Amino Acid Catabolism Overview (glucogenic vs. ketogenic amino acids; brief overview of branched-chain amino acid catabolism and phenylalanine/tyrosine catabolism as representative examples)

1. 1

   Amino acid + α-ketoglutarate ⇌ corresponding α-keto acid + glutamate

   Aminotransferases + glutamate dehydrogenase (PLP-dependent nitrogen removal) 1.4.1.3 ST-0146 Reversible PLP (B6)
   In Alpha-ketoglutarate

   Out Glutamate
   › Notes

   A PLP-dependent aminotransferase commonly initiates catabolism of amino acids whose nitrogen is handled by transamination. The reaction is reversible; glutamate subsequently supplies ammonia through GDH or supplies aspartate for urea synthesis.

2. 2

   Glucogenic carbon skeleton → pyruvate or a gluconeogenic TCA-cycle intermediate

   Multiple pathway-specific catabolic enzymes ST-0147 Irreversible/directional
   In Amino acid carbon skeleton (glucogenic)

   Out Pyruvate Oxaloacetate Alpha-ketoglutarate Succinyl-CoA Fumarate
   › Notes

   Multiple pathway-specific enzymes produce pyruvate (alanine, serine, glycine, cysteine, threonine, tryptophan), oxaloacetate (aspartate, asparagine), α-ketoglutarate (glutamate, glutamine, proline, arginine, histidine), succinyl-CoA (valine, isoleucine, methionine, threonine), or fumarate (phenylalanine, tyrosine). Conversion of these intermediates to glucose requires hepatic or renal gluconeogenesis and consumes ATP/GTP and reducing power; entry into the TCA cycle alone is not synonymous with net glucose production.

3. 3

   Ketogenic carbon skeleton → acetyl-CoA and/or acetoacetate

   Leucine/lysine catabolic enzyme set (purely ketogenic) ST-0148 Irreversible/directional
   In Amino acid carbon skeleton (ketogenic)

   Out Acetyl-CoA Acetoacetate
   › Notes

   Leucine and lysine are exclusively ketogenic; their carbon is converted to acetyl-CoA, acetoacetate, or acetoacetyl-CoA. Isoleucine, phenylalanine, tyrosine, tryptophan, and threonine produce both ketogenic and glucogenic products; acetyl-CoA cannot yield net glucose because both of its carbons are lost as CO₂ during TCA-cycle turnover.

4. 4

   Leucine/isoleucine/valine + α-ketoglutarate ⇌ their respective branched-chain α-keto acids + glutamate

   Branched-chain aminotransferase (BCAT) 2.6.1.42 ST-0149 Reversible PLP (B6)
   In Alpha-ketoglutarate

   Out Glutamate
   › Notes

   BCAT catalyzes the PLP-dependent, reversible first step of BCAA catabolism, mainly in extrahepatic tissues such as skeletal muscle. Leucine yields α-ketoisocaproate, isoleucine yields α-keto-β-methylvalerate, and valine yields α-ketoisovalerate.

5. 5

   Branched-chain α-keto acid + CoA + NAD⁺ → branched-chain acyl-CoA + CO₂ + NADH

   Branched-chain alpha-ketoacid dehydrogenase complex (BCKDH) 1.2.4.4 ST-0150 Irreversible rate-limiting NAD+ NADH
   In CoA-SH NAD+

   Out CO2 NADH
   › Notes

   The mitochondrial branched-chain α-ketoacid dehydrogenase complex (BCKDH) catalyzes irreversible oxidative decarboxylation. It requires TPP (vitamin B1), lipoamide, FAD (vitamin B2), NAD⁺ (vitamin B3), CoA (vitamin B5), and Mg²⁺; this is the committed, rate-limiting step of BCAA oxidation and produces one NADH per keto acid.

