation of tumor cells after monotherapy [ ].

However, PEG-Arg I inhibited T cell proliferation and blocked T cell responses indirectly by inducing accumulation of bone marrow-derived suppressor cells MDSCs. Therefore, L-arginine depletion therapy has a dual role in cancer therapy, with a risk of immunosuppression.

ADI-PEG20, another drug that converts arginine to citcitine, has an unsatisfactory therapeutic effect because of the increased compensatory production of endogenous arginine caused by the overexpression of arginine succinic synthase 1 after monotherapy; however, it can achieve a certain effect in arginine succinic synthase 1-deficient tumor cells [ ].

In addition, cystine or cysteine therapy leads to intracellular GSH depletion and ROS accumulation by increasing AMPK phosphorylation and decreasing mTOR phosphorylation, resulting in cell cycle arrest and cell death in various cancers [ ].

Amino acid transmembrane transport is mediated by various amino acid transport systems within the solute carrier SLC superfamily [ ]. More than 60 SLC proteins have been identified as amino acid transporters [ ].

The relationship between amino acids and their transporters is complex. An amino acid can be transported by several different transporters, whereas a transporter passes through multiple amino acids [ ].

In addition, tumor cells and immune cells have different expression levels of the same transporter [ 72 ].

In tumor cells, the imbalance of amino acid transporters leads to metabolism reprogramming, which changes the intracellular amino acid level and is an important mechanism leading to tumor development [ ].

Therefore, amino acid transporters are reliable targets for tumor therapy. Among the upregulated amino acid transporters in cancer cells, LAT1 SLC7A5 is notable for cancer-specific expression. LAT1 transports almost all the neutral amino acids.

BCH 2-aminobicyclo- 2,2,1 -heptanecarboxylic acid was identified as an inhibitor of LAT1. It inhibited the proliferation of tumor cells in a dose-dependent manner. It also inhibited mTOR phosphorylation and induced cell cycle stasis in the G1 phase [ ].

Another inhibitor of LAT1, JPH KYT , has a high affinity more than a thousand-fold higher than that of BCH [ ].

JPH can lead to inhibition of the mTOR system, which leads to changes in downstream signaling pathways, in which cell cycle regulators such as cyclin-dependent kinase CDK 1—6 are considered to be the most downregulated kinases upstream [ ].

JPH has shown encouraging results in Phase I clinical trials against advanced solid tumors and is currently being used in Phase II studies UMIN [ , ].

LAT1 is also unique in that its expression is tumor-specific and, therefore, can be used for the delivery of antitumor drugs. For example, because melphalan is transported by LAT1, antitumor L-phenylalanine mustard melphalan was designed to improve the cellular uptake of nitrogen mustard [ ].

Similarly, the precursor of sesamol was designed by para-binding of sesamol to L-phenylalanine via a carbamate bond, which significantly enhanced its uptake and toxic effect on tumor cells [ ]. In conclusion, the LAT1-mediated prodrug delivery strategy facilitates the selective uptake of drugs to increase their intracellular concentration and antiproliferative activity by targeting tumor cells that overexpress the LAT1 protein.

SLC1A5 ASCT2 is the main glutamine transporter, and a variety of drugs have been developed for this transporter, such as γ-L-glutamyl-p-nitroanilide GPNA , V, and benzylserine.

Selective pharmacological drugs have been developed based on the first-generation low-efficiency glutamine transport antagonist GPNA, and V, a GPNA derivative, improved the ability to inhibit glutamine uptake in cells by approximately times [ ].

Blocking ASCT2 with V attenuates cancer cell growth and proliferation, and increases cell death and oxidative stress, which together promote antitumor responses [ ].

It has also been found that inhibiting glutamine metabolism with V may increase the expression of PD-L1 in tumor cells, thus inactivating T cells [ 60 ].

The ASCT2 inhibitor benzylserine can significantly reduce glutamine transport in tumor cells, inhibit the mTOR signaling pathway, and reduce the expression of cell cycle regulators, thus inhibiting cell cycle progression [ ].

The amino acid transporter SLC6A14 transports all neutral amino acids, as well as the cationic amino acids lysine and arginine, and is a novel drug target. Alpha-methyltryptophan α-MT , an inhibitor of this transporter, induces amino acid starvation and autophagy in tumor cells by blocking SLC6A14, inhibiting mTOR signal transduction, inducing amino acid starvation, and inhibiting tumor cell growth and proliferation [ ].

