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18.5: Pathways of Amino Acid Degradation

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  • The pathways for amino acid degradation

    In previous sections, we saw how nitrogen is removed from amino acids to produce urea or NH4+, that some amino acids are glucogenic, ketogenic, or both, and the role of tetrahydrofolate derivatives and S-adenosylmethione in 1C transfer reactions. Now we can focus on how the carbon skeletons of amino acids are processeed during degradations.

    Here are some key features of amino acid catabolism that were discussed in the previous section. .

    • some are converted to pyruvate, the end product of glycolysis and the start reactant of gluconeogenesis. Hence, these amino acids are glucogenic;
    • some are converted to acetoacetate-CoA and or acetyl-CoA. Both of these can be converted to ketone bodies (acetoacetate/β-hydroxybutyrate) so these are considered ketogenic. Since the two carbons of the acetyl group of acetyl-CoA are lost as CO2 in the TCA cycle, and their is no reverse for the pyruvate dehydrogenase reaction (pyr → acetyl-CoA), acetyl-CoA formed by amino acid degradation can not be used to create glucose in net fashion;
    • some are metabolized to form TCA intermediates. Since they are added in net fashion to the TCA cycle and don't remove the existing pool of TCA intermediates, they can produce in net fashion direct or indirectly molecules that can be use to produce glucose. These entry reactions to the TCA which replenish or add to TCA intermediates are called anerplerotic (replenishing) reactions. Hence these amino acid are also glucogenic.
    • some have multiple ways to be degraded and can produce both acetyl-CoA and pyruvate, so they are both glucogneic and ketogenic.

    Let's get more explicit:

    • purely ketogenic: only Leu and Lys (the only amino acids whose name starts with L and you have to Love them since there are only 2 amino acids in this category)
    • both: 5 are including the aromatics - Trp, Tyr, Phe - and Ile/Thr
    • purely glucogenic: the rest

    The figure below, also shown in the previous sections, summarizes the fates of the 20 amino acids in their catabolic reactions

    summaryAACsTCACyleKetoGluogeneic.png

    Conversion to Pyruvate: Ala, Trp, Cys, Ser, Gly, Thr

    We ended section 18:3 on the discussion of the Ser Gly One Carbon Cycle (SGOC) so some of this will be a bit of a review.

    Here is an overview of the reactions.  More details are provide for each of the steps below.

    AAtoPyuvate.png

     

    The metabolic steps for the chemical transformations shown in steps A-F are described in more detail below. 

    A.  Tryptophan to Alanine

    This is a multistep process.  The starting material, tryptophan, is highlighted in a red box while the end product of specific interest, Ala, is highlighted in a green box.  No reaction occurs in isolation in a cell, but rather as part of a more complex pathway.   In the figure below, Ala is presented almost as a side product as the modified aromatic ring found in either anthranilate or 3-hydroxyanthranilate continues on to form either acetatoacetate, a ketone body which can breakdown to acetyl-CoA (making trptophan ketogenic as well as glucogenic) or NAD+

     

    TrptoAlatoAcetoacetate.png

     

    B.  Alanine to Pyruvate

    As described in 18.2, the PLP-dependent enyzme ALanine Amino Transferase (ALT), also known as Glutamate Pyruvate Transaminase (GPT), catalyzes this simple transamination reaction:  

    alanine +α−ketoglutarate ↔ pyruvate + glutamate

     

    AlatoPyr.png

    The glutamate produced in this reaction can be oxidatively deaminated to give NH4+ and alpha-ketogluatarate again, giving the net reaction:

    Ala + NAD(P)+ + H2O ↔  Pyr + + NAD(P)H + NH4+ 

    C. Threonine to Glycine

    There are several pathways for this conversion. 

    One involves the conversion of Thr to 2-amino-3-ketobutyrate by threonine-3-dehydrogenase.  

    Rx:  Thr +  NAD+ ↔  2-amino-3-ketobutyrate + NADH

    This is followed by the conversion of 2-amino-3-ketobutyrate to glycine by the enzyme 2-amino-3-ketobutyrate coenzyme A ligase.

