HPD

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0003868 4-hydroxyphenylpyruvate dioxygenase activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetically inferred assignment of the defining, EC-level molecular function of HPD. This is the correct, specific core molecular function. Reason: The IBA assignment matches the biochemically demonstrated activity of HPD and is at the correct level of specificity. HPD catalyzes conversion of 4-hydroxyphenylpyruvate to homogentisate (EC 1.13.11.27), verified for the human enzyme by expression, kinetics and active-site mutagenesis. Supporting Evidence: PMID:34047349 4-Hydroxylphenylpyruvate dioxygenase (HPPD) catalyzes the conversion of 4-hydroxylphenylpyruvate (HPP) to homogentisate, the important step for tyrosine catabolism.
GO:0006572 L-tyrosine catabolic process	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetically inferred involvement in tyrosine catabolism, the core biological process to which HPD contributes. Reason: HPD performs the second, committed dioxygenation step of tyrosine degradation and its loss of function causes tyrosinemia type III. This is a core biological process for the gene. Supporting Evidence: PMID:31537781 Decreased expression of 4-hydroxyphenylpyruvic acid dioxygenase (HPD), a key enzyme for tyrosine metabolism, is a cause of human tyrosinemia.
GO:0000139 Golgi membrane	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Phylogenetically inferred Golgi-membrane localization. HPD is fundamentally a soluble cytosolic enzyme; membrane association is only weakly supported (by-similarity, peripheral) and is not the site of the catalytic reaction. Reason: UniProt records Golgi apparatus membrane as a peripheral-membrane location inferred by similarity to the mouse ortholog (P32755), not as an experimentally established human site. The tyrosine dioxygenation reaction is cytosolic, so this localization is at most a minor/non-core association. Supporting Evidence: PMID:41317403 The tyrosine metabolic process is usually thought to occur in the cytoplasm.
GO:0005789 endoplasmic reticulum membrane	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Phylogenetically inferred ER-membrane localization; as with the Golgi annotation this reflects a weakly supported peripheral-membrane association, not the site of catalysis. Reason: UniProt lists ER membrane as a peripheral-membrane location inferred by similarity to mouse P32755. HPD's dioxygenase reaction is cytosolic, so this is non-core. Supporting Evidence: PMID:41317403 The tyrosine metabolic process is usually thought to occur in the cytoplasm.
GO:0000139 Golgi membrane	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Electronic SubCell mapping duplicating the by-similarity Golgi-membrane location. Reason: Same weakly supported peripheral Golgi-membrane association as the IBA/ISS annotations, generated by UniProt SubCell keyword mapping. Retained as non-core, since the catalytic function is cytosolic.
GO:0001734 mRNA m(6)A methyltransferase activity	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Electronic propagation (from RHEA:55584 / EC:2.1.1.348) of the single-paper moonlighting m6A methyltransferase claim. This is retained but marked non-core; auto-propagating this unusual activity as if it were an established EC identity of HPD would be an over-annotation. Reason: This IEA is an automated mapping of EC 2.1.1.348 to HPD derived from a single 2025 study (PMID:41317403). The underlying activity is experimental but is a surprising moonlighting function for an iron dioxygenase, flagged with a CAUTION note by UniProt. It is kept consistent with the experimental IDA annotation for the same term as a non-core secondary function rather than a defining EC identity; treating it as a core catalytic function would be an over-annotation. Supporting Evidence: PMID:41317403 HPD is a multifunctional enzyme that plays a crucial regulatory role in various biological processes, exhibiting three core biochemical activities: tyrosine‐metabolizing, RNA‐binding, and methyltransferase activities.
GO:0003868 4-hydroxyphenylpyruvate dioxygenase activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic assignment (ARBA / InterPro / RHEA:16189 / EC:1.13.11.27) of the defining molecular function; consistent with the experimental and phylogenetic evidence. Reason: Correct, specific core molecular function supported by multiple orthogonal lines of evidence (biochemistry, structure, phylogeny). Supporting Evidence: PMID:34047349 4-Hydroxylphenylpyruvate dioxygenase (HPPD) catalyzes the conversion of 4-hydroxylphenylpyruvate (HPP) to homogentisate, the important step for tyrosine catabolism.
