L-tyrosine catabolism (hepatic tyrosine degradation to fumarate + acetoacetate)

The main pathway of L-tyrosine degradation, a five-step cytosolic route operating chiefly in the liver (and kidney) that converts tyrosine — including the tyrosine produced from phenylalanine by phenylalanine hydroxylase — to the central-metabolism end-products fumarate and acetoacetate, thereby feeding the carbon skeleton into the TCA cycle and ketone-body pool. Tyrosine aminotransferase (TAT) first transaminates tyrosine with 2-oxoglutarate to 4-hydroxyphenylpyruvate; 4-hydroxyphenylpyruvate dioxygenase (HPD/HPPD) then carries out an unusual oxidative decarboxylation, ring-hydroxylation and side-chain migration to give homogentisate; homogentisate 1,2-dioxygenase (HGD) cleaves the aromatic ring to 4-maleylacetoacetate; maleylacetoacetate isomerase (GSTZ1/MAAI) isomerises this to 4-fumarylacetoacetate; and fumarylacetoacetate hydrolase (FAH) hydrolyses the C-C bond to release fumarate and acetoacetate. Every step has a corresponding inborn error of metabolism: TAT deficiency causes tyrosinemia type II (Richner-Hanhart, oculocutaneous); HPD deficiency causes tyrosinemia type III and hawkinsinuria; HGD deficiency causes alkaptonuria (homogentisate accumulates and its oxidised polymer deposits as ochronotic pigment); GSTZ1/MAAI deficiency is biochemically mild; and FAH deficiency causes the severe hepatorenal tyrosinemia type I, in which the blocked terminal step causes accumulation of the upstream reactive intermediates maleyl-/fumarylacetoacetate and the toxin succinylacetone. Pharmacologically, the herbicide-derived HPD inhibitor nitisinone (NTBC) is the mainstay treatment of tyrosinemia type I: by blocking HPD (the second step) it prevents formation of the toxic downstream metabolites that accumulate when FAH is deficient, and it is also used in alkaptonuria to lower homogentisate.

MODULE:tyrosine_catabolismDRAFTMetabolic Pathwaymodules/tyrosine_catabolism.yaml
L-tyrosine catabolic processGO:0006572 L-phenylalanine catabolic processGO:0006559
GO:0006572
L-tyrosine catabolic process
The module is grounded in the GO biological-process term for L-tyrosine catabolism; every step is annotated to GO:0006572 (and, since Phe is degraded via Tyr, to GO:0006559 L-phenylalanine catabolic process).
Reactome:R-HSA-8963684
Tyrosine catabolism
Step order and reaction stoichiometries follow the human Reactome "Tyrosine catabolism" pathway (R-HSA-8963684) and its member reactions (R-HSA-71155, R-HSA-71163, R-HSA-71164, R-HSA-71173, R-HSA-71181).
file:human/TAT/TAT-ai-review.yaml
TAT gene review (human)
The TAT step grounding (UniProtKB:P17735, GO:0004838, EC 2.6.1.5) matches the completed human TAT review.
file:human/HPD/HPD-ai-review.yaml
HPD gene review (human)
The HPD step grounding (UniProtKB:P32754, GO:0003868, EC 1.13.11.27) matches the completed human HPD review (the nitisinone target).
file:human/HGD/HGD-ai-review.yaml
HGD gene review (human)
The HGD step grounding (UniProtKB:Q93099, GO:0004411, EC 1.13.11.5) matches the completed human HGD review.
file:human/GSTZ1/GSTZ1-ai-review.yaml
GSTZ1 gene review (human)
The GSTZ1/MAAI step grounding (UniProtKB:O43708, GO:0016034, EC 5.2.1.2) matches the completed human GSTZ1 review, whose primary physiological core function is maleylacetoacetate isomerase.
file:human/FAH/FAH-ai-review.yaml
FAH gene review (human)
The FAH step grounding (UniProtKB:P16930, GO:0004334 fumarylacetoacetase activity, EC 3.7.1.2) matches the completed human FAH review.
6Nodes
5Parts
0Variant Sets
0Variants
5Annotons
4Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:tyrosine_catabolism deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Gene-review completeness (5/5 grounded genes reviewed)

5 complete review(s) · 3 with deep research · 0 missing review · 2 reviewed but lacking deep research

Gene Review Complete Deep research
FAH P16930 ✓ ✓ ✗
GSTZ1 O43708 ✓ ✓ ✗
HGD Q93099 ✓ ✓ ✓
HPD P32754 ✓ ✓ ✓
TAT P17735 ✓ ✓ ✓

Details

Context
cytosolGO:0005829
L-tyrosine catabolismMetabolic Pathwaytyrosine_catabolism
L-tyrosine catabolic processGO:0006572 L-phenylalanine catabolic processGO:0006559
Context
cytosolGO:0005829

Five-step hepatic L-tyrosine catabolism grounded to the human enzymes TAT (UniProtKB:P17735, GO:0004838, EC 2.6.1.5), HPD (P32754, GO:0003868, EC 1.13.11.27), HGD (Q93099, GO:0004411, EC 1.13.11.5), GSTZ1/MAAI (O43708, GO:0016034, EC 5.2.1.2) and FAH (P16930, GO:0004334, EC 3.7.1.2). GO molecular-function terms were taken from the human GOA records; Reactome reaction ids and titles were verified against the local reactome cache. Each step uses a PANTHER family selector (generic over paralogs and orthologs) plus a concrete human representative member; these enzymes are essentially single-copy in humans. Upstream, phenylalanine enters this pathway after PAH converts it to tyrosine (see the tetrahydrobiopterin module for the PAH cofactor); downstream, fumarate enters the TCA cycle and acetoacetate the ketone-body pool. The clinically important HPD inhibitor nitisinone (NTBC) and the toxic succinylacetone that accumulates in FAH deficiency are noted in the step role descriptions.

