18.5: Pathways of Amino Acid Degradation

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Learning Goals 

 

(Learning goals written by Claude, Sonnet 4.6, Anthropic)

Amino Acid Catabolism to Pyruvate and Acetyl-CoA

• Trace the catabolic routes by which alanine, serine, cysteine, glycine, threonine, and tryptophan are converted to pyruvate, identifying the type of reaction (transamination, dehydration, deamination) and the cofactor required at each step, and explain how the net reactions for each amino acid are equivalent to deamination followed by carbon skeleton entry into glycolysis or gluconeogenesis.
• Describe the catabolic pathways by which the purely ketogenic amino acids leucine and lysine, along with the dual glucogenic/ketogenic amino acids tryptophan, phenylalanine, tyrosine, and isoleucine, are converted to acetoacetyl-CoA and/or acetyl-CoA, and explain the role of tetrahydrobiopterin (BH4) as an electron carrier in the phenylalanine hydroxylase reaction that converts phenylalanine to tyrosine.

Amino Acid Catabolism to TCA Cycle Intermediates

• Describe the pathways by which glutamine, glutamate, proline, arginine, and histidine are converted to α-ketoglutarate, explaining how each pathway produces a TCA cycle intermediate and why these amino acids are glucogenic.
• Explain the VOMIT pathway — tracing the conversion of valine, odd-chain fatty acid products, methionine, isoleucine, and threonine to propionyl-CoA and then to succinyl-CoA — identifying the three enzymes required (propionyl-CoA carboxylase, methylmalonyl-CoA epimerase, and methylmalonyl-CoA mutase) and the cofactors biotin, ATP, and vitamin B12 used at each step.
• Describe how aspartate and asparagine enter the TCA cycle via oxaloacetate — including the role of L-asparaginase in converting asparagine to aspartate and the subsequent PLP-dependent transamination — and explain the dual role of aspartate as both a carbon source for the TCA cycle and a nitrogen donor in the urea cycle.

Integration of Amino Acid Catabolism with Energy Metabolism

• Explain how the catabolic fate of each amino acid (pyruvate, acetyl-CoA, or a specific TCA intermediate) determines whether it is glucogenic, ketogenic, or both, and use this framework to predict under which physiological conditions — fasting, starvation, diabetes, or fed state — amino acid catabolism makes the largest contribution to gluconeogenesis and energy production.
• Describe how the branched-chain amino acids (leucine, isoleucine, and valine) share common early catabolic steps through branched-chain aminotransferases (BCAT) and the branched-chain α-ketoacid dehydrogenase complex (BCKD), and explain why disruptions in these shared enzymes cause a spectrum of metabolic disorders affecting multiple amino acids simultaneously.

Introduction

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 can be converted into ketone bodies (acetoacetate and β-hydroxybutyrate), which 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 a 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, either 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 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 two 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, except for lysine metabolism.

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

We concluded Section 18.3 with a discussion of the Ser Gly One Carbon Cycle (SGOC), so some of this will be a review.

Figure \(\PageIndex{2}\) shows an overview of the conversion of amino acids to pyruvate. More details are provided for each step 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 above, Ala is presented almost as a side product as the modified aromatic ring found in either anthranilate or 3-hydroxyanthranilate continues to form either acetoacetate, a ketone body which can break down 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, as shown below:

glutamate + H₂O + NAD⁺ →  α-ketoglutarate + NADH + H⁺ 

The sum (net) of the two reactions is: 

Alanine + H₂O + NAD⁺ →  pyruvate + NADH + H⁺ 

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, predominant reaction involves the conversion of Thr to NH₄ ⁺ and α-ketobutyrate by the PLP-dependent enzyme Ser/Thr dehydratase (also called threonine ammonia-lyase).  We saw this enzyme 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), is an oxidative decarboxylation. 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 Krebs cycle metabolites.

Propionyl-CoA is then converted, in several mitochondrial steps, to succinyl-CoA for entry 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 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 the 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 forms bonds to the alpha-carbon of amino acids that are labile to cleavage. In this case, the amino acid threonine dehydrates 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 literature is a bit unclear about the enzymes involved in this reaction. SHMT appears to act on Thr at a lower rate, but a second enzyme, threonine aldolase, which seems to be functional in other organisms, acts on Thr.

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 FH_4^, 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 primarily participates 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, the most abundant free amino acid in the body.  It is especially abundant in development and early milk. It is synthesized predominantly 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 these pathways is utilized to synthesize an interesting derivative of ATP, 3′-phosphoadenosine-5′-phosphosulfate (PAPS), which is subsequently used to produce sulfated sugars essential for 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.

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

Lys metabolism

In the liver, the main pathway (of several) begins with the formation of saccharopine via the transamination of lysine with 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 the enzyme α-aminoadipic semialdehyde synthase, which has two activities (condensation/reduction and hydrolysis/oxidation). Lysine is an essential amino acid because its transamination is irreversible. 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 a single bifunctional enzyme, often referred to as aminoadipic semialdehyde synthase.

