Amino Acid Catabolism Overview (glucogenic vs. ketogenic amino acids; brief overview of branched-chain amino acid catabolism and phenylalanine/tyrosine catabolism as representative examples)
- Compartment
- Cytosol + mitochondrion
- Main tissue
- Liver (mainly); BCAA in muscle
- Rate-limiting
- Branched-chain alpha-ketoacid dehydrogenase complex (BCKDH)
- Steps
- 14
Reaction steps
In source order, 14 total
-
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)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
Glucogenic carbon skeleton → pyruvate or a gluconeogenic TCA-cycle intermediate
› 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
Ketogenic carbon skeleton → acetyl-CoA and/or 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
Leucine/isoleucine/valine + α-ketoglutarate ⇌ their respective branched-chain α-keto acids + glutamate
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
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› 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
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
› 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
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
› 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
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)› 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
L-phenylalanine + O₂ + tetrahydrobiopterin (BH₄) → L-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
L-tyrosine + α-ketoglutarate ⇌ 4-hydroxyphenylpyruvate + glutamate
› Notes
Tyrosine aminotransferase catalyzes this PLP-dependent, reversible reaction. Its activity is induced in liver by glucocorticoids during catabolic states.
-
11
4-Hydroxyphenylpyruvate + O₂ → homogentisate + CO₂
› Notes
4-Hydroxyphenylpyruvate dioxygenase catalyzes oxidative decarboxylation and rearrangement using Fe²⁺. This is an essentially irreversible oxidative step.
-
12
Homogentisate + O₂ → maleylacetoacetate
› Notes
Homogentisate 1,2-dioxygenase opens the aromatic ring using Fe²⁺. Deficiency blocks this reaction and causes alkaptonuria.
-
13
Maleylacetoacetate → fumarylacetoacetate
› Notes
Maleylacetoacetate isomerase uses glutathione as a cofactor. The isomerization prepares the molecule for hydrolytic cleavage.
-
14
Fumarylacetoacetate + H₂O → 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.
Regulation
What speeds each enzyme up and what slows it down
BCKDH complex
Dephosphorylation by BCKDH phosphatase; elevated branched-chain keto acids
Phosphorylation by BCKDH kinase; product/high-energy signals
Insulin promotes BCAA uptake and protein synthesis; fasting, exercise, and cortisol favor BCAA oxidation indirectly
Phenylalanine hydroxylase
Phenylalanine (allosteric/substrate activation); BH₄ availability
BH₄ deficiency; inhibitory phosphorylation states/low substrate
Mainly substrate and cofactor regulated; chronic nutritional/hormonal effects are indirect
Propionyl-CoA carboxylase
Propionyl-CoA availability; biotin sufficiency
Biotin deficiency; product accumulation
No dominant acute hormonal switch; flux follows odd-chain fatty-acid and amino-acid catabolism
Tyrosine aminotransferase
Tyrosine availability
Product accumulation
Glucocorticoids induce hepatic enzyme expression; insulin has opposing fed-state effects
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.
Recent literature
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