18.4: An overview of amino acid metabolism and the role of Cofactors (2024)

  1. Last updated
  2. Save as PDF
  • Page ID
    15034
  • \( \newcommand{\vecs}[1]{\overset { \scriptstyle \rightharpoonup} {\mathbf{#1}}}\)

    \( \newcommand{\vecd}[1]{\overset{-\!-\!\rightharpoonup}{\vphantom{a}\smash{#1}}} \)

    \( \newcommand{\id}{\mathrm{id}}\) \( \newcommand{\Span}{\mathrm{span}}\)

    ( \newcommand{\kernel}{\mathrm{null}\,}\) \( \newcommand{\range}{\mathrm{range}\,}\)

    \( \newcommand{\RealPart}{\mathrm{Re}}\) \( \newcommand{\ImaginaryPart}{\mathrm{Im}}\)

    \( \newcommand{\Argument}{\mathrm{Arg}}\) \( \newcommand{\norm}[1]{\| #1 \|}\)

    \( \newcommand{\inner}[2]{\langle #1, #2 \rangle}\)

    \( \newcommand{\Span}{\mathrm{span}}\)

    \( \newcommand{\id}{\mathrm{id}}\)

    \( \newcommand{\Span}{\mathrm{span}}\)

    \( \newcommand{\kernel}{\mathrm{null}\,}\)

    \( \newcommand{\range}{\mathrm{range}\,}\)

    \( \newcommand{\RealPart}{\mathrm{Re}}\)

    \( \newcommand{\ImaginaryPart}{\mathrm{Im}}\)

    \( \newcommand{\Argument}{\mathrm{Arg}}\)

    \( \newcommand{\norm}[1]{\| #1 \|}\)

    \( \newcommand{\inner}[2]{\langle #1, #2 \rangle}\)

    \( \newcommand{\Span}{\mathrm{span}}\) \( \newcommand{\AA}{\unicode[.8,0]{x212B}}\)

    \( \newcommand{\vectorA}[1]{\vec{#1}} % arrow\)

    \( \newcommand{\vectorAt}[1]{\vec{\text{#1}}} % arrow\)

    \( \newcommand{\vectorB}[1]{\overset { \scriptstyle \rightharpoonup} {\mathbf{#1}}}\)

    \( \newcommand{\vectorC}[1]{\textbf{#1}}\)

    \( \newcommand{\vectorD}[1]{\overrightarrow{#1}}\)

    \( \newcommand{\vectorDt}[1]{\overrightarrow{\text{#1}}}\)

    \( \newcommand{\vectE}[1]{\overset{-\!-\!\rightharpoonup}{\vphantom{a}\smash{\mathbf {#1}}}} \)

    \( \newcommand{\vecs}[1]{\overset { \scriptstyle \rightharpoonup} {\mathbf{#1}}}\)

    \( \newcommand{\vecd}[1]{\overset{-\!-\!\rightharpoonup}{\vphantom{a}\smash{#1}}} \)

