HAO1 (hydroxyacid oxidase 1; also called glycolate oxidase, GO/GOX, or glyoxylate oxidase; HAOX1) is a peroxisomal FMN-dependent (S)-2-hydroxy-acid oxidase of the FMN-dependent alpha-hydroxy acid dehydrogenase family. It is a homotetramer localized to the peroxisomal matrix and is highly expressed in liver. HAO1 has broad substrate specificity but preferentially oxidizes glycolate to glyoxylate, using molecular O2 as the physiological electron acceptor and generating hydrogen peroxide (H2O2); it also oxidizes long-chain 2-hydroxy fatty acids (e.g. 2-hydroxyhexadecanoate, 2-hydroxyoctanoate) with lower efficiency, contributing to fatty-acid alpha-oxidation. Because it produces glyoxylate, the immediate precursor of oxalate, HAO1 is central to hepatic oxalate production, and in primary hyperoxaluria glyoxylate that is not detoxified to glycine is converted to oxalate, causing kidney stones and systemic oxalosis. HAO1 is therefore a validated therapeutic target, and the siRNA drug lumasiran silences hepatic HAO1 to lower oxalate in primary hyperoxaluria.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003973 (S)-2-hydroxy-acid oxidase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Core molecular function of HAO1. This IEA (RHEA:16789 / EC:1.1.3.15) captures the FMN-dependent (S)-2-hydroxy-acid oxidase activity that preferentially oxidizes glycolate to glyoxylate, matching the experimentally determined function. Reason: This is the correct, specific core molecular function and is independently supported by direct experimental IDA annotations (PMID:10777549, PMID:18215067) and by the UniProt catalytic activity records (RHEA:16789, EC 1.1.3.15). Supporting Evidence: file:human/HAO1/HAO1-uniprot.txt Broad substrate specificity (S)-2-hydroxy-acid oxidase that file:human/HAO1/HAO1-uniprot.txt preferentially oxidizes glycolate |
| GO:0005782 peroxisomal matrix | IEA GO_REF:0000120 | ACCEPT | Summary: HAO1 is a soluble peroxisomal matrix enzyme with a C-terminal PTS1 microbody targeting signal. This IEA correctly places it in the peroxisomal matrix. Reason: Consistent with the experimental IDA localization (PMID:10777549) and the UniProt subcellular location; HAO1 carries a C-terminal microbody targeting signal. Supporting Evidence: file:human/HAO1/HAO1-uniprot.txt SUBCELLULAR LOCATION: Peroxisome matrix |
| GO:0010181 FMN binding | IEA GO_REF:0000002 | ACCEPT | Summary: HAO1 is an FMN-dependent flavoenzyme; FMN is the catalytic cofactor. This InterPro-based IEA is correct but represents a supporting cofactor-binding function rather than the core catalytic function. Reason: FMN is the experimentally confirmed cofactor (PMID:17669354, PMID:18215067); multiple FMN-binding residues are annotated in UniProt. Correct but secondary to the oxidase activity. Supporting Evidence: file:human/HAO1/HAO1-uniprot.txt Name=FMN; file:human/HAO1/HAO1-uniprot.txt Belongs to the FMN-dependent alpha-hydroxy acid |
| GO:0016491 oxidoreductase activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: Generic parent term for the oxidase activity. Not wrong, but far less informative than the specific (S)-2-hydroxy-acid oxidase activity that is separately annotated. Reason: GO:0016491 is a high-level ancestor of the specific GO:0003973 activity already annotated with experimental evidence; it adds no information beyond the more specific term. Supporting Evidence: file:human/HAO1/HAO1-uniprot.txt Broad substrate specificity (S)-2-hydroxy-acid oxidase that |
| GO:0019395 fatty acid oxidation | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA machine-learning inference. HAO1 does oxidize long-chain 2-hydroxy fatty acids, but its role is in fatty-acid alpha-oxidation (the specific IDA annotation GO:0001561), not in general fatty acid oxidation (which connotes beta-oxidation-type degradation). Reason: The enzyme's fatty-acid-related role is the more specific alpha-oxidation of 2-hydroxy fatty acids (separately annotated as GO:0001561 with IDA). The broad ARBA-derived "fatty acid oxidation" term is imprecise for this activity. Supporting Evidence: file:human/HAO1/HAO1-uniprot.txt long chain hydroxyacids such PMID:10777549 substrate, glycolate, but is also active on 2-hydroxy fatty acids |