GO:0005634 nucleus	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Electronic SubCell mapping of nuclear localization, duplicating the experimental IDA nuclear localization tied to the moonlighting m6A function. Reason: Nuclear localization of HPD is reported only in the context of its proposed moonlighting nuclear m6A methyltransferase activity (PMID:41317403). It is not the site of the canonical cytosolic tyrosine dioxygenation reaction, so it is retained as non-core. Supporting Evidence: PMID:41317403 HPD localizes in both the nucleus and cytoplasm in colorectal cancer cells and HEK293T cells
GO:0005737 cytoplasm	IEA GO_REF:0000120	ACCEPT	Summary: Electronic assignment of cytoplasmic localization, consistent with HPD being a soluble cytosolic enzyme. Reason: Cytoplasm/cytosol is the established compartment for the tyrosine catabolic reaction catalyzed by HPD, corroborated by Reactome (TAS) and the m6A study's baseline statement about cytoplasmic localization. Supporting Evidence: PMID:41317403 The tyrosine metabolic process is usually thought to occur in the cytoplasm.
GO:0005789 endoplasmic reticulum membrane	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Electronic SubCell mapping duplicating the by-similarity ER-membrane location. Reason: Same weakly supported peripheral ER-membrane association as the IBA/ISS annotations. Non-core relative to the cytosolic catalytic function.
GO:0006572 L-tyrosine catabolic process	IEA GO_REF:0000117	ACCEPT	Summary: ARBA electronic assignment of involvement in tyrosine catabolism, consistent with the core biological role. Reason: Correct core biological process; duplicates the well-supported IBA/ISS/TAS L-tyrosine catabolic process annotations.
GO:0009072 aromatic amino acid metabolic process	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: InterPro2GO assignment to the general aromatic amino acid metabolic process. Correct but less informative than the specific L-tyrosine catabolic process term. Reason: Tyrosine is an aromatic amino acid, so this parent term is not wrong, but it is a broad grouping term subsumed by the more precise and better-evidenced GO:0006572 (L-tyrosine catabolic process) already annotated. It is an over-general electronic annotation.
GO:0016701 oxidoreductase activity, acting on single donors with incorporation of molecular oxygen	IEA GO_REF:0000002	MODIFY	Summary: InterPro2GO parent oxidoreductase/dioxygenase term. Correct branch but too general; the specific child term GO:0003868 is already annotated. Reason: This is the mechanistic parent of the specific 4-hydroxyphenylpyruvate dioxygenase activity. HPD is a well-characterized dioxygenase, so the more precise term GO:0003868 (already present) should be used instead of this general parent. Proposed replacements: 4-hydroxyphenylpyruvate dioxygenase activity
GO:0042803 protein homodimerization activity	IEA GO_REF:0000117	ACCEPT	Summary: ARBA electronic assignment of homodimerization, consistent with the experimentally demonstrated homodimeric quaternary structure. Reason: HPD is a homodimer of identical subunits, established biochemically for the human enzyme and confirmed by crystallography. Homodimerization is a genuine, correctly assigned molecular property (though structural rather than the primary catalytic function). Supporting Evidence: PMID:1339442 These findings suggest that the human 4-hydroxyphenylpyruvic acid dioxygenase is a homodimer of two identical subunits with an M(r) of 43,000.
GO:0006559 L-phenylalanine catabolic process	IEA GO_REF:0000041	ACCEPT	Summary: UniPathway mapping placing HPD in the phenylalanine degradation pathway (phenylalanine is catabolized via tyrosine, then via HPD). Reason: HPD occupies step 3/6 of the L-phenylalanine degradation pathway to acetoacetate and fumarate (phenylalanine is first converted to tyrosine, which is then degraded through HPD). This is a valid, if slightly upstream, pathway placement.
GO:0001734 mRNA m(6)A methyltransferase activity	IDA PMID:41317403 HPD is an m(6)A Methyltransferase that Protects Colorectal C...	KEEP AS NON CORE	Summary: Experimentally reported moonlighting nuclear mRNA m6A methyltransferase activity. This is a genuine experimental (IDA) annotation from a full-text study, but represents an unusual secondary function, not the core identity of HPD; retained as non-core. Reason: PMID:41317403 provides direct experimental evidence: recombinant human HPD purified from E. coli methylates mRNA in vitro without accessory proteins, SAM binding maps to His183/His266, catalytic-motif (CMI) and SAM-site mutants abolish activity, and HPD-knockout mice show reduced global m6A. Per curation policy an experimental IDA annotation supported by full text is not removed. However, this is a surprising moonlighting activity for a non-heme iron dioxygenase, is described by the authors as sharing the tyrosine active-site pocket, and is flagged with a CAUTION note in UniProt; it is therefore kept as a non-core, provisional secondary function rather than a defining molecular function. Supporting Evidence: PMID:41317403 Unlike METTL3, reHPD expressed from E.coli also has m6A methyltransferase activity, which means that HPD acts as an m6A methyltransferase and does not require other proteins. PMID:41317403 Here, we demonstrate that HPD methylates SLC7A11/GPX4 through a moonlighting function, which suppresses CRC ferroptosis and promotes tumor growth.