    \(\newcommand{\avec}{\mathbf a}\) \(\newcommand{\bvec}{\mathbf b}\) \(\newcommand{\cvec}{\mathbf c}\) \(\newcommand{\dvec}{\mathbf d}\) \(\newcommand{\dtil}{\widetilde{\mathbf d}}\) \(\newcommand{\evec}{\mathbf e}\) \(\newcommand{\fvec}{\mathbf f}\) \(\newcommand{\nvec}{\mathbf n}\) \(\newcommand{\pvec}{\mathbf p}\) \(\newcommand{\qvec}{\mathbf q}\) \(\newcommand{\svec}{\mathbf s}\) \(\newcommand{\tvec}{\mathbf t}\) \(\newcommand{\uvec}{\mathbf u}\) \(\newcommand{\vvec}{\mathbf v}\) \(\newcommand{\wvec}{\mathbf w}\) \(\newcommand{\xvec}{\mathbf x}\) \(\newcommand{\yvec}{\mathbf y}\) \(\newcommand{\zvec}{\mathbf z}\) \(\newcommand{\rvec}{\mathbf r}\) \(\newcommand{\mvec}{\mathbf m}\) \(\newcommand{\zerovec}{\mathbf 0}\) \(\newcommand{\onevec}{\mathbf 1}\) \(\newcommand{\real}{\mathbb R}\) \(\newcommand{\twovec}[2]{\left[\begin{array}{r}#1 \\ #2 \end{array}\right]}\) \(\newcommand{\ctwovec}[2]{\left[\begin{array}{c}#1 \\ #2 \end{array}\right]}\) \(\newcommand{\threevec}[3]{\left[\begin{array}{r}#1 \\ #2 \\ #3 \end{array}\right]}\) \(\newcommand{\cthreevec}[3]{\left[\begin{array}{c}#1 \\ #2 \\ #3 \end{array}\right]}\) \(\newcommand{\fourvec}[4]{\left[\begin{array}{r}#1 \\ #2 \\ #3 \\ #4 \end{array}\right]}\) \(\newcommand{\cfourvec}[4]{\left[\begin{array}{c}#1 \\ #2 \\ #3 \\ #4 \end{array}\right]}\) \(\newcommand{\fivevec}[5]{\left[\begin{array}{r}#1 \\ #2 \\ #3 \\ #4 \\ #5 \\ \end{array}\right]}\) \(\newcommand{\cfivevec}[5]{\left[\begin{array}{c}#1 \\ #2 \\ #3 \\ #4 \\ #5 \\ \end{array}\right]}\) \(\newcommand{\mattwo}[4]{\left[\begin{array}{rr}#1 \amp #2 \\ #3 \amp #4 \\ \end{array}\right]}\) \(\newcommand{\laspan}[1]{\text{Span}\{#1\}}\) \(\newcommand{\bcal}{\cal B}\) \(\newcommand{\ccal}{\cal C}\) \(\newcommand{\scal}{\cal S}\) \(\newcommand{\wcal}{\cal W}\) \(\newcommand{\ecal}{\cal E}\) \(\newcommand{\coords}[2]{\left\{#1\right\}_{#2}}\) \(\newcommand{\gray}[1]{\color{gray}{#1}}\) \(\newcommand{\lgray}[1]{\color{lightgray}{#1}}\) \(\newcommand{\rank}{\operatorname{rank}}\) \(\newcommand{\row}{\text{Row}}\) \(\newcommand{\col}{\text{Col}}\) \(\renewcommand{\row}{\text{Row}}\) \(\newcommand{\nul}{\text{Nul}}\) \(\newcommand{\var}{\text{Var}}\) \(\newcommand{\corr}{\text{corr}}\) \(\newcommand{\len}[1]{\left|#1\right|}\) \(\newcommand{\bbar}{\overline{\bvec}}\) \(\newcommand{\bhat}{\widehat{\bvec}}\) \(\newcommand{\bperp}{\bvec^\perp}\) \(\newcommand{\xhat}{\widehat{\xvec}}\) \(\newcommand{\vhat}{\widehat{\vvec}}\) \(\newcommand{\uhat}{\widehat{\uvec}}\) \(\newcommand{\what}{\widehat{\wvec}}\) \(\newcommand{\Sighat}{\widehat{\Sigma}}\) \(\newcommand{\lt}{<}\) \(\newcommand{\gt}{>}\) \(\newcommand{\amp}{&}\) \(\definecolor{fillinmathshade}{gray}{0.9}\)

    Search Fundamentals of Biochemistry

    Amino acid degradation

    We saw how nitrogen is removed from amino acids to produce urea or NH4+ in the previous chapter section. What are the fates of the carbon skeletons that remain? This section is where students might get overwhelmed by the diversity of amino acid degradation pathways, so it helps to realize that carbon skeletons of deaminated amino acids can be used for biosynthesis or energy production and are converted to key glycolytic and TCA intermediates that you have seen many times before. Everything is interconnected which makes the study of metabolism daunting but also fascinating, as organisms try to extract all the energy and molecule-building atoms from a metabolite and minimize waste.