    Rx:  2-amino-3-ketobutyrate + CoASH ↔  Gly +  acetyl-CoA 

    The net of these reactions is

    Rx: Thr +  NAD+ +  CoASH  ↔  Gly +  acetyl-CoA + NADH

     

    second and predominate reaction involves the conversion of Thr to NH4 + and α-ketobutyrate by  the PLP-dependent enyzme Ser/Thr dehydratase (also called threonine ammonia-lyase), an enzyme we have seen in the previous section.  Note this reaction does NOT produce glycine but is an i.

    Rx:  Thr ↔  NH4 + + α-ketobutyrate

     

    α-ketobutyrate can then be converted to proprionyl CoA.

    Rx:  α-ketobutyrate +  NAD+ + CoASH   ↔   proprionyl-CoA + NADH + CO2 + H+

     

    This reaction, catalyzed by the inner mitochondrial membrane branched-chain α-ketoacid dehydrogenase complex (BCKDC or BCKDH complex) is an oxidative decarboxylation reaction.  BCKDC is a member of two other enzymes, pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase, both of which act on short alpha-keto acids to produce key Kreb cycle metabolites.  

    Proprionyl CoA is then converted eventually in several mitochondrial steps to succinyl CoA for entrance into the TCA cycle.  Three enyzmes are required for this conversion:  proprionyl CoA carboxylase, methylmalonyl-CoA epimerase and methylmalonyl-CoA mutase.  Proprionyl carboxylase, like another alpha-keto acid carboxylase (pyruvate carboxylase), requires ATP, Biotin and CO2 (as a substrate) for the carboxylation reaction and hence is often refererd to as an ABC enzyme.

    The three step conversion pathway of proprionyl CoA to succinyl CoA is also used for in the degradation of Valine, Odd-chain fatty acids (which forms multiple 2-carbon acetyl CoA units and 1 3-C proprionyl CoA unit), Methionine and Isoleucine along with Threonine.  This three-step pathway is sometimes referred to as VOMIT pathway.

     

    The third pathway, which we just saw in the previous section, is catalyzed by serine hydroxymethyltransferase (SHMT) (but also called glycine hydroxymethyltransferase or threonine aldolase) and requires the use of both PLP and tetrahydrofolate as cofactors. A 1C methylene is added to tetrahydrofolate (FH4). PLP makes bonds to the alpha-carbon of amino acids labile to cleavage. In this case, the amino acid threonine becomes dehydated through an alpha elimination reaction. However, threonine has an extra CH3 group which is released as acetaldehyde.  Here is the overall reaction.

    Rx:  Thr+ FH + ↔ Glycine + N5,N10-FH4 + acetaldehyde + H2O

    The enyzmes involved in this reaction are a bit unclear in the literature.  It appears that SHMT can act on Thr at a lower rate, but that a second enzyme, threonine aldolase, which seems to be afunctional in mammals, acts in other organisms.

     

    D.  Glycine to Serine

    As mentioned above, this reversible reaction is catalyzed by serine hydroxymethyltransferase (SHMT) (see mechanism in section 18.4) and uses tetrahydrofolate and PLP as cofactors.  Here is the overall reaction, the reverse of the Gly ↔ Ser we saw in 18.4.

    Rx:  Glycine + N5,N10-CH2-FH4 + H2O  ↔  Serine + FH

    Figure A below shows the dehydration reaction and formation of glycine. using PLP as a cofactor. Figure B shows how the released formaldehyde reacts with FHto form N5, N10-methylene FH4, using FH4 as a cofactor

    E.  Serine to Pyruvate

    This reaction is analogous to the Ala → Pyr reaction in Rx B above and is catalyzed by the PLP-dependent enyzme serine/threonine dehydratase/threonine deaminase. 

    Rx:  Serine ↔ Pyr + NH4+

    The enzyme is found in the cytoplasm and is mainly involved in gluconeogensis.

    F.  Cysteine to Pyruvate

    The overall reactions for this conversion are shown in the figure below.  The aspartate aminotransferase used in the production of 3 sulfinylpyruvate is cytosolic and not the same as the more abundant version in the mitochondria.

