HOGA1

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0008700 (R,S)-4-hydroxy-2-oxoglutarate aldolase activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetically-inferred core molecular function. This is the enzyme's defining activity, directly confirmed for the human protein by structural and kinetic study. Reason: This is the precise, correct molecular function of HOGA1, supported by direct biochemical characterization of the recombinant human enzyme and matching the IDA annotation from PMID:21998747. The IBA call is at the right level of specificity and represents the core function. Supporting Evidence: PMID:21998747 The activity of recombinant hHOGA proves that it is indeed the aldolase identified in the genomic analysis of PH3 patients.
GO:0005739 mitochondrion	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetically-inferred mitochondrial localization, consistent with the N-terminal mitochondrial transit peptide and the ortholog-based subcellular location. Reason: HOGA1 carries an N-terminal mitochondrial transit peptide (residues 1-25) and is a mitochondrial-matrix enzyme; the IBA is-active-in mitochondrion annotation is correct. Supporting Evidence: file:human/HOGA1/HOGA1-uniprot.txt Mitochondrion {ECO:0000250\|UniProtKB:Q0P5I5}
GO:0009436 glyoxylate catabolic process	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Phylogenetically-inferred participation in glyoxylate metabolism. HOGA1 is a mitochondrial glyoxylate-generating enzyme in the hydroxyproline degradation pathway. Reason: HOGA1 participates in mitochondrial glyoxylate metabolism, producing glyoxylate as a product of HOG cleavage. Note that HOGA1 generates rather than degrades glyoxylate, so "glyoxylate catabolic process" is a somewhat imperfect descriptor of its direct role; however it is the standard consortium call for the hydroxyproline/glyoxylate pathway and is not wrong at the pathway level. The core BP is hydroxyproline catabolism; retain this as a non-core pathway-participation annotation. Supporting Evidence: PMID:21998747 In the terminal reaction, HOG is cleaved by HOGA to produce pyruvate and glyoxylate.
GO:0005739 mitochondrion	IEA GO_REF:0000120	ACCEPT	Summary: Electronic mitochondrial localization from UniProt SubCell/ARBA, consistent with the transit peptide and experimental data. Reason: Correct localization supported by the mitochondrial targeting sequence and multiple experimental/orthology-based annotations. Supporting Evidence: file:human/HOGA1/HOGA1-uniprot.txt Mitochondrion {ECO:0000250\|UniProtKB:Q0P5I5}
GO:0008700 (R,S)-4-hydroxy-2-oxoglutarate aldolase activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic annotation of the core aldolase activity from the ARBA/RHEA/EC mapping (EC 4.1.3.16, RHEA:30687). Reason: Correct core molecular function, redundant with and consistent with the IBA and IDA annotations to the same term. EC 4.1.3.16 is the enzyme's assigned EC number. Supporting Evidence: PMID:21998747 hHOGA performs a retro-aldol cleavage reaction reminiscent of the trimeric 2-keto-3-deoxy-6-phosphogluconate aldolases.
GO:0009436 glyoxylate catabolic process	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Electronic (ARBA) annotation to glyoxylate catabolic process, duplicating the IBA/IMP calls to the same term. Reason: Same reasoning as the IBA glyoxylate catabolic process annotation - a valid pathway-participation term but not the core BP (which is hydroxyproline catabolism). Keep as non-core. Supporting Evidence: PMID:21998747 In the terminal reaction, HOG is cleaved by HOGA to produce pyruvate and glyoxylate.
GO:0016829 lyase activity	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: InterPro2GO electronic annotation to the broad parent term lyase activity, based on the DapA-like domain. Reason: "lyase activity" is a correct but uninformatively general ancestor of the specific molecular function (GO:0008700, an aldolase, which is a carbon-carbon lyase). It is subsumed by the more precise aldolase-activity annotations and adds no information; mark as over-annotated rather than removed since it is not wrong. Supporting Evidence: PMID:21998747 hHOGA performs a retro-aldol cleavage reaction reminiscent of the trimeric 2-keto-3-deoxy-6-phosphogluconate aldolases.
GO:0106009 (4S)-4-hydroxy-2-oxoglutarate aldolase activity	IEA GO_REF:0000116	ACCEPT	Summary: RHEA-based electronic annotation of the (4S)-stereospecific aldolase activity (RHEA:35639). Reason: HOGA1 cleaves the (4S) enantiomer of HOG (RHEA:35639), so this stereospecific child term is correct. The enzyme also acts on the (4R) form, hence the broader (R,S) term GO:0008700 is retained as the primary MF; both are legitimate. Supporting Evidence: PMID:21998747 Previous studies have shown that the bovine kidney, bovine liver, and rat liver enzymes have equal activity against the R- and S-forms of HOG
GO:0005515 protein binding	IPI PMID:27499296 Mitochondrial Protein Interaction Mapping Identifies Regulat...	MARK AS OVER ANNOTATED	Summary: High-throughput mitochondrial protein-interaction screen; captured interaction with STARD7 (Q9NQZ5). Uninformative bare "protein binding" term. Reason: "protein binding" (GO:0005515) is an uninformative molecular-function term that does not describe HOGA1's activity. This IPI derives from a large-scale mitochondrial protein-interaction mapping study, with no evidence that the interaction is functionally relevant to the aldolase. Per curation policy, bare protein-binding IPIs are marked as over-annotated rather than removed. Supporting Evidence: PMID:27499296 Mitochondrial Protein Interaction Mapping Identifies Regulators of Respiratory Chain Function.