| GO:0047639 alcohol oxidase activity | IEA GO_REF:0000116 | MARK AS OVER ANNOTATED | Summary: RHEA-based IEA (RHEA:25311, glycolate + O2 = glyoxylate + H2O2). Although glycolate has a hydroxyl group, the informative and correct molecular function term for this reaction is the (S)-2-hydroxy-acid oxidase activity (GO:0003973), not the generic "alcohol oxidase activity". Reason: The Rhea-to-GO mapping assigns a less-specific, potentially misleading MF term; the glycolate oxidation reaction is properly captured by the (S)-2-hydroxy-acid oxidase activity already annotated with experimental evidence. Supporting Evidence: file:human/HAO1/HAO1-uniprot.txt preferentially oxidizes glycolate |
| GO:0047969 glyoxylate oxidase activity | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Oxidation of glyoxylate to oxalate (EC 1.2.3.5). HAO1 can catalyze this reaction in vitro, but it is a low-efficiency secondary activity that is "most likely not relevant under normal conditions"; the primary reaction is glycolate to glyoxylate. Reason: A genuine but physiologically minor in vitro activity (kcat/KM far below that for glycolate). Retained but marked non-core because glycolate oxidation, not glyoxylate oxidation, is the primary physiological function. Supporting Evidence: PMID:18215067 oxidation of glycolate to glyoxylate is the primary reaction catalyzed by GO, while the oxidation of glyoxylate to oxalate is most likely not relevant under normal conditions |
| GO:0005777 peroxisome | IEA GO_REF:0000120 | ACCEPT | Summary: HAO1 is a peroxisomal enzyme. This IEA (parent of the more specific peroxisomal matrix term) correctly places HAO1 in the peroxisome. Reason: Correct organelle localization, consistent with the experimental IDA to the peroxisomal matrix (PMID:10777549) and the UniProt subcellular location. Supporting Evidence: file:human/HAO1/HAO1-uniprot.txt SUBCELLULAR LOCATION: Peroxisome matrix |
| GO:0006979 response to oxidative stress | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl ortholog-transfer inference. HAO1 is a producer of H2O2 (a reactive oxygen species) rather than a component of the cellular response to oxidative stress; there is no direct evidence that HAO1 participates in defending against oxidative stress. Reason: The activity generates H2O2 as a by-product; casting HAO1 as part of the "response to oxidative stress" over-interprets an electronic ortholog transfer and does not reflect a validated protective role. Supporting Evidence: file:human/HAO1/HAO1-uniprot.txt leading to the production of H2O2 |
| GO:0006545 glycine biosynthetic process | IEA GO_REF:0000041 | KEEP AS NON CORE | Summary: UniPathway mapping (UPA00288). The glyoxylate produced by HAO1 is transaminated by alanine-glyoxylate aminotransferase to form glycine, so HAO1 provides an upstream substrate for peroxisomal glycine synthesis rather than performing a glycine-synthetic step itself. Reason: HAO1 contributes the glyoxylate substrate for glycine biosynthesis (a genuine upstream role recorded in the UniProt pathway annotation) but does not itself catalyze glycine formation; retained as a non-core, contributory process. Supporting Evidence: file:human/HAO1/HAO1-uniprot.txt Amino-acid biosynthesis; glycine biosynthesis |
| GO:0005782 peroxisomal matrix | IDA PMID:10777549 Identification and characterization of HAOX1, HAOX2, and HAO... | ACCEPT | Summary: Direct experimental demonstration that HAO1 (HAOX1) is targeted to peroxisomes; it is a soluble matrix enzyme. This is the primary evidence for the peroxisomal matrix localization. Reason: Experimental IDA localization of the human enzyme to peroxisomes, consistent with the UniProt subcellular location and the presence of a C-terminal PTS1 signal. Supporting Evidence: PMID:10777549 targeted to peroxisomes and have 2-hydroxy acid |