6. 6

   Leucine-derived isovaleryl-CoA → 3-methylcrotonyl-CoA → 3-methylglutaconyl-CoA → HMG-CoA → acetoacetate + acetyl-CoA

   ↪ 3-methylcrotonyl-CoA → 3-methylglutaconyl-CoA → HMG-CoA → acetoacetate + acetyl-CoA

   Isovaleryl-CoA dehydrogenase ST-0151 Irreversible/directional ATP FAD Biotin (B7) Bicarbonate/CO2
   In Leucine-derived isovaleryl-CoA

   Out 3-Methylcrotonyl-CoA
   › Notes

   Isovaleryl-CoA dehydrogenase uses FAD, 3-methylcrotonyl-CoA carboxylase uses biotin, ATP, and bicarbonate, and downstream hydratase/lyase reactions form the final ketogenic products. Thus leucine is exclusively ketogenic.

7. 7

   Isoleucine-derived 2-methylbutyryl-CoA → tiglyl-CoA → 2-methyl-3-hydroxybutyryl-CoA → 2-methylacetoacetyl-CoA → acetyl-CoA + propionyl-CoA

   ↪ tiglyl-CoA → 2-methyl-3-hydroxybutyryl-CoA → 2-methylacetoacetyl-CoA → acetyl-CoA + propionyl-CoA

   Acyl-CoA dehydrogenases (BCAA branch) 1.3.8.- ST-0152 Irreversible/directional NAD+ FAD
   In Isoleucine-derived 2-methylbutyryl-CoA

   Out Tiglyl-CoA
   › Notes

   Dehydrogenase, hydratase, dehydrogenase, and thiolase reactions process the acyl chain; the first dehydrogenation uses FAD and the hydroxyacyl dehydrogenase uses NAD⁺. Propionyl-CoA is converted by propionyl-CoA carboxylase (biotin, ATP, bicarbonate), methylmalonyl-CoA epimerase, and methylmalonyl-CoA mutase (adenosylcobalamin) to succinyl-CoA, so isoleucine is both ketogenic and glucogenic.

8. 8

   Valine-derived isobutyryl-CoA → methacrylyl-CoA → 3-hydroxyisobutyryl-CoA → methylmalonate semialdehyde → propionyl-CoA → succinyl-CoA

   ↪ methacrylyl-CoA → 3-hydroxyisobutyryl-CoA → methylmalonate semialdehyde → propionyl-CoA → succinyl-CoA

   FAD-dependent dehydrogenase step (BCAA branch) ST-0153 Irreversible/directional NAD+ FAD Biotin (B7) Cobalamin (B12)
   In Valine-derived isobutyryl-CoA

   Out Methacrylyl-CoA
   › Notes

   FAD-dependent dehydrogenation, hydration, hydrolysis, NAD⁺-dependent oxidation, and the biotin- and adenosylcobalamin-dependent propionyl-CoA pathway yield succinyl-CoA. Therefore valine is glucogenic.

9. 9

   L-phenylalanine + O₂ + tetrahydrobiopterin (BH₄) → L-tyrosine + H₂O + dihydrobiopterin (BH₂)

   Phenylalanine hydroxylase (PAH) 1.14.16.1 ST-0154 Irreversible NADPH O2 H2O BH4
   In Phenylalanine O2 Tetrahydrobiopterin (BH4)

   Out Tyrosine H2O Dihydrobiopterin (BH2)
   › Notes

   Phenylalanine hydroxylase (PAH) catalyzes this irreversible hydroxylation; BH₄ is regenerated from BH₂ by dihydropteridine reductase using NADPH. This is the committed entry step for phenylalanine degradation and is also required to generate tyrosine when dietary tyrosine is insufficient.

10. 10

    L-tyrosine + α-ketoglutarate ⇌ 4-hydroxyphenylpyruvate + glutamate

    Tyrosine aminotransferase (TAT) ST-0155 Reversible PLP (B6)
    In Tyrosine Alpha-ketoglutarate

    Out 4-Hydroxyphenylpyruvate Glutamate
    › Notes

    Tyrosine aminotransferase catalyzes this PLP-dependent, reversible reaction. Its activity is induced in liver by glucocorticoids during catabolic states.

