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18.5: Pathways of Amino Acid Degradation

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    Search Fundamentals of Biochemistry


    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-adenosylmethionine in 1C transfer reactions. Now we can focus on how the carbon skeletons of amino acids are processed during degradation.

    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 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 a net fashion to the TCA cycle and don't remove the existing pool of TCA intermediates, they can produce in a net 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 are, including the aromatics - Trp, Tyr, Phe - along with Ile/Thr
    • purely glucogenic: the rest

    Figure \(\PageIndex{1}\), also shown in the previous sections, summarizes the fates of the 20 amino acids in their catabolic reactions


    Figure \(\PageIndex{1}\): Fates of the 20 amino acids in their catabolic reactions


    Given the myriad of enzymes and pathways involved, we won't delve into the mechanisms for the reactions or the structures of the enzymes, with the exception of one for lysine metabolism.

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

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

    Figure \(\PageIndex{2}\) shows an overview of the conversion of amino acids to pyruvate. More details are provided for each of the steps below.


    Figure \(\PageIndex{2}\): Overview of conversion of amino acids to pyruvate

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

    Tryptophan to alanine and on to acetoacetate

    This is a multistep process as shown in Figure \(\PageIndex{3}\).


    Figure \(\PageIndex{3}\): Conversion of Tryptophan to Alanine and to acetoacetate

    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 acetoacetate, a ketone body which can breakdown to acetyl-CoA (making tryptophan ketogenic as well as glucogenic) or NAD+.


    Alanine to Pyruvate

    As described in 18.2, and shown in Figure \(\PageIndex{4}\), the PLP-dependent enzyme ALanine Amino Transferase (ALT), also known as Glutamate Pyruvate Transaminase (GPT), catalyzes this simple transamination reaction:

    alanine +α−ketoglutarate ↔ pyruvate + glutamate


    Figure \(\PageIndex{4}\): Alanine to pyruvate

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

    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

    These reactions are illustrated in Figure \(\PageIndex{5}\).


    Figure \(\PageIndex{5}\): Threonine to glycine

    A second and predominate reaction involves the conversion of Thr to NH4 + and α-ketobutyrate by the PLP-dependent enzyme 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 intermediate, α-ketobutyrate.

    Rx: Thr ↔ NH4 + + α-ketobutyrate

    α-ketobutyrate can then be converted to propionyl-CoA.

    Rx: α-ketobutyrate + NAD+ + CoASH ↔ propionyl-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.

    Propionyl CoA is then converted eventually in several mitochondrial steps to succinyl CoA for entrance into the TCA cycle. Three enzymes are required for this conversion: propionyl CoA carboxylase, methylmalonyl-CoA epimerase, and methylmalonyl-CoA mutase. Propionyl 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 referred to as an ABC enzyme.

    The three-step conversion pathway of propionyl CoA to succinyl CoA is also used for in the degradation of Valine, Odd-chain fatty acids (which form multiple 2-carbon acetyl CoA units and 1 3-C propionyl 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 dehydrated through an alpha-elimination reaction. However, threonine has an extra CH3 group which is released as acetaldehyde. Here is the overall reaction.

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

    The enzymes 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.

    Glycine to Serine

    As mentioned above, this reversible reaction is catalyzed by serine hydroxymethyltransferase (SHMT) (see the 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 + FH4

    Figure \(\PageIndex{6}\) shows the serine dehydratase reaction presented in Chapter 18.4 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 FH4 to form N5,N10-methylene FH4, using FH4 as a cofactor.


    Figure \(\PageIndex{6}\): Reversible reaction of Serine to Glycine

    Serine to Pyruvate

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

    Rx: Serine ↔ Pyr + NH4+

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

    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.

    The reaction pathway is shown in Figure \(\PageIndex{7}\).