SLC3A2 forms a heterodimer amino acid transporter with SLC7A5 or SLC7A Although SLC7A5 and SLC7A11 are actual transporters, they require SLC3A2 as a partner to recruit them into the plasma membrane [ ].

Treatment with the humanized anti-SLC3A2 monoclonal antibody IGN showed antitumor efficacy in leukemia-derived and non-small cell lung cancer models [ 72 ]. IGN causes tumor cell death through NK cell-mediated cytotoxicity and inhibits the uptake of amino acids such as phenylalanine by tumor cells [ ].

The cystine glutamate reverse transporter SLC7A11 xCT helps fight oxidative stress by promoting GSH-mediated antioxidant defenses. Therefore, xCT may be a promising target for cancer therapies.

The xCT transport inhibitor sulfasalazine induced a decrease in cysteine and GSH and led to enhanced mitochondrial metabolism, resulting in increased ROS production, which triggered oxidative damage [ ].

Glutamine antagonists have a long history of use. In addition, two other compounds, acivicin and azaserine, are also glutamine antagonists [ 96 ]. However, owing to the important role of glutamine metabolism in normal tissue physiology, these compounds also cause varying levels of gastrointestinal toxicity, myelosuppression, and neurotoxicity, and were therefore deprecated [ 96 ].

The prodrug developed on this basis, JHU, is a well-tolerated, brain-penetrating glutamine antagonist, and a promising new drug for treatment [ ]. JHU can release 6-diazooxygen-L-deamine when cleaved by tumor cathepsin, thus playing a specific killing role in tumors [ ]. Notably, this drug can differentially metabolize cancer cells and T cells, not only starving the cancer cells, but also making the TME a more suitable microenvironment for effector T cells, thus enhancing their attack on the tumors [ ].

The tryptophan decomposing enzyme is frequently expressed in human tumors, which causes tumor cells to consume a large amount of tryptophan and produce many toxic products, resulting in immune suppression.

Previous studies suggest that most human tumors constitutively express IDO, which is an important mechanism of tumor immune tolerance [ , ].

In addition, tryptophan-decomposing enzyme activity is easily blocked by drug inhibitors [ ]. Indoximod 1-MT is the first IDO1 inhibitor to enter clinical development for cancer treatment [ ]. It can eliminate Kyn production, inhibit tryptophan consumption, and restore T cell proliferation.

The 1-MT prodrug NLG can significantly enhance the antitumor response of T cells [ ]. It can be rapidly metabolized to 1-MT upon entry into the body, increasing its bioavailability five-fold, and has shown a safe toxicological profile at the intended therapeutic dose.

Epacadostat is another selective inhibitor of IDO1 [ ]. An in vitro experiment has shown that epacadostat promotes effector T cell growth and IFN-γ production and reduces the conversion to Tregs [ ].

The novel small-molecule inhibitor NTRC —0 can effectively counteract IDO1-induced changes in tryptophan and Kyn levels [ ]. BMS is a highly effective and selective inhibitor of IDO1 that can effectively inhibit Kyn synthesis in IDO1-overexpressed cells [ ]. Originally used as antidepressants, TDO inhibitors are also being explored as cancer treatments, such as C91 and LM10 [ ].

Navoximod NLG selectively inhibits IDO1 and TDO2, thereby reducing the proportion of Tregs and increasing T cell activation [ ]. In addition to directly inhibiting IDO1, targeting the events upstream of IDO1 is an alternative strategy. A successful example of this approach is the tyrosine kinase inhibitor imatinib, which inhibits IDO1 expression [ ].

Furthermore, induction of IDO1 in the TME can be prevented by inhibiting the activity of cyclooxygenase-2 COX-2 , a key enzyme for PGE2 production, which is capable of inducing IDO1 expression. A preclinical study has shown that COX-2 inhibition can reduce IDO1 levels and inhibit tumor growth and metastasis [ ].

Overexpression of ARG in MDSCs can lead to L-arginine deletion in the TME, thus inducing T cell apoptosis [ ]. N-hydroxy-l-arginine NOHA is an ARG inhibitor that significantly inhibits ARG1 expression. It can restore the responsiveness of tumor-infiltrating T cells to stimulation, while inducing cell cycle arrest and apoptosis and reducing spermine production [ ].

NOHA also inhibits the MDSC-mediated expansion of Tregs [ ]. Nω-hydroxyl-non-arginine nor NOHA can eliminate stagnation of T cell proliferation and facilitate an immune attack against cancer cells [ ]. CB is an ARG1 inhibitor. By inhibiting ARG, CB effectively blocks MDSC-mediated immunosuppression and reduces tumor growth by increasing the supply of arginine required for T cell proliferation [ ].