Connections

tat_step -> hpd_step Provides Input For
4-hydroxyphenylpyruvate from TAT is the substrate of HPD.
hpd_step -> hgd_step Provides Input For
Homogentisate from HPD is the substrate of HGD.
hgd_step -> gstz1_step Provides Input For
4-maleylacetoacetate from HGD is isomerised by GSTZ1/MAAI.
gstz1_step -> fah_step Provides Input For
4-fumarylacetoacetate from GSTZ1 is hydrolysed by FAH.
Part 1: transamination (entry step)
L-tyrosine + 2-oxoglutarate to 4-hydroxyphenylpyruvate + L-glutamateReactiontat_step

Annotons

TAT: tyrosine aminotransferase
tat_activity
Participant: Family: Tyrosine aminotransferase family (TAT)
Family:
Tyrosine aminotransferase family (TAT)PANTHER:PTHR45744
Representative Members: TAT (human)UniProtKB:P17735

Function

L-tyrosine:2-oxoglutarate transaminase activityGO:0004838
Substrates: L-tyrosine 2-oxoglutarate
Products: 4-hydroxyphenylpyruvate L-glutamate

Locations

cytosolGO:0005829

PLP-dependent, glucocorticoid/glucagon-inducible cytosolic aminotransferase that commits tyrosine to catabolism. Deficiency causes tyrosinemia type II (Richner-Hanhart syndrome).

Part 2: oxidative decarboxylation to homogentisate
4-hydroxyphenylpyruvate + O2 to homogentisate + CO2Reactionhpd_step

Annotons

HPD/HPPD: 4-hydroxyphenylpyruvate dioxygenase
hpd_activity
Participant: Family: 4-hydroxyphenylpyruvate dioxygenase family (HPD)
Family:
4-hydroxyphenylpyruvate dioxygenase family (HPD)PANTHER:PTHR11959
Representative Members: HPD (human)UniProtKB:P32754

Function

4-hydroxyphenylpyruvate dioxygenase activityGO:0003868
Substrates: 4-hydroxyphenylpyruvate dioxygen
Products: homogentisate carbon dioxide

Locations

cytosolGO:0005829

Fe(II)-dependent dioxygenase performing a combined oxidative decarboxylation, ring hydroxylation and side-chain migration. The molecular target of the drug nitisinone (NTBC): inhibiting HPD blocks the pathway upstream of the toxic FAH-deficiency intermediates, which is why NTBC treats tyrosinemia type I. HPD deficiency itself causes tyrosinemia type III and hawkinsinuria.

Part 3: aromatic ring cleavage
homogentisate + O2 to 4-maleylacetoacetateReactionhgd_step

Annotons

HGD: homogentisate 1,2-dioxygenase
hgd_activity
Participant: Family: Homogentisate 1,2-dioxygenase family (HGD)
Family:
Homogentisate 1,2-dioxygenase family (HGD)PANTHER:PTHR11056
Representative Members: HGD (human)UniProtKB:Q93099

Function

homogentisate 1,2-dioxygenase activityGO:0004411
Substrates: homogentisate dioxygen
Products: 4-maleylacetoacetate

Locations

cytosolGO:0005829

Fe(II)-dependent ring-cleaving dioxygenase (assembles as a hexamer, a dimer of trimers). Deficiency causes alkaptonuria: homogentisate accumulates and its oxidised polymer deposits in connective tissue (ochronosis), giving dark urine, ochronotic arthropathy and cardiac-valve/renal disease.

Part 4: cis-trans isomerization
4-maleylacetoacetate to 4-fumarylacetoacetateReactiongstz1_step

Annotons

GSTZ1/MAAI: maleylacetoacetate isomerase
gstz1_activity
Participant: Family: Maleylacetoacetate isomerase / GST-zeta family (GSTZ1)
Family:
Maleylacetoacetate isomerase / GST-zeta family (GSTZ1)PANTHER:PTHR42673
Representative Members: GSTZ1 (human)UniProtKB:O43708

Function

maleylacetoacetate isomerase activityGO:0016034
Substrates: 4-maleylacetoacetate glutathione (cofactor)
Products: 4-fumarylacetoacetate

Locations

cytosolGO:0005829

Glutathione-dependent cis-trans isomerase of the glutathione- transferase zeta superfamily; the tyrosine-pathway role is its main physiological function. Also biotransforms the drug dichloroacetate (which mechanism-based-inactivates the enzyme). MAAI deficiency is biochemically mild.

Part 5: terminal hydrolysis to central metabolites
4-fumarylacetoacetate to fumarate + acetoacetateReactionfah_step

Annotons

FAH: fumarylacetoacetate hydrolase
fah_activity
Participant: Family: Fumarylacetoacetate hydrolase family (FAH)
Family:
Fumarylacetoacetate hydrolase family (FAH)PANTHER:PTHR43069
Representative Members: FAH (human)UniProtKB:P16930

Function

fumarylacetoacetase activityGO:0004334
Substrates: 4-fumarylacetoacetate water
Products: fumarate acetoacetate

Locations

cytosolGO:0005829

Terminal step: hydrolyses fumarylacetoacetate to fumarate (into the TCA cycle) and acetoacetate (a ketone body). Deficiency causes the severe hepatorenal tyrosinemia type I — the block causes toxic accumulation of maleyl-/fumarylacetoacetate and succinylacetone, treated by blocking the pathway upstream with nitisinone.