| GO:0047969 glyoxylate oxidase activity | IDA PMID:10777549 Identification and characterization of HAOX1, HAOX2, and HAO... | KEEP AS NON CORE | Summary: Experimental demonstration that HAOX1 can oxidize glyoxylate to oxalate. This is a genuine but physiologically minor activity relative to the primary glycolate oxidation. Reason: A real, experimentally supported in vitro activity implicated in oxalate production (and PH1 pathophysiology), but a low-efficiency side reaction rather than the core physiological function. Retained as non-core. Supporting Evidence: PMID:10777549 implicate HAOX1 as a mediator of PH1 pathophysiology |
| GO:0047969 glyoxylate oxidase activity | IDA PMID:17669354 Purification and characterization of recombinant human liver... | KEEP AS NON CORE | Summary: Characterization of recombinant human liver glycolate oxidase confirming it can contribute to oxalate production. As above, glyoxylate-to-oxalate oxidation is a minor secondary activity relative to glycolate oxidation. Reason: Experimentally supported minor activity; the same physiologically-minor glyoxylate oxidase reaction. Retained as non-core, deferring to the curator's experimental annotation. Supporting Evidence: PMID:17669354 to the production of oxalate with formation of kidney stones |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9033235 | MARK AS OVER ANNOTATED | Summary: This Reactome annotation reflects the transient cytosolic pool of HAO1 cargo prior to PTS1-dependent peroxisomal import (the "Cargo of PEX5S,L translocates from the cytosol to the peroxisomal matrix" reaction), not the steady-state functional location. Reason: HAO1 is synthesized in the cytosol and imported into peroxisomes; the cytosolic annotation captures a transit state of the peroxisomal import pathway rather than a distinct cytosolic function. The functional location is the peroxisomal matrix. Supporting Evidence: file:human/HAO1/HAO1-uniprot.txt SUBCELLULAR LOCATION: Peroxisome matrix |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9033236 | MARK AS OVER ANNOTATED | Summary: As above, this Reactome cytosol annotation derives from the peroxisomal protein import pathway (PEX5:cargo docking), representing an import-transit state rather than a steady-state cytosolic localization. Reason: Reflects the cytosolic phase of PTS1-mediated peroxisomal import, not an independent cytosolic function; the mature enzyme resides in the peroxisomal matrix. Supporting Evidence: file:human/HAO1/HAO1-uniprot.txt SUBCELLULAR LOCATION: Peroxisome matrix |
| GO:0005782 peroxisomal matrix | TAS Reactome:R-HSA-389842 | ACCEPT | Summary: Reactome-curated peroxisomal matrix localization ("HAO1 tetramer oxidizes glycolate to glyoxylate"), consistent with the experimental and UniProt evidence. Reason: Correct steady-state functional location, agreeing with the IDA (PMID:10777549) and UniProt subcellular location. Supporting Evidence: file:human/HAO1/HAO1-uniprot.txt SUBCELLULAR LOCATION: Peroxisome matrix |
| GO:0005782 peroxisomal matrix | TAS Reactome:R-HSA-389862 | ACCEPT | Summary: Reactome-curated peroxisomal matrix localization associated with the "Conversion of glyoxylate to oxalate" reaction. Correct localization. Reason: Correct peroxisomal matrix localization, consistent with experimental and UniProt evidence. Supporting Evidence: file:human/HAO1/HAO1-uniprot.txt SUBCELLULAR LOCATION: Peroxisome matrix |
| GO:0005782 peroxisomal matrix | TAS Reactome:R-HSA-9033235 | ACCEPT | Summary: Reactome peroxisomal matrix localization (peroxisomal import pathway). Consistent with the mature functional location of HAO1. Reason: Correct peroxisomal matrix localization; the destination of the PTS1-mediated import pathway. Supporting Evidence: file:human/HAO1/HAO1-uniprot.txt SUBCELLULAR LOCATION: Peroxisome matrix |
| GO:0003973 (S)-2-hydroxy-acid oxidase activity | IDA PMID:10777549 Identification and characterization of HAOX1, HAOX2, and HAO... | ACCEPT | Summary: Direct experimental demonstration that HAOX1 has 2-hydroxy acid oxidase activity and is most active on glycolate. This is the core molecular function of HAO1. Reason: Primary experimental evidence for the core (S)-2-hydroxy-acid oxidase activity, with glycolate as the preferred substrate. Supporting Evidence: PMID:10777549 targeted to peroxisomes and have 2-hydroxy acid PMID:10777549 substrate, glycolate, but is also active on 2-hydroxy fatty acids |