GO:0005634 nucleus	IDA PMID:41317403 HPD is an m(6)A Methyltransferase that Protects Colorectal C...	KEEP AS NON CORE	Summary: Experimentally observed nuclear localization of HPD, associated with its proposed moonlighting m6A function. Reason: Nuclear localization was demonstrated by immunofluorescence and nucleoplasm fractionation (PMID:41317403), but only in the context of the moonlighting nuclear m6A activity. The canonical tyrosine dioxygenation reaction is cytosolic, so nuclear localization is retained as non-core. Supporting Evidence: PMID:41317403 HPD localizes in both the nucleus and cytoplasm in colorectal cancer cells and HEK293T cells
GO:0005737 cytoplasm	IDA PMID:41317403 HPD is an m(6)A Methyltransferase that Protects Colorectal C...	ACCEPT	Summary: Experimentally observed cytoplasmic localization, the compartment of the canonical tyrosine catabolic reaction. Reason: Cytoplasmic/cytosolic localization is the established site of HPD's dioxygenase reaction and was directly observed in this study. Supporting Evidence: PMID:41317403 HPD localizes in both the nucleus and cytoplasm in colorectal cancer cells and HEK293T cells
GO:0003868 4-hydroxyphenylpyruvate dioxygenase activity	IDA PMID:34047349 Functional role of residues involved in substrate binding of...	ACCEPT	Summary: Direct experimental demonstration of the core dioxygenase activity of the human enzyme, including kinetics and active-site mutagenesis. Reason: This study measured HPP dioxygenation kinetics (KM 0.2 mM, kcat 2.0 s-1) and mapped substrate-binding residues (Gln251, Gln265, Gln334, Asn363) by mutagenesis, directly establishing the core molecular function for human HPD. Supporting Evidence: PMID:34047349 4-Hydroxylphenylpyruvate dioxygenase (HPPD) catalyzes the conversion of 4-hydroxylphenylpyruvate (HPP) to homogentisate, the important step for tyrosine catabolism.
GO:0000139 Golgi membrane	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Golgi-membrane localization transferred by sequence similarity from the mouse ortholog (P32755). Reason: By-similarity transfer of a peripheral Golgi-membrane location from mouse HPD. Not experimentally established in human and not the site of catalysis; retained as non-core.
GO:0005737 cytoplasm	ISS GO_REF:0000024	ACCEPT	Summary: Cytoplasmic localization transferred by similarity from the mouse ortholog; consistent with the established cytosolic enzyme. Reason: Cytoplasm is the correct compartment for the HPD dioxygenase reaction and is independently supported by experimental (IDA) and Reactome (TAS) annotations.
GO:0005789 endoplasmic reticulum membrane	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ER-membrane localization transferred by similarity from mouse P32755. Reason: By-similarity peripheral ER-membrane association; not the catalytic compartment. Retained as non-core.
GO:0003868 4-hydroxyphenylpyruvate dioxygenase activity	IDA PMID:1339442 Primary structure deduced from complementary DNA sequence an...	ACCEPT	Summary: Direct demonstration that the cloned human enzyme is catalytically active, establishing the core molecular function. Reason: Expression of the human HPD cDNA in cultured cells produced detectable dioxygenase enzymic activity absent in mock-transfected controls, confirming HPD as the 4-hydroxyphenylpyruvate dioxygenase. Supporting Evidence: PMID:1339442 Enzymic activity of the enzyme was detected in the transfected cells but not in the mock transfected cells.
GO:0042803 protein homodimerization activity	IDA PMID:1339442 Primary structure deduced from complementary DNA sequence an...	ACCEPT	Summary: Experimental evidence that the human enzyme is a homodimer of identical subunits. Reason: The quaternary structure of HPD as a homodimer was established here and later confirmed crystallographically. Correct molecular property, though structural rather than the defining catalytic activity. Supporting Evidence: PMID:1339442 These findings suggest that the human 4-hydroxyphenylpyruvic acid dioxygenase is a homodimer of two identical subunits with an M(r) of 43,000.
GO:0005515 protein binding	IPI PMID:31537781 HPD degradation regulated by the TTC36-STK33-PELI1 signaling...	KEEP AS NON CORE	Summary: Experimental protein-protein interactions of HPD with its stability/ degradation regulators (molecular chaperone TTC36, kinase STK33, and E3 ligase PELI1). Bare "protein binding" is uninformative, but these are genuine experimental IPI annotations with defined partners; retained as non-core regulatory interactions. Reason: PMID:31537781 shows by co-immunoprecipitation that HPD is bound and regulated by TTC36, STK33 (which phosphorylates HPD at T382) and PELI1 (which polyubiquitylates and degrades HPD). Per curation policy an experimental IPI is not removed, and although the generic "protein binding" term is uninformative, these interactions concern regulation of HPD stability rather than its catalytic function, so they are marked non-core. No single more-informative adapter/receptor molecular-function term applies, since HPD is the regulated substrate here. Supporting Evidence: PMID:31537781 we demonstrate that molecular chaperone TTC36, which is highly expressed in liver, is associated with HPD and reduces the binding of protein kinase STK33 to HPD