Glutamine is converted to glutamate by GLS and glutamate is converted to α-KG by two types of reactions [ ]. Transaminases convert amino groups from glutamic acid to ketoacids to produce α-KG and other amino acids.

The other enzyme is glutamate deaminase GDH , which releases ammonia and produces α-KG without consuming ketoacid.

Glutaminase is a key target for glutamine metabolism, and GLS inhibitors have been used in various cancers [ ]. There are three main GLS inhibitors: telaglenastat CB , BPTES, and GLS inhibitor CB is an effective, selective, and reversible GLS inhibitor that allosterically inhibits the dimer-to-tetramer GLS transition, a key step in enzyme activation [ ].

Inhibition of glutaminase by CB significantly reduces the production of GSH, resulting in increased ROS and apoptosis [ ]. However, another study found that CB showed an early effect in pancreatic cancer cells, but the tumor cells soon adopted an adaptive metabolic network to maintain glutamine metabolism and proliferation in a GLS-independent manner [ ].

Uncertainty regarding the efficacy of CB suggests the need for continued mechanistic, pharmacological, and translational research [ ]. Inhibition of glutamine metabolism by BPTES can increase the expression of PD-L1 in tumor cells, thus inactivating T cells [ 60 ].

Glutaminase inhibitor functions as an allosteric GLS inhibitor [ ] and has been found to have a good effect on tumor stem cells in glioblastoma and diminished tumor growth [ ]. These findings highlight the importance of glutamine metabolism and support GLS as a therapeutic target for tumors.

Glutamate deaminase is also a target of glutamine metabolism. It has recently been reported that shRNA or GDH-specific inhibitor R targeting GDH leads to a significant reduction in α-KG and glutamine-dependent RNA biosynthesis, as well as an increase in ROS levels [ ].

However, another study showed that the inhibition of GDH leads to increased cytoplasmic aspartate aminotransferase expression [ ]. Thus, sufficient reducing power is generated to resist ROS and support cancer cell survival. These results suggest that targeting GDH alone may induce the activation of other metabolic pathways to reduce ROS and upregulate α-KG production, resulting in therapeutic tolerance.

In addition to the three most studied amino acids glutamine, arginine, and tryptophan , recent studies have strongly suggested that tumor cells have a strong ability to synthesize serine de novo through the glycerol phosphate dehydrogenase PHGDH pathway.

In a typical pathway for the synthesis of serine, PHGDH catalyzes the conversion of glycerate 3-phosphate produced during glycolysis to hydroxypyruvate 3-phosphate, the first rate-limiting step [ 96 ].

In addition, the reduction of serine by inhibiting PHGDH resulted in the inhibition of serine-based sphingolipid synthesis, an increase in bypass metabolic pathways, and the accumulation of the metabolite deoxysphingolipid, which has previously been reported as an anticancer factor [ ]. Therefore, inhibition of PHGDH may play an antitumor role.

Several PHGHD inhibitors have been identified. CBR can inhibit de novo serine synthesis in tumor cells and produce selective toxicity in cancer cell lines with high serine biosynthesis activity [ ].

The small-molecule inhibitor NCT can also reduce serine production and inhibit the growth of cancer cells [ ]. PEG-KYNase is a recombinant enzyme that degrades Kyn into an immunoinert metabolite.

PEG-KYNase has been shown to be therapeutic in multiple mouse models for tumor when used alone or in combination with checkpoint blocking [ ]. Degradation of Kyn inhibits AhR activation. The modified kynureninase can degrade extracellular Kyn and has shown remarkable efficacy in mouse tumor models [ ].

Aryl hydrocarbon receptor antagonists also attenuate immunosuppression and inhibit tumor growth. IDB-AhRi is an AhR antagonist that blocks the nuclear transposition of AhR and increases the expression of IFN-γ and TNF-α. Selective AhR inhibitors CH can block the immunosuppressive effects of Tregs [ ], inhibit Th17 differentiation [ ], and reduce PD-1 expression [ ].

Targeting amino acid metabolism is theoretically feasible, and preclinical and clinical trials of drugs are being carried out extensively. However, some challenges remain to be resolved. Drugs that target metabolism are typically administered systemically, which increases their potential toxic effects in normal tissues.

Amino acids are important nutrients; therefore, blocking their metabolism can easily affect multiple organs of the body. This is why some of the previously studied drugs that target amino acid metabolism have many side effects in normal organs, such as the gastrointestinal tract.