    ADD INTRO

    CystoPyr.png

    Other important metabolites are made from cysteine catabolic pathways.  One is taurine, which is actually the most abundant free amino acid in the body and is especially abundant in development and early milk.  It is synthesized predominately in the liver.  It is unclear if hypotaurine is converted to taurine in a non-enzymatics fashion or by an oxidase/dehydrogenase.

    The sulfate produced in the pathways is used to make an interesting derivative of ATP, 3′-phosphoadenosine-5′-phosphosulfate (PAPS), which is used to produced sulfated sugars using in glycolipid and proteoglycan synthesis.

     SulfatetoPAPS.png

     

    Conversion to Acetyl-CoA: Trp, Lys, Phe, Tyr, Leu, Ile, Thr

    An overview of the the many reactions in ketogenic amino acid degration is shown in the slide below.  The red boxed amino acids are those that form either acetoacetate (a ketone body) or acetyl-CoA directly (green boxes).  Some of the carbons are color coded red or green to indicate where they end up.

     

    AAtAcetylCoA.png

    A. Trp to acetyl-CoA

    Fortunately, we have explored the conversion of non-ring part of tryptophan to alanine and to a precursor of acetoacetyl Coa (2-amino-3-carboxymuconate 6-semialdehyde - ACMS) and to NAD+ (quinolinate).  ACMS, through the action of ACMS decarboxylase leads to acetoacetyl CoA and then to acetyl-CoA as shown below.As Trp is a ketogenic amino acids, it seems seem appropriate to show the steps that lead to acetyl-CoA even at the risk of providing too much detail.

     

    Trp_fromACMS_to acetoacetate.png

     

    B. Lys metabolism

    "here are several, at least three, pathways for lysine catabolism but the primary pathway utilized within the liver is one that begins with the formation of an adduct between lysine and 2-oxoglutarate (α-ketoglutarate) called saccharopine. Lysine catabolism is unusual in the way that the ε-amino group is transferred to 2-oxoglutarate and into the general nitrogen pool. The reaction is a transamination in which the ε-amino group is transferred to the α-keto carbon of 2-oxoglutarate forming the metabolite, saccharopine. Unlike the majority of transamination reactions, this one does not employ pyridoxal phosphate as a cofactor. The formation of saccharopine and its hydrolysis to α-aminoadipic-6-semialdehyde is catalyzed by the bifunctional enzyme α-aminoadipic semialdehyde synthase. This reaction results in the amino nitrogen remaining with the α-carbon of 2-oxoglutarate, producing glutamate and α-aminoadipic-6-semialdehyde. Because this transamination reaction is not reversible, lysine is an essential amino acid. Mammalian α-aminoadipic semialdehyde synthase is encoded by the AASS gene found on chromosome 7q31.32 and is composed of 25 exons encoding a mitochondrially localized protein of 926 amino acids. The N-terminal half of the AASS protein harbors the lysine:2-oxoglutarate reductase activity and the C-terminal half harbors the saccharopine dehydrogenase activity. The ultimate end-product of lysine catabolism, via this saccharopine pathway, is acetoacetyl-CoA."

    LystoAdipateOn.png

    "Lysine-oxoglutarate reductase (LOR)/
    saccharopine dehydrogenase (SDH), which reside on a single bifunctional polypeptide (LOR/SDH"

    C,D. Phenylalanine conversion to Tyrosine and continues to acetoacetate

    We'll follow the conversion of phenyalanine to tyrosine, which continues on to acetoacetate, making Phe and Tyr both ketogenic amino acids, and in subsequent steps that produces fumarate.  The can enter the TCA cycle leading to the net production of oxalacetate, which can be pulled of into gluconeogeneis, making both Phe and Try glucogenic as well.

    In addition, we will explore the chemistry of yet one more cofactor the facilitates electron flow in the conversion of Phe to Try in the first step, catalysed by the enyzme tyrosine hydroxlase.  That cofactor is tetrahydrobiopterin (BH4).

    Biochemistry. 2013 Feb 12; 52(6): 1062–1073.