    Here are some key features of amino acid catabolism:

    • 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 acetoacetyl-CoA and or acetyl-CoA. Bothcan 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 there 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 anet fashion to the TCA cycle and don't remove the existing pool of TCA intermediates, they can produce in anet fashion directly or indirectly molecules that can be used to produce glucose. These entry reactions to the TCA which replenish or add to TCA intermediates are called anaplerotic (replenishing) reactions. Hence these amino acids are also glucogenic.
    • some have multiple ways to be degraded and can produce both acetyl-CoA and pyruvate, so they are both glucogenic 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 including the aromatics - Trp, Tyr, Phe - and Ile/Thr
    • purely glucogenic: the rest

    General hints if an amino acid is glucogenic and/or ketogenic derived from their structure.

    Fully or Partly Ketogenic Amino Acids: Amino acids except for Arg that have a continuous chain of 3 or more carbon atoms in their side chains and hence are more "fat-like" are ketogenic or ketogenic/glucogenic. These include Lys, Leu, Ile, and the aromatic amino acids Phe, Trp, and Tyr and exclude Val. (note: Thr, which is both ketogenic and glucogenic, doesn't fit this rule). The fully or partly ketogenic amino acids are shown in Figure \(\PageIndex{1}\).

    Purely Glucogenic Amino Acids (for Pyr and/or TCA intermediates): Which amino acids producewhich intermediate? Except for glycine, it's pretty easy to remember. The number of carbons in the intermediate formed is the same as the number of carbons in the longest chain in the amino acid.

    These amino acids form the 5C TCA intermediate alpha-ketoglutarate (2-oxoglutarate) and are shown in Figure \(\PageIndex{2}\).

    18.4: An overview of amino acid metabolism and the role of Cofactors (4)

    These amino acids form either the 4C TCA intermediate succinate or oxaloacetate. Amino acids with more oxidized 4C atoms in the continuous chain produced oxaloacetate (which is more oxidized than succinate), while the least oxidized ones produce succinate acid (which is more reduced than oxaloacetate). These amino acids are shown in Figure \(\PageIndex{3}\).

    18.4: An overview of amino acid metabolism and the role of Cofactors (5)

    The 3C amino acids, Ser, Ala, and Cysform pyruvate, as shown in Figure \(\PageIndex{4}\). The only 2C amino acid, glycine, does as well.

    18.4: An overview of amino acid metabolism and the role of Cofactors (6)

    Figure \(\PageIndex{4}\): Glucogenic Amino Acids Converted to 3C pyruvate

    A full figure summarizing everything above is shown in Figure \(\PageIndex{5}\)!

    18.4: An overview of amino acid metabolism and the role of Cofactors (7)

    With a little help from my friends: Cofactors and Amino Acid Catabolism

    The myriad of breaking, making, and rearranging of carbon atoms in amino acid catabolism is daunting. As with all reactions, a pathway for a flow of electrons and stabilization of transition states and intermediates must be in place for the reactions to occur. All methods of catalysis (general acid/base, covalent/nucleophilic catalysis, electrostatic/metal ion catalysis, preferential stabilization of the transition state occur. Yet some reactions need additional"helpers" or "cofactors" to facilitate electron flow and shuttle small motifs (from electrons in redox reactions to methyl groups in methylases) from one molecule to another. We've seen the important role of pyridoxal phosphate in transaminations/aminotransferases in the previous section. Even the terminology cofactor is a bit confusing since analogous terms are used in different contexts:

    • cofactors - nonprotein small molecules or ions (divalent ions, transition metal ions, and Fe/S clusters for example) that must bind to an enzyme, but once bound usually stay put. That is, they don't dissociate during the catalytic cycle. For instance, PLP must initially bind to an enzyme but then becomes covalently attached through a Schiff base through the epsilon amino group of a Lys in the catalytic site. That linkage might swap with an incoming amino acid substrate, for example, but reforms in the catalytic cycle so the enzyme remains functional.
    • coenzyme - a vitamin derivative organic cofactor, as compared to inorganic ions, for example. Coenzyme is a poor historical name that persists.
    • prosthetic group - this is usually a coenzyme that is either covalently bound (like PLP) or noncovalently bound with such a low KD (like FAD/FADH2-containing enzymes) that they stay bound
    • cosubstrate - these bind as substrate (for example NAD+), and depart as products (for example NADH).