Moreover, although amino acid metabolism is significantly elevated in many tumors, therapies targeting amino acid metabolism in patients with tumors have not yielded satisfactory therapeutic results.

This may reflect the complexity of the TME. Our understanding of the metabolic interactions in this microenvironment is rudimentary, making it difficult to kill tumor cells without harming the antitumor immune cells.

T cells also consume large amounts of glutamine when activated and proliferating [ ]. Therefore, we need to consider whether depletion of the amino acid pool in the TME has a greater effect on tumor or T cells, as both cells benefit from the increase in local amino acids.

The third challenge is that the metabolism of tumor cells is plastic. The intracellular metabolism forms a complex network. When a node is blocked, cells can bypass it through compensatory mechanisms. Targeting an amino acid metabolic node alone may induce compensatory amino acid replenishment via other pathways.

As mentioned earlier, pancreatic cancer cells have a compensatory metabolic network for GLS inhibitors [ ]. After prolonged GLS inhibition, the tumor showed compensatory glutamine metabolism and growth recovery.

Finally, different tumors are dependent on different amino acids, and even the same tumor may exhibit different metabolic requirements, which increases the difficulty of targeting amino acid metabolism.

For example, breast cancer cells show systemic differences in glutamine dependence, with basal cells favoring glutamine dependence and luminal cells favoring glutamine independence [ ].

In addition, a high amino acid intake does not imply dependence. One previous study has shown that although luminal breast cancer cell lines consume almost the same amount of glutamine as triple negative breast cancer cells, the former are not sensitive to glutamine uptake inhibition [ ].

Therefore, defining the metabolic characteristics of cancer subtypes is necessary to reveal how metabolic vulnerability can be exploited therapeutically [ ]. Thus, before the clinical application of amino acid starvation therapy, not only should the metabolic dependence of specific cancer types be studied [ , ] but the need for combination therapy in the face of this metabolic complexity should also be considered, which may be more effective.

In eukaryotes, mTOR and GCN2 are amino acid sensors, and the signaling pathways mediated by these two sensors are involved in the adaptive switching to alternative fuels when a certain metabolic pathway is inhibited. Therefore, combination therapies targeting amino acids and one of these two amino acid receptors have been proposed.

The increased metabolism of glutamine promotes its resistance to mTOR inhibition, and the expression of GLS increases after mTOR inhibition [ ]. Therefore, the simultaneous use of glutaminase and mTOR inhibitors can achieve improved antitumor effects.

There was a synergistic effect between CB and mTOR inhibitor [ ]. In addition, inhibiting glutamine metabolism into GSH combined with the mTOR inhibitor can enhance tumor cell death [ ]. GCN2 inhibitors GCN2iA sensitize tumor cells to asparaginase by reducing the expression of asparagine synthase, thereby reducing de novo protein synthesis levels [ ].

In recent years, immunotherapy has made great progress, and ICB and adoptive cell therapy have been used in clinical practice; however, a large proportion of patients do not benefit from immunotherapy.

Amino acid metabolism plays an important role in T cell immunity. Therefore, immunotherapy combined with targeted amino acid metabolism may be a new direction for tumor treatment.

The targeted therapy of amino acid metabolism combined with immunotherapy still mainly focuses on the three main amino acids, glutamine, arginine, and tryptophan.

Glutamine transporter inhibitor V and GLS inhibitor BPTES, when used in combination with anti-PD-L1 antibodies, strongly promoted the effector function of T cells [ 60 ]. Immunotherapy of the PD-1 checkpoint combined with glutamine-targeting JHU showed significantly increased response rates compared to those of PD-1 monotherapy [ ].

These results demonstrate the correlation between tumor glutamine metabolism and antitumor immunity and suggest that the combined targeting of glutamine metabolism and PD-L1 is a promising therapeutic approach that can significantly enhance the antitumor effect.

CB, an ARG1 inhibitor, showed a highly potent antitumor effect when used in combination with anti-PD-1 antibodies or anti-CTLA-4 antibodies [ ].

Inhibition of ARG2 in conjunction with PD-1 blocking therapy may improve the response to immunotherapy. One Study has shown that plasma Kyn:Trp ratio increases in patients with tumors during pembrolizumab treatment [ ].

These findings suggest that the high expression level of IDO and the corresponding increase in Kyn may be the underlying factors that induce tolerance to ICB therapy.