    Published online 2013 Jan 29. doi: 10.1021/bi301675e

    PMCID: PMC3572726

    NIHMSID: NIHMS438181

    PMID: 23327364

    The Kinetic Mechanism of Phenylalanine Hydroxylase: Intrinsic Binding and Rate Constants from Single Turnover Experiments

    Kenneth M. Roberts, Jorge Alex Pavon,§ and Paul F. Fitzpatrick*

    A possible mechanism is shown below.  

     "1) oxidation of the pterin cofactor to form the reactive hydroxylating intermediate, followed by 2) insertion of oxygen into the amino acid substrate (). Supporting this view is the observation that pterin oxidation can become uncoupled from amino acid oxidation, either when nonphysiological amino acids are used as substrates () or in a variety of TyrH active-site mutants "

     

    PhetoTyr.png

    As in the case with the the conversion of dihydrofolate back to tetrahydrofolate (FH4) by dihydrofolate reductase, the 4a-OH-BH4 is conveted to dihydrobiopterin and then to tetrahydrobiopterin by dihyrobiopterin reductase.  

    Here is the full pathway for the conversion of Phe and Tyr to acetoacetate and fumarate

     

    PheTyrtoAcAcandFumarate.png

     

     

    henylalanine normally has only two fates: incorporation into polypeptide chains, and hydroxylation to tyrosine via the tetrahydrobiopterin-requiring phenylalanine hydroxylase (PAH) reaction. Thus, phenylalanine catabolism always ensues in the pathway of tyrosine biosynthesis followed by tyrosine catabolism. Tyrosine is equally important for protein biosynthesis as well as an intermediate in the biosynthesis of the catecholamines: dopamine, norepinephrine and epinephrine (see Amino Acid Derivatives).

    The pathway of tyrosine degradation involves conversion to fumarate and acetoacetate, allowing phenylalanine and tyrosine to be classified as both glucogenic and ketogenic. The catabolism of tyrosine involves five reactions, four of which have been shown to associated with inborn errors in metabolism and three of these result in clinically significant disorders. The first reaction of tyrosine catabolism involves the nuclear genome encoded mitochondrial enzyme tyrosine aminotransferase and generates the corresponding ketoacid, p-hydroxyphenylpyruvic acid.

    Like most aminotransferase reaction, tyrosine aminotransferase utilizes 2-oxoglutarate (α-ketoglutarate) as the amino acceptor with the consequent generation of glutamate. Tyrosine aminotransferase is encoded by the TAT gene on chromosome 16q22.2 which is composed of 12 exons that generate a protein of 454 amino acids. The second reaction of tyrosine catabolism is catalyzed by 4-hydroxyphenylpyruvate dioxygenase which is encoded by the HPD gene located on chromosome 12q24.31 which is composed of 17 exons that generate two alternatively spliced mRNAs encoding proteins of 393 amino acids (isoform 1) and 354 amino acids (isoform 2).

    The product of the HPD reaction is homogentisic acid (homogentisate). Homogentisate is oxidized by the second dioxygenase enzyme of tyrosine catabolism, homogentisate oxidase. Homogentisate oxidase is encoded by the homogentisate 1,2-dioxygenase gene, HGD. The HGD gene is located on chromosome 3q13.33 and is composed of 16 exons that encode a protein of 445 amino acids.

    Oxidation of homogentisate yields 4-maleylacetoacetate which is isomerized to 4-fumarylacetoacetate by the enzyme glutathione S-transferase zeta (ζ) 1 which is encoded by the GSTZ1 gene. Glutathione S-transferase zeta 1 was formerly called 4-maleylacetoacetate isomerase or maleylacetoacetate cistrans-isomerase. The GSTZ1 gene is located on chromosome 14q24.3 and is composed of 9 exons that generate four alternatively spliced mRNAs, each of which encode a distinct protein isoform.

    Fumarylacetoacetate is hydrolyzed to fumarate and acetoacetate by the enzyme fumarylacetoacetate hydrolase which is encoded by the FAH gene located on chromosome 15q25.1 and is composed of 15 exons that generate a 419 amino acid protein.