GO:0003868 4-hydroxyphenylpyruvate dioxygenase activity	IDA PMID:31537781 HPD degradation regulated by the TTC36-STK33-PELI1 signaling...	ACCEPT	Summary: Direct experimental annotation of the core dioxygenase activity within the HPD-degradation study. Reason: The study treats HPD as the key tyrosine-metabolizing dioxygenase whose loss causes tyrosinemia, consistent with the well-established core molecular function. Supporting Evidence: PMID:31537781 HPD catalyzes the reaction of 4-hydroxy-phenylpyruvic acid to homogentisic acid
GO:0006572 L-tyrosine catabolic process	IDA PMID:31537781 HPD degradation regulated by the TTC36-STK33-PELI1 signaling...	ACCEPT	Summary: Experimental evidence linking HPD activity/expression to the tyrosine catabolic process, with loss causing tyrosinemia. Reason: Reduced HPD expression (via the TTC36-STK33-PELI1 axis) blocks tyrosine catabolism and produces tyrosinemia in mice, directly supporting HPD's involvement in the L-tyrosine catabolic process. Supporting Evidence: PMID:31537781 Ttc36-/- mice have reduced HPD expression in the liver and exhibit tyrosinemia
GO:0070062 extracellular exosome	HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos...	KEEP AS NON CORE	Summary: High-throughput detection of HPD in urinary exosome proteomics. A minor, non-core localization typical of large-scale exosome datasets. Reason: HPD was identified in a large-scale urinary exosome/phosphoproteome screen. Such high-throughput proteomic localizations are frequently incidental and do not reflect the functional cytosolic site of the enzyme; retained as non-core.
GO:0005829 cytosol	TAS Reactome:R-HSA-71163	ACCEPT	Summary: Reactome-asserted cytosolic localization for the HPD dioxygenation reaction; this is the core functional compartment. Reason: Reactome places the "HPD dioxygenates HPP" reaction in the cytosol, matching the established compartment of tyrosine catabolism. This is the core cellular location.
GO:0003868 4-hydroxyphenylpyruvate dioxygenase activity	ISS GO_REF:0000024	ACCEPT	Summary: Sequence-similarity transfer of the core molecular function from the mouse ortholog. Reason: Consistent with the experimentally and phylogenetically established core function; correctly specific.
GO:0006572 L-tyrosine catabolic process	ISS GO_REF:0000024	ACCEPT	Summary: Sequence-similarity transfer of the core biological process from the mouse ortholog. Reason: Consistent with the well-supported core involvement in tyrosine catabolism.
GO:0006572 L-tyrosine catabolic process	TAS PMID:7851880 Structure of the human 4-hydroxyphenylpyruvic acid dioxygena...	ACCEPT	Summary: Author-asserted (TAS) involvement of HPD in tyrosine catabolism, from the gene-structure paper. Reason: This foundational HPD gene-characterization paper describes HPD as the tyrosine-catabolic enzyme whose deficiency underlies tyrosinemia type III, supporting the core biological process.
GO:0046872 metal ion binding	IDA PMID:34047349 Functional role of residues involved in substrate binding of...	NEW	Summary: Metal-ion (Fe(2+)) binding required for catalysis, supported by structural and biochemical evidence for the catalytic iron center but not currently captured in GOA; proposed as a new molecular-function annotation. Reason: HPD binds one catalytic Fe(2+) ion per subunit via His183, His266 and Glu349 (a 2-His-1-carboxylate facial triad), essential for the dioxygenation reaction and the site inhibited by nitisinone. Metal ion binding is a genuine, well-supported core molecular property of the enzyme (crystallized in complex with cobalt/iron ions and annotated as a Fe(2+) cofactor in UniProt), yet it is absent from the GOA molecular-function annotations. It is therefore proposed as a NEW annotation. Supporting Evidence: PMID:34047349 the carboxyl group of HPP interacted by a H-bond network formed by Gln334, Glu349 (the metal-binding ligand), and Asn363 (in the C-terminal helix)

Gene Description

Existing Annotations Review

Core Functions

Catalyzes the second step of tyrosine catabolism: the Fe(II)-dependent dioxygenation of 3-(4-hydroxyphenyl)pyruvate with molecular oxygen to yield homogentisate and CO2 (EC 1.13.11.27), acting in the cytosol.

Binds one catalytic non-heme Fe(2+) ion per subunit via a 2-His-1-carboxylate facial triad (His183, His266, Glu349), which is required for the dioxygenation reaction and is the site inhibited by the drug nitisinone (NTBC).

References

Deep Research

Falcon

📚 Additional Documentation

Notes

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