In addition, numerous experiments have demonstrated that tumor cells expressing IDO can suppress immune cells through tryptophan starvation and that AhR is involved in tumor immune escape. Therefore, combination therapy targeting the Trp-Kyn-AhR axis in immunotherapy has strong translational rationality and good preclinical effects; however, the clinical trial effect of combination therapy is not satisfactory [ ] and has reignited the combinatorial approach debate.

This may be because of the role of TDO in immune escape, although its role in tumors is not as important as that of IDO. Therefore, the dual inhibitors of IDO and TDO may be more effective. Inadequate persistence of CAR-T cells in vivo leads to poor therapeutic outcomes and disease recurrence [ ].

In the TME, nutrient deficiency, accumulation of large amounts of toxic metabolites, hypoxia, and low PH create a unique environment that promotes tumor growth and suppresses immunity. It has been found that poor proliferation and persistence of T cells is one of the main reasons why adoptive cell therapy has no or a weak response [ ].

Therefore, in vitro cultured immune cells also require potent metabolic capacity to enhance their adaptability to harsh environments. The upregulation of amino acid transporters SLC1A5 and SLC7A5 may improve the function of CAR-NK and CAR-T cells [ 28 ]. In a recent study, authors found that re-engineering CAR-T cells to express SLC7A5 or SLC7A11 can promote CAR-T cells proliferation and IFN-γ release under low tryptophan or cystine conditions [ ].

Another approach is to consider the loading of functional amino acid-metabolizing enzymes. Because of the low expression of argininosuccinate synthase and ornithine transcarbamylase, T cells are susceptible to arginine depletion [ 46 ].

Thus, T cells can be reengineered to express functional argininosuccinate synthase or ornithine transcarbamylase enzymes in conjunction with different CARs, which increases CAR-T cell proliferation without reducing cytotoxicity. Another major strategy is to enhance immune cytotoxicity. This can be achieved through simultaneous or sequential application of drugs that directly target amino acid metabolism.

For example, CD19 CAR-T had no effect on IDO-positive tumors but was restored in combination with 1-MT [ 20 ]. In contrast, CAR-T cell cytotoxicity can be enhanced by regulating T cell metabolism during in vitro expansion. In vitro-amplified CAR-T cells showed phenotypic heterogeneity, most of which were effector memory T cell or effector T cell subpopulations, and naïve T cell and central memory T cell populations, which showed stronger cytotoxicity, were very low.

Transformation of differentiated subsets is closely related to the metabolic adaptability of T cells.

Similarly, a recent study found that dynamic in vitro culture can enhance the antitumor activity of immune cells [ ].

Dynamic culture can increase glutamine metabolic flux and promote ATP production. These cells are in a high metabolic state to produce increased amounts of energy. These findings provide new insights into the expansion of immune cells in vitro. However, it is worth noting that over-enhancing the cytotoxicity of CAR-T may produce toxic levels of cytokines and over-activation of immune system, leading to cytokine release syndrome or neurotoxicity [ ].

Therefore, it is very important to have the right window of treatment. With the continuous optimization of CAR molecules and the development of combination therapy, it is believed that CAR-T cell therapy will be safer and more efficient.

In recent years, significant progress has been made in amino acid metabolism reprogramming in the TME. As an increasing number of mechanisms have been elucidated, targeting amino acid metabolism opens up new avenues for the treatment of cancer patients.

Tumor control by targeting various stages of amino acid metabolism, including the inhibition of amino acid uptake, transport, and metabolism, has demonstrated to be a promising therapeutic strategy.

In addition, the presence of complex crosstalk between amino acid metabolism and T cells in the TME is becoming clear, which may determine the fate of T cells and play a considerable role in immune escape in tumors.

In this regard, the limited amino acids in the TME and high metabolic activity of tumor cells result in nutrient competition between tumor cells and T cells and produce a large number of toxic metabolites.

Furthermore, complex metabolic crosstalk between amino acids, glucose, and lipids can influence T cell immunity. The profound significance of amino acid metabolism in T cells has made it a popular topic in oncotherapy.

Targeting amino acid metabolism combined with ICB or adoptive cell therapy can significantly enhance the efficacy of immunotherapy by strengthening the effector functions of T cells. In conclusion, targeting amino acid metabolism is a promising therapeutic strategy; however, many challenges remain to be addressed.

For example, because drugs are usually administered throughout the body, targeting amino acid metabolism will inevitably cause toxic side effects. Even if the drug reaches the tumor site, there is no guarantee that the drug can target the tumor with high specificity and without affecting the antitumor immune cells.