    The fumarate end product of tyrosine catabolism feeds directly into the TCA cycle for further oxidation. The acetoacetate is activated to acetoacetyl-CoA via the action of the mitochondrial ketone body utilization enzyme, succinyl-CoA:3-oxoacid-CoA transferase (SCOT) which is encoded by the OXCT1 (3-oxoacid-CoA transferase 1) gene. Acetoacetate can also be activated in the cytosol by the cytosolic enzyme, acetoacetyl-CoA synthetase (AACS)."

    E.  Leu to Acetoacetate

    dkfjdkjf

    "The first step in each case is a transamination using a pyridoxal phosphate-dependent BCAA aminotransferase (termed a branched-chain aminotransferase, BCAT), with 2-oxoglutarate (α-ketoglutarate) as amine acceptor."

     

    LeutoAcAc.png

    F.  Isoleucine to Acetyl-CoA

    kdjkdjfkjd

     

    IletoAcetylCoA.png

     

    Conversion to α-ketoglutarate: Pro, Glu, Gln, Arg,His

     

    A.  Proline and Arginine

     

    aldehyde dehydrogenase 4 family, member A1 (ALDH4A1) or D1-pyrroline-5-carboxylate dehydrogenase, (P5CDH)

    "lutamate that results from ornithine and proline catabolism can then be converted to 2-oxoglutarate (α-ketoglutarate) in a transamination reaction. Therefore, ornithine and proline are both glucogenic. Since arginine is metabolized to urea and ornithine, and the resulting ornithine is a glucogenic precursor, arginine is also a glucogenic amino acid."

    The overall pathway is shown below

     

    ArgProGlu_AAdecompo.png

     

    B.  Histidine

    dfdfd

    dfd

    HistoGlu_AAdecompo.png

    C.  Glutamine and Glutamic Acid

    As described in the reactions above, can be converted to α-ketoglutarate through transamination reactions.  Also as described in sections 18.x, gluatamine can be deaminated through the action of glutaminase to form glutamine which can likewise form α-ketoglutarate, a gluconeogenic intermediate.

    Conversion to succinyl-CoA: Met, Ile, Thr, Val

    We just saw that two branched chain amino acids, Leu and Ile, are converted to acetyl-CoA and hence are ketogenic (E and F above).  Another branched chain hydrophobic amino acid, Val, and also Leu again, can be converted to succinyl-CoA which can be converted to α-ketoglutarate in the Kreb's cycle in net fashion and hence are glucogenic amino acids.  We saw in the introduction to amino acids that produce acetyl-CoA that threonine and isoleucine, two branched chains amino acids, also form proprionyl-CoA which goes on to succinyl CoA. So, let's consider Val, another branched chain amino acid, before we consider Met, both of which have 3 Cs in their side chains.

     

    Val

    sdsdf

     

    ValtoSuccinylCoA.png

     

    Methionine

    The principal fates of the essential amino acid methionine are incorporation into polypeptide chains, and use in the production of cysteine and α-ketobutyrate via the reaction pathway involving the synthesis of SAM and cysteine as described above. The transulfuration reactions that produce cysteine from homocysteine and serine also produce α-ketobutyrate, the latter being converted first to propionyl-CoA and then via a 3-step process to succinyl-CoA.

    In the catabolism of methionine the α-ketobutyrate is converted to propionyl-CoA. The propionyl-CoA is converted, via a mitochondrially-localized three reaction ATP-dependent pathway, to succinyl-CoA. The succinyl-CoA can then enter the TCA cycle for further oxidation. The enzymes required for this conversion are propionyl-CoA carboxylase, methylmalonyl-CoA epimerase, and methylmalonyl-CoA mutase, respectively. Propionyl-CoA carboxylase is called an ABC enzyme due to the requirements for ATP, Biotin, and CO2 for the reaction. The clinical significance of methylmalonyl-CoA mutase in this pathway is that it is one of only two enzymes that requires a vitamin B12-derived co-factor for activity. The other B12-requiring enzyme is methionine synthase (see the Cysteine Synthesis section above). This propionyl-CoA conversion pathway is also required for the metabolism of the amino acids valine, isoleucine, and threonine and fatty acids with an odd number of carbon atoms. For this reason this three-step reaction pathway is often remembered by the mnemonic as the VOMIT pathway, where V stands for valine, O for odd-chain fatty acids, M for methionine, I for isoleucine, and T for threonin