    Here is a table of common nonmetallic cofactors.

    Cofactor Vitamin Derivative Carrier
    biotin H - biotin 1 C - CO2 (most oxidized)
    tetrahydrofolic acid (FH4 or THF) B9 - folic acid 1C - formyl, -(C=O)H, methylene (-CH2) (more reduced) and methyl -CH3
    cobalamin B12 - cobalamin methyl CH3
    thiamine pyrophosphate B1 - Thiamine 2C group
    coenzyme A B5 - pantothenic acids acetyl (CH3-C=O) and acyl (R-C=O)
    pyridoxal phosphate B6 - pyridoxine amino and carboxyl groups
    NAD+/NADP+ B3 - Niacin electrons
    FAD/FMN B2 - riboflavin electrons

    Examples of other nonvitamin cofactors include S-adenosylmethionine (SAM or adoMet), a carrier of methyl groups, coenzyme Q, a carrier of electrons, tetrahydrobiopterin, a carrier of oxygen and electrons, and of course heme, a carrier of electrons.

    We've already described amino acid deaminationreactions using PLP. Now let's consider the biochemistry of two of these cofactors involved in 1 C transfers in amino acid metabolism in more detail, tetrahydrofolate (FH4) and SAM.

    Tetrahydrofolate (FH4)

    Tetrahydrofolate (FH4) is a key cofactor in the metabolism of amino acids but it is also critical in the biosynthesis of nucleotides. It is also commonly abbreviated as THF, especially in the names of enzymes that use it. To avoid confusion with chemists'use of THF for tetrahydrofuran, it will be referred to mostly here as FH4 but the enzymes will be named as derivatives of the abbreviation XHF (X = D for dihydro and T for tetrahydro.

    FH4 is a carrier of 1 C units in various oxidation states. It receives 1C units and then transfers them to other species. The structure of FH4 and derivatives carrying 1 C units with different oxidation numbers (indicating their oxidation state) are shown in Figure \(\PageIndex{6}\).

    18.4: An overview of amino acid metabolism and the role of Cofactors (8)

    FH4 is made from the vitamin folate (bacteria, fungi, and most plants can synthesize it), which gets converted first to dihydrofolate (FH2),and then tetrahydrofolate (FH4), using NADPH as a reducing substrate "cofactor", by the enzyme dihydrofolate reductase. The model below shows this small enzyme with NADPH (NADP+) and folate bound to DHFR (7dfr). Folate (FOL) is shown in salmon space fill while NADPH is shown in cyan.

    Figure \(\PageIndex{7}\) shows an interactive iCn3D model of dihydrofolate reductase with bound NADPH (NADP+) and folate (7dfr).

    18.4: An overview of amino acid metabolism and the role of Cofactors (9)

    18.4: An overview of amino acid metabolism and the role of Cofactors (10) Figure \(\PageIndex{7}\): Dihydrofolate reductase with bound NADP+ and folate (7dfr). (Copyright; author via source). Click the image for a popup or use this external link: https://structure.ncbi.nlm.nih.gov/i...ojdpBZuQH8Lm96

    Folate (FOL) and NADP+ (NAP) are shown in spacefill and CPK colors. The side chain of Asp 27 is shown in sticks and CPK colors. The oxygen atoms of two water molecules interacting with folate are shown as red spheres. A disordered and hence mobile loop (residues 16-20) that is involved in binding the nicotinamide is shown in cyan.