In addition, the plasticity of tumor cell metabolism and differences in amino acid dependence make it difficult to select drugs.

Therefore, how can we target tumor cell metabolism while avoiding the toxic effects on immune and normal cells? How do we define the metabolic subtypes of tumor cells? How do we prevent tumors from developing resistance to targeted metabolic drugs?

In recent years, with the vigorous development of metabolomics, such as high-resolution mass spectrometry [ ], determining the metabolic subtypes of tumors is possible, which is conducive to individualized targeted therapy. However, targeted amino acid metabolism in combination with immunotherapy has made significant breakthroughs in both preclinical and clinical trials, promising to overcome the limits of treatment for patients with advanced cancer.

To date, several highly specific small-molecule inhibitors targeting amino acid metabolic pathways, such as the IDO inhibitor BM, ARG inhibitor CB, and kynureninase, have been evaluated in multiple clinical trials as monotherapy or in combination with ICB [ 37 ].

Future research will help reveal key features of amino acid metabolism in the TME based on T cell immunity, which will provide important insights into the design of effective drugs targeting amino acid metabolism and combining with immunotherapy. Martínez-Reyes I, Chandel NS.

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Lysine is synthesized from aspartate via the diaminopimelate DAP pathway. The initial two stages of the DAP pathway are catalyzed by aspartokinase and aspartate semialdehyde dehydrogenase.

These enzymes play a key role in the biosynthesis of lysine , threonine , and methionine. Transcription of aspartokinase genes is regulated by concentrations of the subsequently produced amino acids, lysine, threonine, and methionine.

The higher these amino acids concentrations, the less the gene is transcribed. ThrA and LysC are also feed-back inhibited by threonine and lysine. Finally, DAP decarboxylase LysA mediates the last step of the lysine synthesis and is common for all studied bacterial species.

The formation of aspartate kinase AK , which catalyzes the phosphorylation of aspartate and initiates its conversion into other amino acids, is also inhibited by both lysine and threonine , which prevents the formation of the amino acids derived from aspartate.

Additionally, high lysine concentrations inhibit the activity of dihydrodipicolinate synthase DHPS. So, in addition to inhibiting the first enzyme of the aspartate families biosynthetic pathway, lysine also inhibits the activity of the first enzyme after the branch point, i.

the enzyme that is specific for lysine's own synthesis. The biosynthesis of asparagine originates with aspartate using a transaminase enzyme.

The enzyme asparagine synthetase produces asparagine, AMP , glutamate, and pyrophosphate from aspartate, glutamine , and ATP. In the asparagine synthetase reaction, ATP is used to activate aspartate, forming β-aspartyl-AMP. Glutamine donates an ammonium group, which reacts with β-aspartyl-AMP to form asparagine and free AMP.

Two asparagine synthetases are found in bacteria. Both are referred to as the AsnC protein. They are coded for by the genes AsnA and AsnB. AsnC is autogenously regulated, which is where the product of a structural gene regulates the expression of the operon in which the genes reside.

The stimulating effect of AsnC on AsnA transcription is downregulated by asparagine. However, the autoregulation of AsnC is not affected by asparagine. Biosynthesis by the transsulfuration pathway starts with aspartic acid.

Relevant enzymes include aspartokinase , aspartate-semialdehyde dehydrogenase , homoserine dehydrogenase , homoserine O-transsuccinylase , cystathionine-γ-synthase , Cystathionine-β-lyase in mammals, this step is performed by homocysteine methyltransferase or betaine—homocysteine S-methyltransferase.

Methionine biosynthesis is subject to tight regulation. The repressor protein MetJ, in cooperation with the corepressor protein S-adenosyl-methionine, mediates the repression of methionine's biosynthesis.

The regulator MetR is required for MetE and MetH gene expression and functions as a transactivator of transcription for these genes. MetR transcriptional activity is regulated by homocystein, which is the metabolic precursor of methionine.

It is also known that vitamin B12 can repress MetE gene expression, which is mediated by the MetH holoenzyme. In plants and microorganisms, threonine is synthesized from aspartic acid via α-aspartyl-semialdehyde and homoserine.

Homoserine undergoes O -phosphorylation; this phosphate ester undergoes hydrolysis concomitant with relocation of the OH group. The biosynthesis of threonine is regulated via allosteric regulation of its precursor, homoserine , by structurally altering the enzyme homoserine dehydrogenase.