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

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: https://structure.ncbi.nlm.nih.gov/i...Pi1c7Y5A9DmLa8

The cyan domain represents the lysine-oxoglutarate reductase (LOR) domain, which is connected by an alpha helix to the magenta saccharopine dehydrogenase (SDH) domain.

Phenylalanine is converted to Tyrosine and continues to acetoacetate

We'll follow the conversion of phenylalanine to tyrosine, which proceeds to acetoacetate, resulting in both phenylalanine and tyrosine (ketogenic amino acids), and subsequently produces 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 is required that facilitates electron flow in the conversion of Phe to Try in the first step, catalyzed by the enzyme tyrosine hydrolase. That cofactor is tetrahydrobiopterin (BH₄). The reaction involves the hydroxylation of BH_4, followed by 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 of converting 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 converting 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

Histidine

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

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

As described above, histidine can be converted to α-ketoglutarate via transamination reactions. Additionally, we described in a previous section how glutamine can be deaminated by glutaminase to form glutamate, which can subsequently be converted to α-ketoglutarate, a gluconeogenic intermediate.

Conversion to succinyl-CoA: Met and the branched-chain amino acids Ile, Thr, Val

We have just seen that two branched-chain amino acids, Leu and Ile, are converted to acetyl-CoA and, therefore, are ketogenic (E and F above). The branched-chain hydrophobic amino acids, Val and Leu, can be converted to succinyl-CoA, which can be converted to α-ketoglutarate in the Krebs' cycle in a 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-chain amino acids, also form propionyl-CoA, which is then converted to succinyl-CoA. So, let's consider Val, another branched-chain amino acid, before we consider Met, both of which have three C atoms in their side chains.

Valine

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

Methionine can be metabolized to S-adenosylhomocysteine (SAM) and on to cysteine and α-ketobutyrate, which can also be produced by a transsulfuration reaction that produces cysteine. That product is metabolized using branched-chain dehydrogenases to produce succinyl-CoA, a key intermediate in the TCA cycle. Three enzymes are needed to convert the α-ketobutyrate to succinyl-CoA. Propionyl-CoA carboxylase uses ATP, biotin, and CO_2, while the methylmalonyl-CoA mutase requires vitamin B12. An additional enzyme is involved in an epimerase reaction, which converts D-methylmalonyl-Co 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

Using the enzyme L-asparaginase, asparagine is converted to NH₃ and aspartate. Aspartate is then transaminated to form oxaloacetate, a reactant in gluconeogenesis. Aspartate participates in the urea cycle, which helps eliminate nitrogen. Glutamate also acquires NH₃ through the reaction catalyzed by glutamine synthase.

Both amino acids serve as substrates for transamination reactions that produce TCA cycle intermediates. Glutamate dehydrogenase can lead to alpha-ketoglutarate.

Glutamate and aspartate play important roles 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 SUMMARY GRAPHIC From Reactome shows "Cellular metabolism of amino acids and related molecules includes the pathways for the catabolism of amino acids, the biosynthesis of the nonessential amino acids (alanine, arginine, aspartate, asparagine, cysteine, glutamate, glutamine, glycine, proline, and serine) and selenocysteine, the synthesis of urea, and the metabolism of carnitine, creatine, choline, polyamides, melanin, and amine-derived hormones. The metabolism of amino acids provides a balanced supply for protein synthesis. In the fasting state, the catabolism of amino acids derived from the breakdown of skeletal muscle protein and other sources is coupled to the processes of gluconeogenesis and ketogenesis to meet the body’s energy needs in the absence of dietary energy sources."

Provided by Reactome. Citation Accessed on Wed, May 15, 2024.  Fabregat A, Sidiropoulos K, Viteri G, Marin-Garcia P, Ping P, Stein L, D'Eustachio P, Hermjakob H. Reactome diagram viewer: data structures and strategies to boost performance. Bioinformatics (Oxford, England). 2018 Apr;34(7) 1208-1214. doi: 10.1093/bioinformatics/btx752. PubMed PMID: 29186351. PubMed Central PMCID: PMC6030826.   Image:  https://reactome.org/PathwayBrowser/#/R-HSA-71291&PATH=R-HSA-1430728

Summary

(Summary written by Claude, Sonnet 4.6, Anthropic)

This chapter provides a comprehensive account of the catabolic pathways that convert the carbon skeletons of all 20 amino acids into central metabolic intermediates, emphasizing the convergence of diverse pathways onto a small number of entry points into glycolysis and the TCA cycle.

The chapter begins by reviewing the four catabolic outcomes: conversion to pyruvate (glucogenic), to acetyl-CoA or acetoacetyl-CoA (ketogenic), to TCA cycle intermediates (glucogenic through anaplerotic reactions), or to both (glucogenic and ketogenic). Only leucine and lysine are purely ketogenic; tryptophan, phenylalanine, tyrosine, isoleucine, and threonine are both ketogenic and glucogenic; all others are purely glucogenic.