    As FH4 is a key substrate in many reactions, including nucleotide synthesis (as we shall see later), this enzyme is a key target for chemotherapy to kill cancer cells which require robust nucleotide synthesis for rapid cell proliferation. One such drug, which inhibits the enzyme, methotrexate, is shown in Figure \(\PageIndex{8}\).

    18.4: An overview of amino acid metabolism and the role of Cofactors (11)

    Before getting into the nitty-gritty of amino acid degradation and tetrahydrofolate chemistry, let's take a look at the mechanism by which dihydrofolate reductase, DHFR, catalyzes the sequential reduction by 2 NADPH molecules of folate to tetrahydrofolate. This is illustrated in Figure \(\PageIndex{9}\).

    18.4: An overview of amino acid metabolism and the role of Cofactors (12)

    One Carbon Chemistry: The Interconversion of FH4 1C derivatives

    Tetrahydrofolate is a carrier for 1C units in metabolism. As such, is it intimately involved in many anabolic and catabolic reactions. These include thymidine and purine biosynthesis and amino acids metabolism through reactions involving serine, glycine (both with 1C in their side chains), and methionine (with 1C after the sulfur in the side chain). The reactions take place in both the cytoplasm and mitochondria. FH4 is involved directly or indirectly in epigenetic control of DNA expression as well, as methylation of both DNA and histones is critical to gene expression. The myriad of 1C derivatives of FH4 make the biochemistry complex, but as the transfer of 1C is a critical job in both the breakdown of the carbon skeleton of amino acids and biosynthesis, we need to explore it. The complexity is simplified by noting that the 1C derivatives have only three different oxidation states (+2, 0, and -2), as noted in Figure \(\PageIndex{10}\).

    18.4: An overview of amino acid metabolism and the role of Cofactors (13)

    1C units usually enter FH4 as the N5,N10 methylene unit. This is made in both the cytoplasm and mitochondria since 1C-derivatizedFH4 appears not to cross the mitochondrial membranes. The methylene derivative, with a 1C oxidation # of 0, can be reduced to form methyl (oxidation # -2) or oxidized to methenyl or formyl groups (oxidation # +2).

    We will see some of these reactions again in chapters dealing with amino acid and nucleotide biosynthesis. That's not a bad thing - learning occurs best on the repetition of material in different contexts.

    Methylcobalamin and5N-methyl FH4

    Methyl groups can be stored and subsequently transferred from 5N-methyl FH4to another cofactor, cobalamine to form methylcobalamin (Vitamin B12). The -CH3can then be transferred to homocysteine (the side chain is the same as for Cys but with 1 extrac -CH2- methylene group)to form methionine. This adds to the complexity of 1C transfer but the iCn3D models below should help you to differentiate the chemical structures of each.

    Here is a model of methylcobalamin (vitamin B12)in ball and stick form.

    Note the -CH3connected to the center cobalt in the macrocyclic ring.

    In contrast, here is the structure of N5-methyl FH4.

    The-CH3here is connected to a ring N5 of FH4.

    Serine Hydroxymethyltransferase (SHMT): A complex reaction needed two cofactors - PLP and FH4

    Let's look in detail at one mechanism that shows how a 1C methylene is added to tetrahydrofolate (FH4). The mechanism shown is for serine dehydratase, aka serine hydroxymethyltransferase. The enzyme not only uses tetrahydrofolate as a substrate but also PLP, which, as we have seen previously, makes bonds to the alpha-carbon of amino acids labile to cleavage. In this case, the amino acid serine becomes dehydrated through an alpha-elimination reaction. Here is the overall reaction.

    Serine + FH4 ↔ Glycine + N5,N10-CH2-FH4 + H2O

    Figure \(\PageIndex{11}\) shows the dehydration reaction and formation of glycineusing PLP as a cofactor. Figure B shows how the released formaldehyde reacts with FH4 to form N5,N10-methylene FH4,using FH4 as a cofactor. As this is needed in purine and thymidylate synthesis, SHMT is a target for malaria treatment as well.

