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.

Function consistency and core coverage

5 gene-function check(s) reflected in core functions · 0 conflict(s) · 3 evidence or coverage gap(s) (10 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

AnnotonParticipantFunctionAssessment
tat_activity TAT (human)
UniProtKB:P17735
Family Representative 		L-tyrosine:2-oxoglutarate transaminase activity
GO:0004838 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hpd_activity HPD (human)
UniProtKB:P32754
Family Representative 		4-hydroxyphenylpyruvate dioxygenase activity
GO:0003868 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hgd_activity HGD (human)
UniProtKB:Q93099
Family Representative 		homogentisate 1,2-dioxygenase activity
GO:0004411 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
gstz1_activity GSTZ1 (human)
UniProtKB:O43708
Family Representative 		maleylacetoacetate isomerase activity
GO:0016034 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
fah_activity FAH (human)
UniProtKB:P16930
Family Representative 		fumarylacetoacetase activity
GO:0004334 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
tat_activity Tyrosine aminotransferase family (TAT)
PANTHER:PTHR45744
Family 		L-tyrosine:2-oxoglutarate transaminase activity
GO:0004838 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR45744.
hpd_activity 4-hydroxyphenylpyruvate dioxygenase family (HPD)
PANTHER:PTHR11959
Family 		4-hydroxyphenylpyruvate dioxygenase activity
GO:0003868 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR11959.
hgd_activity Homogentisate 1,2-dioxygenase family (HGD)
PANTHER:PTHR11056
Family 		homogentisate 1,2-dioxygenase activity
GO:0004411 		Family Supported
Family review supports GO:0004411 FAMILY_WIDE. Defining activity of every characterized member across bacteria, fungi, plants and animals; the family has a single populated subfamily.
gstz1_activity Maleylacetoacetate isomerase / GST-zeta family (GSTZ1)
PANTHER:PTHR42673
Family 		maleylacetoacetate isomerase activity
GO:0016034 		Family Function Unreviewed
Family review leaves GO:0016034 UNRESOLVED. Safe for the eukaryotic GSTZ1/MAAI clade and for the bacterial MaiA-type members, and demonstrably wrong for Ralstonia NagL (maleylpyruvate isomerase, GO:0050077 by IDA) and unsupported for E. coli YfcF and YibF. Because those members share subfamilies with genuine MAAI (NagL and YfcF are in SF21 with HmgC and the Pseudomonas and Vibrio MaiA proteins; YibF is in SF4 with human GSTZ1), the applicability cannot be scoped by subfamily and the scope is recorded as unresolved rather than forced into SUBFAMILY_ONLY. A member-level decision is needed, driven by whether the organism runs a homogentisate pathway and whether the protein has an assayed substrate.
fah_activity Fumarylacetoacetate hydrolase family (FAH)
PANTHER:PTHR43069
Family 		fumarylacetoacetase activity
GO:0004334 		Family Supported
Family review supports GO:0004334 FAMILY_WIDE. The family is functionally coherent; the activity is placed at the root node and held by every reviewed member. The tyrosine_catabolism module already uses the base family for this step.

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.