The amino acids that converge on pyruvate represent a structurally diverse group unified by short carbon chains and a common dependence on PLP-dependent enzymes. Alanine undergoes a single transamination with α-ketoglutarate catalyzed by ALT/GPT to yield pyruvate and glutamate directly — a reversible reaction of central importance in the glucose-alanine cycle. Serine is dehydrated by serine/threonine dehydratase (a PLP-dependent enzyme) to yield pyruvate and NH₄⁺. Cysteine follows a more complex oxidative pathway via cysteine sulfinyl intermediates, producing 3-sulfinylpyruvate, which spontaneously decomposes to pyruvate and sulfite; an important byproduct of cysteine catabolism is taurine, the most abundant free amino acid in the body. Glycine and threonine are interconverted with serine via the SHMT reaction using both PLP and FH4. Threonine is also catabolized by two additional routes: threonine-3-dehydrogenase produces glycine and acetyl-CoA (making threonine partly ketogenic), and threonine deaminase produces α-ketobutyrate, which enters the VOMIT pathway as propionyl-CoA. Tryptophan catabolism is particularly complex, producing alanine (glucogenic) as a side product while the ring system is degraded to 2-amino-3-carboxymuconate 6-semialdehyde (ACMS), which can be converted to acetoacetyl-CoA (ketogenic) or to quinolinate, an intermediate in NAD⁺ biosynthesis.

The purely ketogenic and dual glucogenic/ketogenic amino acids are catabolized to acetoacetyl-CoA and acetyl-CoA through extended pathways. Lysine catabolism begins unusually: unlike all other amino acids, its α-amino group is not removed by PLP-dependent transamination. Instead, it condenses with α-ketoglutarate to form saccharopine via a bifunctional enzyme (aminoadipic semialdehyde synthase) that possesses both lysine-oxoglutarate reductase and saccharopine dehydrogenase activities, ultimately yielding acetoacetyl-CoA. This irreversibility explains why lysine is an essential amino acid. Leucine undergoes PLP-dependent transamination by branched-chain aminotransferase (BCAT), followed by oxidative decarboxylation by the branched-chain α-ketoacid dehydrogenase complex (BCKD) — an enzyme mechanistically analogous to pyruvate dehydrogenase and α-ketoglutarate dehydrogenase — and subsequent FAD-dependent dehydrogenation by isovaleryl-CoA dehydrogenase, ultimately yielding acetoacetate and acetyl-CoA. Phenylalanine is first hydroxylated to tyrosine by phenylalanine hydroxylase using tetrahydrobiopterin (BH4) as an electron carrier; the oxidized dihydrobiopterin is regenerated by dihydrobiopterin reductase using NADPH. Tyrosine catabolism then proceeds through homogentisate to fumarate (glucogenic) and acetoacetate (ketogenic), making both phenylalanine and tyrosine dual-fate amino acids. Isoleucine uses BCAT and BCKD in its initial degradation steps, shared with valine and leucine, before diverging to yield acetyl-CoA (ketogenic) and propionyl-CoA (glucogenic via succinyl-CoA).

Five amino acids — glutamine, glutamate, proline, arginine, and histidine — converge on α-ketoglutarate and are therefore glucogenic. Proline and arginine are first converted to glutamate through ring opening and oxidative steps, and glutamate then undergoes oxidative deamination by glutamate dehydrogenase to yield α-ketoglutarate and NH₄⁺. Histidine undergoes a series of deamination and hydration reactions to form glutamate. Glutamine is converted to glutamate by glutaminase, releasing its amide nitrogen as NH₄⁺.

The VOMIT pathway — named for the substrates valine, odd-chain fatty acids, methionine, isoleucine, and threonine — converts propionyl-CoA to succinyl-CoA in three steps that are shared across all these substrates. Propionyl-CoA carboxylase (requiring biotin, ATP, and CO₂) produces (S)-methylmalonyl-CoA; methylmalonyl-CoA epimerase interconverts the S and R epimers; and methylmalonyl-CoA mutase (requiring adenosylcobalamin/vitamin B12) performs the radical-based rearrangement to succinyl-CoA, a TCA cycle intermediate and anaplerotic entry point. Valine catabolism follows this pathway after BCAT and BCKD reactions, while methionine catabolism first passes through the SAM cycle and transsulfuration to produce cysteine and α-ketobutyrate, which also feeds into propionyl-CoA. Aspartate and asparagine, the final amino acids discussed, enter the TCA cycle via oxaloacetate: asparagine is first deaminated by L-asparaginase to aspartate, and aspartate undergoes PLP-dependent transamination with α-ketoglutarate (catalyzed by AST/GOT) to form oxaloacetate, which can enter either the TCA cycle or gluconeogenesis. In the broader context of fasting and starvation, amino acid catabolism supplies both gluconeogenic and ketogenic precursors, integrating protein breakdown with carbohydrate and lipid metabolism to sustain energy production when dietary carbon is unavailable.