| GO:0001561 fatty acid alpha-oxidation | IDA PMID:18215067 Active site and loop 4 movements within human glycolate oxid... | KEEP AS NON CORE | Summary: HAO1 oxidizes long-chain 2-hydroxy fatty acids (e.g. 2-hydroxyoctanoate, 2-hydroxyhexadecanoate), a step within the fatty-acid alpha-oxidation pathway. This is a genuine but secondary role relative to glycolate oxidation. Reason: Experimentally supported involvement in alpha-oxidation via oxidation of 2-hydroxy fatty acids, but performed with much lower catalytic efficiency than glycolate oxidation; retained as a non-core biological process. Supporting Evidence: PMID:10777549 substrate, glycolate, but is also active on 2-hydroxy fatty acids file:human/HAO1/HAO1-uniprot.txt long chain hydroxyacids such |
| GO:0003973 (S)-2-hydroxy-acid oxidase activity | IDA PMID:18215067 Active site and loop 4 movements within human glycolate oxid... | ACCEPT | Summary: Structural and kinetic study confirming the FMN-dependent (S)-2-hydroxy-acid oxidase activity, with glycolate oxidation to glyoxylate as the primary reaction. Core molecular function. Reason: Direct experimental (structural/kinetic) support for the core (S)-2-hydroxy-acid oxidase activity; the study explicitly identifies glycolate-to-glyoxylate as the primary catalyzed reaction. Supporting Evidence: PMID:18215067 catalyzes the FMN-dependent oxidation of glycolate to glyoxylate and glyoxylate to oxalate PMID:18215067 oxidation of glycolate to glyoxylate is the primary reaction catalyzed by GO, while the oxidation of glyoxylate to oxalate is most likely not relevant under normal conditions |
| GO:0010181 FMN binding | IDA PMID:18215067 Active site and loop 4 movements within human glycolate oxid... | ACCEPT | Summary: Crystal structures of HAO1 in complex with FMN directly demonstrate FMN binding. FMN is the catalytic cofactor of this flavoenzyme. Reason: Direct structural evidence (PDB complexes with FMN) for FMN binding; correct cofactor-binding function, secondary to the core oxidase activity. Supporting Evidence: PMID:18215067 catalyzes the FMN-dependent oxidation of glycolate to glyoxylate and glyoxylate to oxalate file:human/HAO1/HAO1-uniprot.txt Name=FMN; |
| GO:0046296 glycolate catabolic process | IDA PMID:18215067 Active site and loop 4 movements within human glycolate oxid... | ACCEPT | Summary: HAO1 catalyzes the committed oxidation of glycolate to glyoxylate, the primary catabolic fate of glycolate. This is a core biological process for HAO1. Reason: Direct experimental support; glycolate oxidation to glyoxylate is identified as the primary reaction catalyzed by the enzyme, making glycolate catabolism a core process. Supporting Evidence: PMID:18215067 oxidation of glycolate to glyoxylate is the primary reaction catalyzed by GO, while the oxidation of glyoxylate to oxalate is most likely not relevant under normal conditions |
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Download this section (compressed HTML)Q: Under physiological hepatic conditions, what fraction of glyoxylate that is ultimately converted to oxalate originates from HAO1-generated glyoxylate versus other sources (e.g. hydroxyproline metabolism)?
Q: Does HAO1-generated peroxisomal H2O2 have any regulated signaling or redox role, or is it purely a metabolic by-product handled by peroxisomal catalase?
Experiment: Quantitative flux analysis in primary human hepatocytes with graded HAO1 knockdown (mimicking lumasiran) to measure the contribution of HAO1 to glyoxylate and oxalate pools.
Experiment: Structure-guided kinetic profiling of HAO1 against the full spectrum of L-2-hydroxy acid and 2-hydroxy fatty acid substrates to define its in vivo substrate hierarchy beyond glycolate.
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