    Figure \(\PageIndex{7}\): Cysteine to pyruvate

    Other important metabolites are made from cysteine catabolic pathways. One is taurine, which is 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-enzymatic 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 produce sulfated sugars using in glycolipid and proteoglycan synthesis. This is illustrated in Figure \(\PageIndex{8}\).


    Figure \(\PageIndex{8}\): Sulfate conversion to PAPS

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

    An overview of the many reactions in ketogenic amino acid degradation is shown in Figure \(\PageIndex{9}\). 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.


    Figure \(\PageIndex{9}\): Ketogenic amino acid pathway

    Trp to acetyl-CoA

    Fortunately, we have explored the conversion of the non-ring part of tryptophan to alanine and 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 in Figure \(\PageIndex{10}\). As Trp is a ketogenic amino acid, it seems appropriate to show the steps that lead to acetyl-CoA even at the risk of providing too much detail.

    Trp_fromACMS_to acetoacetate052422.svg

    Figure \(\PageIndex{10}\): Part 2 - Tryptophan to acetyl-CoA

    Lys metabolism

    In the liver, the main pathway (of several) starts with the formation of saccharopine from the transamination reaction of lysine and α-ketoglutarate, allowing the ε-amino group of lysine to enter the nitrogen metabolic pool. This transamination does not use pyridoxal phosphate (PLP). The first two steps of the reaction are catalyzed by an enzyme, α-aminoadipic semialdehyde synthase, with two activities (condensation/reduction and hydrolysis/oxidation). Lysine is an essential amino acid since the transamination is not reversible. Figure \(\PageIndex{11}\) shows pathways for the conversion of lysine to acetoacetyl-CoA and acetyl-CoA.


    Figure \(\PageIndex{11}\): Pathways for conversion of lysine to acetoacetyl-CoA and acetyl-CoA.

    The lysine-oxoglutarate reductase (LOR) and saccharopine dehydrogenase (SDH) are found in one bifunctional enzyme, often called aminoadipic semialdehyde synthase.

    Figure \(\PageIndex{12}\) shows an interactive iCn3D model of the AlphaFold predicted structure of aminoadipic semialdehyde synthase (Q9UDR5)

    AlphaFold predicted structure of aminoadipic semialdehyde synthase (Q9UDR5).png

    NIH_NCBI_iCn3D_Banner.svg Figure \(\PageIndex{12}\): AlphaFold predicted structure of aminoadipic semialdehyde synthase (Q9UDR5). (Copyright; author via source). Click the image for a popup or use this external link:

    The cyan domain represents the lysine-oxoglutarate reductase (LOR) domain. It is connected by a well-predicted alpha helix to the magenta saccharopine dehydrogenase (SDH) domain.

    Phenylalanine conversion to Tyrosine and continues to acetoacetate

    We'll follow the conversion of phenylalanine to tyrosine, which continues on to acetoacetate, making Phe and Tyr both ketogenic amino acids, and in subsequent steps that produce fumarate. They can enter the TCA cycle leading to the net production of oxaloacetate, which can be pulled off into gluconeogenesis, making both Phe and Try glucogenic as well.

    A new cofactor that facilitates electron flow in the conversion of Phe to Try in the first step, catalyzed by the enzyme tyrosine hydrolase, is required. That cofactor is tetrahydrobiopterin (BH4). The reaction involves the hydroxylation of BH4 and then its transfer to phenylalanine. Figure \(\PageIndex{13}\) shows a possible mechanism for the conversion of phenylalanine to tyrosine with tetrahydrobiopterin (BH4).


    Figure \(\PageIndex{13}\): Conversion of phenylalanine to tyrosine with tetrahydrobiopterin (BH4)

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

    Figure \(\PageIndex{14}\) shows the full pathway for the conversion of Phe and Tyr to acetoacetate and fumarate.


    Figure \(\PageIndex{14}\): Conversion of phenylalanine and tyrosine to acetoacetate and fumarate

    Leu to Acetoacetate

    The conversion of leucine to acetoacetate is shown in Figure \(\PageIndex{15}\).