    18.4: An overview of amino acid metabolism and the role of Cofactors (14)

    Glu 57 plays a key role as a general acid/base throughout the catalytic cycle of the enzyme.

    Pathway diagrams showing a myriad of reactants, products, and enzymes can be confusing to students (and to authors as well). It's useful to think about them and see them in different ways. Here is another way to present the conversion of FH4 and its various 1C intermediates. Figure \(\PageIndex{12}\) concentrates on the outputs of 1C FH4 derivatives (shown in blue eclipses).

    18.4: An overview of amino acid metabolism and the role of Cofactors (15)

    The enzymes catalyzing these reactions are shown in the table below. This figure applies to both catabolic and anabolic reactions using FH4 derivatives. Oxidation numbers for the 1C adducts are shown. Any reaction that involves a change in redox state must use NAD(P)+/NAD(P)H as a redox reagent.

    • N5,N10-methylene FH4 gives thymidine and serine
    • N5-methyl FH4 gives methionine
    • N10-formyl FH4 gives formate, purines, and CO2
    • N5-formyl serves more as a passive reservoir of 1C units.

    Table \(\PageIndex{1}\): Enzymes catalyzing interconversions of THF derivatives

    Abbreviation Enzyme Name
    ALDH 10-formyltetrahydrofolate((aldehyde) dehydrogenase.
    DHFR Dihydrofolate reductase
    MTHFD methylenetetrahydrofolate dehydrogenase
    MTHFD1 C-1-tetrahydrofolate synthase, cytoplasmic
    MTHFD1L monofunctional tetrahydrofolate synthase, mitochondrial
    MTHFD2/L methylenetetrahydrofolate dehydrogenase 2/2-like
    MTFMT mitochondrial methionyl-tRNA formyltransferase
    MTHFR methylenetetrahydrofolate reductase
    MTR methionine synthase
    TYMS thymidylate synthetase

    A key enzyme in these reactions, methylene-THF reductase (MTHFR), irreversibly removes 1C from the cycle depicted above as it forms N5-methyl FH4. As this reaction is a reduction, it requires a reducing agent (NADPH in yeast and animals and NADH in plants). This irreversible removal would deplete the cycle shown so it is allosterically regulated (inhibited) by another methylating agent, S-adenosylmethionine (SAM aka adoMet), as we will see next. Plant versions of the enzyme are reversible so there is no need for regulation by SAM in this feedback loop process.

    S-adenosylmethionine (SAM), also known asadoMet

    N5-methyl FH4 appears to have one function, to methylate a molecule called homocysteine (same as Cys but with an extra -CH2 in the side chain) to methionine. This is adenosylated (not phosphorylated!) with ATP to produce S-adenosylmethionine (SAM), a more potent methylating agent than N5-methyl FH4. SAM is hence part of a cycle involving N5-methyl-FH4. The methyl group of N5-methyl FH4 reacts with homocysteine to produce methionine, catalyzed by the enzyme methionine synthase, which requires cobalamin (vitamin B12) as a cofactor. The combined Figure \(\PageIndex{13}\) adds the Met and Folate cycles (showing the outputs of the 1C Folate metabolism cycle

    18.4: An overview of amino acid metabolism and the role of Cofactors (16)

    Figure \(\PageIndex{14}\) shows the structures of molecules in the Met Cycle.

    18.4: An overview of amino acid metabolism and the role of Cofactors (17)

    The mechanism of methyl transfers using SAM as the -CH3 donor involves a SN2 attack by a nucleophile of the substrate on the CH3 of SAM, with the electron pair from the C-S bond going to the positively charged sulfonium sulfur, a great "electron sink". An analogous nucleophilic attack on the terminal CH3 of plain old methionine would not be readily enabled. Hence SAM, with its charged S, has a much higher methyl transfer potential than N5-CH3-FH4.