This reaction occurs at a key branch point in the pathway, with the substrate homoserine serving as the precursor for the biosynthesis of lysine, methionine, threonin and isoleucine. High levels of threonine result in low levels of homoserine synthesis.

The synthesis of aspartate kinase AK , which catalyzes the phosphorylation of aspartate and initiates its conversion into other amino acids, is feed-back inhibited by lysine , isoleucine , and threonine , which prevents the synthesis of the amino acids derived from aspartate.

So, in addition to inhibiting the first enzyme of the aspartate families biosynthetic pathway, threonine also inhibits the activity of the first enzyme after the branch point, i.

the enzyme that is specific for threonine's own synthesis. In plants and microorganisms, isoleucine is biosynthesized from pyruvic acid and alpha-ketoglutarate.

Enzymes involved in this biosynthesis include acetolactate synthase also known as acetohydroxy acid synthase , acetohydroxy acid isomeroreductase , dihydroxyacid dehydratase , and valine aminotransferase. In terms of regulation, the enzymes threonine deaminase, dihydroxy acid dehydrase, and transaminase are controlled by end-product regulation.

the presence of isoleucine will downregulate threonine biosynthesis. High concentrations of isoleucine also result in the downregulation of aspartate's conversion into the aspartyl-phosphate intermediate, hence halting further biosynthesis of lysine , methionine , threonine , and isoleucine.

coli , the biosynthesis begins with phosphorylation of 5-phosphoribosyl-pyrophosphate PRPP , catalyzed by ATP-phosphoribosyl transferase.

Phosphoribosyl-ATP converts to phosphoribosyl-AMP PRAMP. His4 then catalyzes the formation of phosphoribosylformiminoAICAR-phosphate, which is then converted to phosphoribulosylformimino-AICAR-P by the His6 gene product.

After, His3 forms imidazole acetol-phosphate releasing water. His5 then makes L -histidinol-phosphate, which is then hydrolyzed by His2 making histidinol.

His4 catalyzes the oxidation of L -histidinol to form L -histidinal, an amino aldehyde. In the last step, L -histidinal is converted to L -histidine. In general, the histidine biosynthesis is very similar in plants and microorganisms.

The enzymes are coded for on the His operon. This operon has a distinct block of the leader sequence, called block This leader sequence is important for the regulation of histidine in E.

The His operon operates under a system of coordinated regulation where all the gene products will be repressed or depressed equally. The main factor in the repression or derepression of histidine synthesis is the concentration of histidine charged tRNAs. The regulation of histidine is actually quite simple considering the complexity of its biosynthesis pathway and, it closely resembles regulation of tryptophan.

In this system the full leader sequence has 4 blocks of complementary strands that can form hairpin loops structures. When histidine charged tRNA levels are low in the cell the ribosome will stall at the string of His residues in block 1.

This stalling of the ribosome will allow complementary strands 2 and 3 to form a hairpin loop. The loop formed by strands 2 and 3 forms an anti-terminator and translation of the his genes will continue and histidine will be produced.

However, when histidine charged tRNA levels are high the ribosome will not stall at block 1, this will not allow strands 2 and 3 to form a hairpin. Instead strands 3 and 4 will form a hairpin loop further downstream of the ribosome.

When the ribosome is removed the His genes will not be translated and histidine will not be produced by the cell. Serine is the first amino acid in this family to be produced; it is then modified to produce both glycine and cysteine and many other biologically important molecules.

Serine is formed from 3-phosphoglycerate in the following pathway:. The conversion from 3-phosphoglycerate to phosphohydroxyl-pyruvate is achieved by the enzyme phosphoglycerate dehydrogenase.

This enzyme is the key regulatory step in this pathway. Phosphoglycerate dehydrogenase is regulated by the concentration of serine in the cell. At high concentrations this enzyme will be inactive and serine will not be produced. At low concentrations of serine the enzyme will be fully active and serine will be produced by the bacterium.

Glycine is biosynthesized from serine, catalyzed by serine hydroxymethyltransferase SHMT. The enzyme effectively replaces a hydroxymethyl group with a hydrogen atom. SHMT is coded by the gene glyA.

The regulation of glyA is complex and is known to incorporate serine, glycine, methionine, purines, thymine, and folates, The full mechanism has yet to be elucidated. Homocysteine is a coactivator of glyA and must act in concert with MetR.

PurR binds directly to the control region of glyA and effectively turns the gene off so that glycine will not be produced by the bacterium. The genes required for the synthesis of cysteine are coded for on the cys regulon.