11. 11

    4-Hydroxyphenylpyruvate + O₂ → homogentisate + CO₂

    4-Hydroxyphenylpyruvate dioxygenase 1.13.11.27 ST-0156 Irreversible Fe2+ O2
    In 4-Hydroxyphenylpyruvate O2

    Out Homogentisate CO2
    › Notes

    4-Hydroxyphenylpyruvate dioxygenase catalyzes oxidative decarboxylation and rearrangement using Fe²⁺. This is an essentially irreversible oxidative step.

12. 12

    Homogentisate + O₂ → maleylacetoacetate

    Homogentisate 1,2-dioxygenase (HGD) 1.13.11.5 ST-0157 Irreversible/directional Fe2+ O2
    In Homogentisate O2

    Out Maleylacetoacetate
    › Notes

    Homogentisate 1,2-dioxygenase opens the aromatic ring using Fe²⁺. Deficiency blocks this reaction and causes alkaptonuria.

13. 13

    Maleylacetoacetate → fumarylacetoacetate

    Maleylacetoacetate isomerase ST-0158 Irreversible/directional Glutathione
    In Maleylacetoacetate

    Out Fumarylacetoacetate
    › Notes

    Maleylacetoacetate isomerase uses glutathione as a cofactor. The isomerization prepares the molecule for hydrolytic cleavage.

14. 14

    Fumarylacetoacetate + H₂O → fumarate + acetoacetate

    Fumarylacetoacetate hydrolase (FAH) 3.7.1.2 ST-0159 Irreversible/directional H2O
    In Fumarylacetoacetate H2O

    Out Fumarate Acetoacetate
    › Notes

    Fumarylacetoacetate hydrolase (FAH) yields one glucogenic product (fumarate) and one ketogenic product (acetoacetate). This establishes phenylalanine and tyrosine as both glucogenic and ketogenic.

Showing all 14 steps.

Overview

Amino-acid catabolism first removes or transfers nitrogen, then directs the carbon skeleton to a limited set of metabolic entry points. Glucogenic amino acids yield pyruvate or a tricarboxylic-acid-cycle intermediate that can support net gluconeogenesis; ketogenic amino acids yield acetyl-CoA or acetoacetate/acetoacetyl-CoA and cannot give net glucose in humans. Leucine and lysine are exclusively ketogenic; isoleucine, phenylalanine, tyrosine, tryptophan, and threonine are both glucogenic and ketogenic; the remaining standard amino acids are glucogenic.

Cellular location

Initial nitrogen transfer is widespread in cytosol and mitochondria, while much oxidative carbon-skeleton catabolism occurs in mitochondria. Liver is the major organ for disposal of amino nitrogen and for many amino-acid degradation pathways, but skeletal muscle is the principal site of early branched-chain amino-acid (BCAA) transamination and substantial BCAA oxidation. Phenylalanine hydroxylation and most tyrosine degradation are especially important in liver; phenylalanine hydroxylase is also physiologically relevant in kidney.

Net energetics

There is no single net energy yield for amino-acid catabolism because each carbon skeleton enters metabolism at a different point and nitrogen disposal costs energy. BCKDH yields 1 NADH per branched-chain keto acid, while BCAA acyl-CoA dehydrogenase steps yield FADH2 equivalents; carboxylation of propionyl-CoA costs 1 ATP, and conversion to succinyl-CoA requires adenosylcobalamin. PAH consumes reducing equivalents indirectly because regeneration of BH₄ from BH₂ consumes 1 NADPH; complete oxidation of downstream acetyl-CoA/TCA intermediates yields ATP according to tissue redox conditions, but urea formation costs four high-energy phosphate bonds for each urea formed.

Clinical significance

Classification as glucogenic or ketogenic predicts the metabolic consequences of fasting and explains why leucine/lysine cannot maintain blood glucose. BCKDH deficiency causes maple syrup urine disease, with accumulation of BCAAs and their keto acids, neurotoxicity, and a characteristic sweet odor; treatment includes dietary BCAA restriction and, in responsive cases, thiamine. PAH deficiency or impaired BH₄ metabolism causes phenylketonuria (PKU), requiring early dietary phenylalanine restriction and tyrosine supplementation; homogentisate dioxygenase deficiency causes alkaptonuria, and FAH deficiency causes tyrosinemia type I.