    above from med chem

     

    below from smpdb

    Methionine metabolism in mammals happens within two pathways, a methionine cycle and a transsulfuration sequence. These pathways have three common reactions with both pathways including the transformation of methionine to S-adenosylmethionine (SAM), the use of SAM in many different transmethylation reactions resulting in a methylated product plus S-adenosylhomocysteine, and the conversion of S-adenosylhomocysteine to produce the compounds homocysteine and adenosine. The reactions mentioned above not only produce cysteine, they also create a-ketobutyrate. This compound is then converted to succinyl-CoA through a three step process after being converted to propionyl-CoA. If the amino acids cysteine and methionine are available in enough quantity, the pathway will accumulate SAM and this will in turn encourage the production of cysteine and a-ketobutyrate, which are both glucogenic, through cystathionine synthase. When there is a lack of methionine, there is a decrease in the production of SAM, which limits cystathionine synthase activity.

     

    Mine:

    MEt to SAM give Met product + SAHC which produces homcys and adenosie  also alpha keto butyrate  which then proprionyl  and to succinyll coa. If enough cys and met acumulate SAM lead to Cys and alpha keto 

    MettoSuccinylCoA.png

     

    Special: Branched Chains

    . The three branched-chain amino acids, isoleucine, leucine, and valine enter the catabolic pathway via the action of the same two enzymes. The initial deamination of all three amino acids is catalyzed by one of two branched-chain amino acid transaminases (BCATc or BCATm). The resulting α-ketoacids are then oxidatively decarboxylated via the action of the enzyme complex, branched-chain ketoacid dehydrogenase (BCKD). The BCKD reaction generates the CoA derivatives of the decarboxylated ketoacids while also generating the reduced electron carrier, NADH. After these first two reactions the remainder of the catabolic pathways for the three amino acids diverges. The third reaction of branched-chain amino acid catabolism involves a dehydrogenation step that involve three distinct enzymes, one for each of the CoA derivatives generated via the BCKD reaction. This latter dehydrogenation step also yields additional reduced electron carrier as FADH2. The third reaction of isoleucine catabolism involves the enzyme short/branched-chain acyl-CoA dehydrogenase (SBCAD). The SBCAD enzyme is encoded by the ACADSB gene. The third reaction of leucine catabolism involves the enzyme isovaleryl-CoA dehydrogenase (IVD). The third reaction of valine catabolism involves the enzyme isobutyryl-CoA dehydrogenase (IBD). The IBD enzyme is encoded by the acyl-CoA dehydrogenase family, member 8 (ACAD8) gene. These CoA dehydrogenases belong to the same family of enzymes involved in the process of mitochondrial fatty acid oxidation.

     

    Finally, Asp and Asn

    med:  

    Asparaginase (see above) is also widely distributed within the body, where it converts asparagine into ammonia and aspartate. Aspartate can serve as an amino donor in transamination reacions yielding oxaloacetate, which follows the gluconeogenic pathway to glucose.

    Glutamate and aspartate are important in collecting and eliminating amino nitrogen via glutamine synthetase and the urea cycle, respectively. The catabolic path of the carbon skeletons involves simple 1-step aminotransferase reactions that directly produce net quantities of a TCA cycle intermediate. The glutamate dehydrogenase reaction operating in the direction of 2-oxoglutarate (α-ketoglutarate) production provides a second avenue leading from glutamate to gluconeogenesis.

    Following from:Lieu, E.L., Nguyen, T., Rhyne, S. et al. Amino acids in cancer. Exp Mol Med 52, 15–30 (2020).