    Figure \(\PageIndex{15}\): Conversion of leucine to acetoacetate

    The first reaction is a transamination using the PLP-dependent branched-chain aminotransferase (BCAT) with α-ketoglutarate.

    Isoleucine to Acetyl-CoA

    Figure \(\PageIndex{16}\) shows the pathway for the conversion of isoleucine to acetyl-CoA.


    Figure \(\PageIndex{16}\): Pathway for conversion of isoleucine to acetyl-CoA.

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

    Proline and Arginine

    The conversion of proline (bottom left) to glutamate (top left) is shown in Figure \(\PageIndex{17}\).


    Figure \(\PageIndex{17}\): Conversion of proline (bottom left) to glutamate (top left)

    Glutamate can then form α-ketoglutarate so the reaction is glucogenic.

    The conversions of arginine (and proline) to α-ketoglutarate are shown in Figure \(\PageIndex{18}\).


    Figure \(\PageIndex{18}\): Conversion of arginine and proline to α-ketoglutarate


    The conversion of histidine to α-ketoglutarate is shown in Figure \(\PageIndex{19}\).


    Figure \(\PageIndex{19}\): Conversion of histidine to α-ketoglutarate

    As described in the reactions above, can be converted to α-ketoglutarate through transamination reactions. Also, we described in a previous section how glutamine 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 and the branched-chain amino acids 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 propionyl-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.


    The conversion of valine to succinyl-CoA is shown in Figure \(\PageIndex{20}\).


    Figure \(\PageIndex{20}\): Conversion of valine to succinyl-CoA

    The other two amino acids with branched-chain carbon chains (isoleucine and leucine), use the same enzymes as valine to enter the degradation pathway. They start with branched-chain transaminases (BCATc or BCATm) followed by oxidative decarboxylation reactions catalyzed by branched-chain ketoacid dehydrogenase (BCKD). Three different enzymes are required for the following dehydrogenase reaction. These are short/branched-chain acyl-CoA dehydrogenase (SBCAD) for isoleucine, isovaleryl-CoA dehydrogenase (IVD) for leucine, and isobutyryl-CoA dehydrogenase (IBD) for valine.


    Methionine can be metabolized to S-adenosylhomocysteine (SAM) and on to cysteine and α-ketobutyrate, which can also be produced by a transsulfuration reaction, the produces cysteine. That product is metabolized using branched chains dehydrogenases to eventually produce succinyl-CoA, a TCA intermediate. Three enzymes are needed to convert the α-ketobutyrate to succinyl-CoA. Propionyl-CoA carboxylase uses ATP, biotin, and CO2 while the methylmalonyl-CoA mutase requires vitamin B12. An addition enzyme is an epimerase reaction in which D-methylmalonyl-CoA into L-methylmalonyl-CoA The conversion of propionyl-CoA to succinyl-CoA also occurs for branched-chain amino acids (Val, Ile, Thr) as well as Met, and in addition Odd number fatty acids. This odd assortment of substrates for conversion to succinyl-CoA leads to the name VOMIT pathways. These reactions are illustrated in Figure \(\PageIndex{21}\).


    Figure \(\PageIndex{21}\): Methionine conversion to succinyl-CoA

    Finally, Aspartate and Asparagine

    Asparagine is converted to NH3 and aspartate using the enzyme asparagine. Aspartate is then used in a transamination reaction to form oxaloacetate, a gluconeogenic precursor. Aspartate participates in the urea cycle as a way to eliminate nitrogen. Glutamate also acquires NH3 through the reaction catalyzed by glutamine synthase.

    Both amino acids are substrates for transamination reactions to produce TCA intermediates. Glutamate dehydrogenase can lead to alpha-ketoglutarate.

    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.

    This page titled 18.5: Pathways of Amino Acid Degradation is shared under a not declared license and was authored, remixed, and/or curated by Henry Jakubowski and Patricia Flatt.