    In the actual reaction catalyzed by methionine synthase (MS) in mammals, the methyl -CH3 from N5-methyl FH4 is first transferred to cobalamin, a derivative of vitamin B12, to form methylcobalamin, which then transfers it to homocysteine. The structure of the C-terminal half of B12-dependent Methionine Synthase from E. Coli with bound adenosylhomocysteine bound (3iva) is shown below and in this link:

    Figure \(\PageIndex{15}\) shows an interactive iCn3D model of the C-terminal half of B12-dependent Methionine Synthase from E. Coli with bound adenosylhomocysteine bound (3iva)

    18.4: An overview of amino acid metabolism and the role of Cofactors (18)

    18.4: An overview of amino acid metabolism and the role of Cofactors (19) Figure \(\PageIndex{15}\): C-terminal half of B12-dependent Methionine Synthase from E. Coli with bound adenosylhomocysteine bound (3iva). (Copyright; author via source). Click the image for a popup or use this external link: https://structure.ncbi.nlm.nih.gov/i...E7jTsdvVvx1M1A

    In mammals, vitamin B12 is a key cofactor in only two enzymes, one being methionine synthase. The other catalyzes the conversion of methylmalonyl-CoA (derived from the metabolism ofIle, Thr, Val and Met (as we will see in the next chapter section)to succinyl-CoA in the citric acid cycle.If vitamin B12 is lacking, N5-methyl FH4 builds up when it can't be transferred to cobalamin to form methylcobalamin, the direct methylating agent in methionine synthesis catalyzed by methionine synthase. Hence homocysteine builds up as it can't form methionine. Since the enzyme that converts N5,N10-methylene FH4 to N5-methyl FH4, methylenetetrahydrofolate reductase (MTHFR), is irreversible, levels of N5-methyl FH4are high. You can viewN5-methyl FH4as a storage form of folate so if there is a lack of B12, the use of thisstorage form of folate becomes impaired.Results of B12 deficiency include megaloblastic anemia.

    The Serine Glycine One Carbon (SGOC) Metabolic Cycle

    Figure 12 shows the coupled Folate and Methionine cycles that emphasize the intermediates involved in the 1C -CH3 transfer reaction, an important part of amino acid metabolism and other anabolic and catabolic reactions as well. Interpreting metabolic figures is complicated. Each is designed to emphasize certain selected features. Another way to present Figure 12 is to emphasize metabolites involved in 1C chemistry in general. Figure \(\PageIndex{145}\) shows what has been called the Serine Glycine One Carbon (SGOC) metabolic cycle. It is just a redrawn version of Figure 12 with attention drawn to non-FH4molecules involved in 1C transfers, namely serine, glycine, and also formate.

    18.4: An overview of amino acid metabolism and the role of Cofactors (20)

    This cycle and its key substrates, serine, and glycine, integrate many metabolic pathways and controls the conversion of serine and glycine into outputs essential for other pathways. We will see this cycle again in the chapter on the biosynthesis of amino acids. The pathway is especially important in tumor cells, which need precursors for nucleic acid, protein, and lipid synthesis.

    18.4: An overview of amino acid metabolism and the role of Cofactors (2024)
    Top Articles
    Latest Posts
    Recommended Articles
    Article information

    Author: Gov. Deandrea McKenzie

    Last Updated:

    Views: 5782

    Rating: 4.6 / 5 (46 voted)

    Reviews: 93% of readers found this page helpful

    Author information

    Name: Gov. Deandrea McKenzie

    Birthday: 2001-01-17

    Address: Suite 769 2454 Marsha Coves, Debbieton, MS 95002

    Phone: +813077629322

    Job: Real-Estate Executive

    Hobby: Archery, Metal detecting, Kitesurfing, Genealogy, Kitesurfing, Calligraphy, Roller skating

    Introduction: My name is Gov. Deandrea McKenzie, I am a spotless, clean, glamorous, sparkling, adventurous, nice, brainy person who loves writing and wants to share my knowledge and understanding with you.