    Amino acids in Cancer Metabolism

    Metabolic reprogramming is a staple of cancer cell growth and proliferation. Both essential and nonessential amino acids (EAAs and NEAAs) support altered metabolism by serving as energy sources, biosynthetic molecules, and mediators of redox balance. Amino acids produce metabolic intermediates, such as acetyl-CoA, that sustain energy synthesis through the citric acid cycle. Amino acids also provide building blocks for nucleotide synthesis and lipogenesis that are critical to a cell’s ability to grow and develop. To circumvent the effects of oxidative stress, amino acids can regulate redox balance through their production of glutathione. Furthermore, EAA catabolism contributes to the generation of NEAAs through chemical reactions, including those mediated by transaminases. Amino acids are in green, and other metabolites are in red. Orange represents transporters. Yellow boxes signify enzymes. SHMT1 serine hydroxymethyltransferase, cytosolic, BCAT branched-chain amino acid transaminase, mitochondrial, BCAA branched-chain amino acid (valine, leucine, isoleucine), BCKA branched-chain ketoacid, GOT1 aspartate transaminase, cytosolic (AST), GLS glutaminase, GS glutamine synthetase (cytosolic and mitochondrial), ASNS asparagine synthetase, PRODH pyrroline-5-carboxylate dehydrogenase, PYCR pyrroline-5-carboxylate reductase, P5C pyrroline-5-carboxylate, GSH glutathione, Gly glycine, Ser serine, Met methionine, Met cycle methionine cycle, Gln glutamine, Cys cysteine, Glu glutamate, Asp aspartate, Pro proline, Asn asparagine, Arg arginine, PRPP phosphoribosyl pyrophosphate, acetyl-coA acetyl-coenzyme A, α-KG alpha-ketoglutaric acid, OAA oxaloacetic acid, LAT1 large-neutral amino acid transporter 1, SLC25A44 solute carrier family 25 member 44, GLUT glucose transporter, TCA cycle the tricarboxylic acid (also known as the citric acid cycle).

    Fig. 1

    This figure has been adapted from Lieu, E.L., Nguyen, T., Rhyne, S. et al. Amino acids in cancer. Exp Mol Med 52, 15–30 (2020). https://doi.org/10.1038/s12276-020-0375-3,  This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.  To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

     

    Also metabolites from aa special function in epigentics and redox balance

    Following from:Lieu, E.L., Nguyen, T., Rhyne, S. et al. Amino acids in cancer. Exp Mol Med 52, 15–30 (2020).

    a Amino acids provide metabolic intermediates for epigenetic regulation. One-carbon units from the methionine (shown here) and folate cycle serve as a methyl donor for DNA and histone methyltransferases, while acetyl-CoA from BCAAs and leucine can be utilized for histone acetylation. b Amino acid-derived acetyl-CoA is also involved in protein acetylation modification; a thrombopoietin (TPO)-responsive homodimeric receptor, CD110, activates lysine catabolism, which generates acetyl-CoA for LRP6 (a Wnt signaling protein) acetylation and promotes the self-renewal of tumor-initiating cells of colorectal cancer24c Elevated kynurenine (Kyn) levels originating from tryptophan via the enzymes tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) have been shown in several cancers, including Hodgkin lymphoma, lung cancer, and ovarian cancer. Kynurenine promotes tumor cell survival by both inducing T-cell death and inducing immune tolerance in dendritic cells (DCs). Methylation and acetylation are represented by red Me and blue Ac circles, respectively. Histone methylation and acetylation are represented by curved lines. DNA methylation is represented by a straight line. Amino acids are in green, and other metabolites are in red. Orange represents receptors. Yellow boxes signify proteins. SAM S-adenosylmethionine, SAH S-adenosyl homocysteine, Met methionine, Thr threonine, BCAAs branched-chain amino acids, Leu leucine, Lys lysine, Acetyl-CoA acetyl-coenzyme A, Trp tryptophan, Kyn kynurenine, IFN-γ interferon gamma, mTORC1 mammalian target of rapamycin complex 1, TDH threonine dehydrogenase, EP300 histone acetyltransferase p300, HAT histone acetyltransferase, CD110 myeloproliferative leukemia protein (thrombopoietin receptor), TPO thrombopoietin, IDO indoleamine 2,3-dioxygenase, TDO tryptophan 2,3-dioxygenase, CTLA-4 cytotoxic T-lymphocyte-associated protein 4, TR cell, regulatory T cell.

    Fig. 3

    This figure has been adapted from Lieu, E.L., Nguyen, T., Rhyne, S. et al. Amino acids in cancer. Exp Mol Med 52, 15–30 (2020). https://doi.org/10.1038/s12276-020-0375-3,  This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.  To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

     

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