HAL (histidine ammonia-lyase, histidase; EC 4.3.1.3) catalyzes the first and committed step of L-histidine catabolism, the non-oxidative deamination of L-histidine to trans-urocanate (urocanic acid) plus ammonia. It is a member of the PAL/histidase (aromatic amino acid ammonia-lyase) family and uses an autocatalytically formed 4-methylideneimidazol-5-one (MIO) prosthetic group, generated by cyclization and dehydration of an internal Ala-Ser-Gly tripeptide, as its catalytic electrophile. The active enzyme is a homotetramer that acts in the cytosol. In the liver, this reaction initiates the pathway that degrades histidine ultimately to L-glutamate; in the skin/epidermis, the urocanate product is a major UV-absorbing chromophore of the stratum corneum. Expression is enriched in liver and skin. Loss-of-function variants cause the autosomal recessive inborn error of metabolism histidinemia, characterized by elevated histidine and reduced urocanate in body fluids.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0006548 L-histidine catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred (IBA) annotation to the histidine catabolic process. This is the correct, core biological process for HAL: it catalyzes the first committed step of L-histidine degradation. Consistent with the UniProt pathway annotation and the enzymatic reaction. Supporting Evidence: file:human/HAL/HAL-uniprot.txt glutamate; N-formimidoyl-L-glutamate from L-histidine: step 1/3. |
| GO:0004397 histidine ammonia-lyase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred (IBA) annotation to histidine ammonia-lyase activity. This is the core molecular function of HAL, matching the UniProt RecName, EC 4.3.1.3, and the catalytic-activity reaction. Retained as core. Supporting Evidence: file:human/HAL/HAL-uniprot.txt Reaction=L-histidine = trans-urocanate + NH4(+); Xref=Rhea:RHEA:21232, |
| GO:0003824 catalytic activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: InterPro2GO (IEA) mapping to the root molecular-function term catalytic activity. Not wrong, but uninformatively general: HAL has a specific, well-established activity (histidine ammonia-lyase, GO:0004397) that is already annotated. Over-annotation relative to the specific term. Proposed replacements: histidine ammonia-lyase activity |
| GO:0004397 histidine ammonia-lyase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (IEA) annotation to the correct, specific molecular function (histidine ammonia-lyase activity), based on ARBA/InterPro/RHEA/EC mappings. Consistent with the experimental and phylogenetic annotations to the same term. Core function. Supporting Evidence: file:human/HAL/HAL-uniprot.txt RecName: Full=Histidine ammonia-lyase; |
| GO:0005737 cytoplasm | IEA GO_REF:0000002 | MODIFY | Summary: InterPro2GO (IEA) location annotation to cytoplasm. HAL is a soluble cytosolic enzyme, so this is correct but less precise than the cytosol (GO:0005829) annotation already present from Reactome. Retained as non-core; the more specific cytosol term is preferred. Proposed replacements: cytosol |
| GO:0006548 L-histidine catabolic process | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (IEA) annotation to the histidine catabolic process, duplicating the IBA and TAS annotations to the same term from independent pipelines. Correct core biological process. Supporting Evidence: file:human/HAL/HAL-uniprot.txt glutamate; N-formimidoyl-L-glutamate from L-histidine: step 1/3. |
| GO:0016841 ammonia-lyase activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: InterPro2GO (IEA) mapping to the parent term ammonia-lyase activity. This is a correct but overly general ancestor of the specific histidine ammonia-lyase activity (GO:0004397) that HAL enables and that is already annotated. Over-annotation relative to the specific term. Proposed replacements: histidine ammonia-lyase activity |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" from a high-throughput AP-MS interactome screen (BioPlex; IntAct with UniProtKB:Q86WX3 = RPS19BP1). The UniProt record notes the same P42357-RPS19BP1 interaction (NbExp=2). This uninformative term does not describe HAL's function and the single low-throughput-corroborated interaction has no established biological role for histidase. Kept but marked as over-annotated per policy (experimental IPI not removed). Supporting Evidence: file:human/HAL/HAL-uniprot.txt P42357; Q86WX3: RPS19BP1; NbExp=2; IntAct=EBI-10049552, EBI-4479407; |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" from a second high-throughput proteomics/interactome map (multimodal U2OS cell map; IntAct with UniProtKB:Q86WX3 = RPS19BP1). As above, this uninformative term does not capture HAL's catalytic function and no biological role is established for the interaction. Kept but marked as over-annotated per policy (experimental IPI not removed). |
| GO:0031670 cellular response to nutrient | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronically transferred (Ensembl Compara IEA, GO_REF:0000107) from a rat ortholog annotation to "cellular response to nutrient". This is a vague, indirectly transferred process term with no direct experimental support in human HAL and no basis in the enzyme's established function. It reflects transcriptional/dietary regulation of the ortholog rather than a core evolved function of the gene product. Marked as over-annotated. |
| GO:0006548 L-histidine catabolic process | TAS Reactome:R-HSA-70921 | ACCEPT | Summary: Author statement (TAS) from Reactome's Histidine catabolism pathway. HAL catalyzes the first step of this pathway. Correct core biological process. Supporting Evidence: Reactome:R-HSA-70921 The major pathway of histidine catabolism, annotated here, proceeds in four steps to yield glutamate |
| GO:0004397 histidine ammonia-lyase activity | EXP PMID:15806399 Molecular characterization of histidinemia: identification o... | ACCEPT | Summary: Experimental (EXP) annotation to histidine ammonia-lyase activity, assigned by Reactome from the histidinemia mutation study. The paper establishes that histidase (histidine ammonia lyase, EC 4.3.1.3) deficiency causes histidinemia and identifies four disease missense mutations in the human HAL gene, providing genetic evidence linking this human gene product to the histidine ammonia-lyase activity. This is the core molecular function. Supporting Evidence: PMID:15806399 and decreased urocanic acid in blood and skin and results from histidase PMID:15806399 report describes the first mutations occurring in the coding region of the |
| GO:0005829 cytosol | TAS Reactome:R-HSA-70899 | ACCEPT | Summary: Author statement (TAS) from Reactome localizing HAL to the cytosol, where it catalyzes histidine to urocanate + NH4+. Consistent with HAL being a soluble cytosolic enzyme. Correct cellular location; preferred over the more general cytoplasm IEA annotation. Supporting Evidence: Reactome:R-HSA-70899 Cytosolic histidine ammonia lyase (HAL) catalyzes the reaction of histidine to form urocanate and NH4+ |
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