The integration of sulfur is positively regulated by CysB. Effective inducers of this regulon are N-acetyl-serine NAS and very small amounts of reduced sulfur.

CysB functions by binding to DNA half sites on the cys regulon. These half sites differ in quantity and arrangement depending on the promoter of interest. There is however one half site that is conserved.

It lies just upstream of the site of the promoter. There are also multiple accessory sites depending on the promoter. In the absence of the inducer, NAS, CysB will bind the DNA and cover many of the accessory half sites.

Without the accessory half sites the regulon cannot be transcribed and cysteine will not be produced. It is believed that the presence of NAS causes CysB to undergo a conformational change. This conformational change allows CysB to bind properly to all the half sites and causes the recruitment of the RNA polymerase.

The RNA polymerase will then transcribe the cys regulon and cysteine will be produced. Further regulation is required for this pathway, however.

CysB can down regulate its own transcription by binding to its own DNA sequence and blocking the RNA polymerase. In this case NAS will act to disallow the binding of CysB to its own DNA sequence.

OAS is a precursor of NAS, cysteine itself can inhibit CysE which functions to create OAS. Without the necessary OAS, NAS will not be produced and cysteine will not be produced.

There are two other negative regulators of cysteine. These are the molecules sulfide and thiosulfate , they act to bind to CysB and they compete with NAS for the binding of CysB.

Pyruvate, the result of glycolysis , can feed into both the TCA cycle and fermentation processes. Reactions beginning with either one or two molecules of pyruvate lead to the synthesis of alanine, valine, and leucine. Feedback inhibition of final products is the main method of inhibition, and, in E.

coli , the ilvEDA operon also plays a part in this regulation. Alanine is produced by the transamination of one molecule of pyruvate using two alternate steps: 1 conversion of glutamate to α-ketoglutarate using a glutamate-alanine transaminase, and 2 conversion of valine to α-ketoisovalerate via Transaminase C.

Not much is known about the regulation of alanine synthesis. The only definite method is the bacterium's ability to repress Transaminase C activity by either valine or leucine see ilvEDA operon.

Other than that, alanine biosynthesis does not seem to be regulated. Valine is produced by a four-enzyme pathway.

It begins with the condensation of two equivalents of pyruvate catalyzed by acetohydroxy acid synthase yielding α-acetolactate. This is catalyzed by acetohydroxy isomeroreductase. The third step is the dehydration of α, β-dihydroxyisovalerate catalyzed by dihydroxy acid dehydrase.

In the fourth and final step, the resulting α-ketoisovalerate undergoes transamination catalyzed either by an alanine-valine transaminase or a glutamate-valine transaminase.

Valine biosynthesis is subject to feedback inhibition in the production of acetohydroxy acid synthase. The leucine synthesis pathway diverges from the valine pathway beginning with α-ketoisovalerate.

α-Isopropylmalate synthase catalyzes this condensation with acetyl CoA to produce α-isopropylmalate. An isomerase converts α-isopropylmalate to β-isopropylmalate. The final step is the transamination of the α-ketoisocaproate by the action of a glutamate-leucine transaminase.

Leucine, like valine, regulates the first step of its pathway by inhibiting the action of the α-Isopropylmalate synthase. The genes that encode both the dihydroxy acid dehydrase used in the creation of α-ketoisovalerate and Transaminase E, as well as other enzymes are encoded on the ilvEDA operon.

This operon is bound and inactivated by valine , leucine , and isoleucine. Isoleucine is not a direct derivative of pyruvate, but is produced by the use of many of the same enzymes used to produce valine and, indirectly, leucine.

When one of these amino acids is limited, the gene furthest from the amino-acid binding site of this operon can be transcribed. When a second of these amino acids is limited, the next-closest gene to the binding site can be transcribed, and so forth.

The commercial production of amino acids usually relies on mutant bacteria that overproduce individual amino acids using glucose as a carbon source. Some amino acids are produced by enzymatic conversions of synthetic intermediates.

Aspartic acid is produced by the addition of ammonia to fumarate using a lyase.

Acix you for visiting nature. Plant-based antioxidant rich foods Amino acid metabolism regulation using a browser version with limited support for CSS. Regularion obtain the aicd experience, Amino acid metabolism regulation recommend you metabolim a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Free amino acids, including theanine, glutamine and glutamate, contribute greatly to the pleasant taste and multiple health benefits of tea. Amino acids in tea plants are mainly synthesized in roots and transported to new shoots, which are significantly affected by nitrogen N level and forms.

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