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MARK AS OVER ANNOTATED	Summary: High-throughput affinity-purification interactome screen (BioPlex); captured interaction with USP47 (Q96K76). Uninformative bare "protein binding" term. Reason: Uninformative "protein binding" term from a proteome-scale interactome dataset, with no evidence of functional relevance to HOGA1's catalytic role. Marked as over-annotated per policy on bare protein-binding IPIs. Supporting Evidence: PMID:28514442 Architecture of the human interactome defines protein communities and disease networks.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: High-throughput binary (Y2H) interactome screen (HuRI); captured interaction with CIMAP1A (Q96PU9). Uninformative bare "protein binding" term. Reason: Uninformative "protein binding" term from a systematic binary-interactome map, with no evidence of functional relevance to the aldolase activity. Marked as over-annotated per policy on bare protein-binding IPIs. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: High-throughput affinity-purification interactome screen (BioPlex 3.0); captured interaction with USP47 (Q96K76). Uninformative bare "protein binding" term. Reason: Uninformative "protein binding" term from a proteome-scale interactome dataset, duplicating the other HT interaction annotations. Marked as over-annotated per policy on bare protein-binding IPIs. Supporting Evidence: PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	ACCEPT	Summary: High-throughput identification of HOGA1 in the high-confidence human mitochondrial proteome. Reason: Independent proteomic evidence for mitochondrial localization, consistent with the transit peptide and all other localization annotations. Supporting Evidence: PMID:34800366 Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
GO:0005739 mitochondrion	ISS GO_REF:0000024	ACCEPT	Summary: Sequence-similarity transfer of mitochondrial localization from the bovine ortholog (Q0P5I5). Reason: Correct localization; the bovine ortholog was purified from kidney mitochondria and human HOGA1 has the corresponding transit peptide. Supporting Evidence: PMID:21998747 mitochondrial enzyme purified from bovine kidney
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-6784423	ACCEPT	Summary: Reactome-curated localization of the HOGA1-catalyzed HOG cleavage reaction to the mitochondrial matrix. Reason: Mitochondrial matrix is the precise sub-compartment for this soluble matrix aldolase; more specific than "mitochondrion" and consistent with the pathway context. This is the best cellular-component term. Supporting Evidence: Reactome:R-HSA-6784423 aldol-cleaves 4-OH-2-oxoglutarate (HOG) to glyoxylate and pyruvate
GO:0005739 mitochondrion	ISS PMID:21998747 Structural and biochemical studies of human 4-hydroxy-2-oxog...	ACCEPT	Summary: Sequence-similarity-based mitochondrial localization annotation (BHF-UCL), referencing the structural/biochemical paper and bovine ortholog. Reason: Correct mitochondrial localization; the human enzyme was characterized from the mitochondrial hydroxyproline pathway and the bovine ortholog was purified from kidney mitochondria. Supporting Evidence: PMID:21998747 mitochondrial enzyme purified from bovine kidney
GO:0008700 (R,S)-4-hydroxy-2-oxoglutarate aldolase activity	IDA PMID:21998747 Structural and biochemical studies of human 4-hydroxy-2-oxog...	ACCEPT	Summary: Direct assay of recombinant human HOGA1 aldolase activity, including crystal structure, catalytic-residue mutagenesis (Lys196, Tyr168), and kinetics. Reason: This is the definitive experimental demonstration of HOGA1's core molecular function. Recombinant human enzyme performs retro-aldol cleavage of HOG; catalytic mutants (K196A, Y168F) abolish activity, establishing the mechanism. Core function. Supporting Evidence: PMID:21998747 The Y168F and K196A hHOGA variants exhibited no enzymatic activity PMID:21998747 The activity of recombinant hHOGA proves that it is indeed the aldolase identified in the genomic analysis of PH3 patients.
GO:0019470 trans-4-hydroxy-L-proline catabolic process	IDA PMID:21998747 Structural and biochemical studies of human 4-hydroxy-2-oxog...	ACCEPT	Summary: HOGA1 catalyzes the terminal (final) step of the four-enzyme mitochondrial hydroxyproline degradation pathway. Reason: This is the core biological process for HOGA1. The enzyme catalyzes the terminal step of 4-hydroxyproline catabolism, and UniProt describes its function as catalyzing the final step in the metabolic pathway of hydroxyproline. Supporting Evidence: PMID:21998747 The degradation pathway for 4-Hyp (Figure 1) involves the step-wise action of four mitochondrial enzymes file:human/HOGA1/HOGA1-uniprot.txt Catalyzes the final step in the metabolic pathway of
GO:0033609 oxalate metabolic process	IMP PMID:21896830 Primary hyperoxaluria type III gene HOGA1 (formerly DHDPSL) ...	KEEP AS NON CORE	Summary: HOGA1 variants influence urinary oxalate; loss-of-function mutations cause primary hyperoxaluria type 3, linking HOGA1 function to oxalate homeostasis. Reason: The connection to oxalate metabolism is real but indirect - HOGA1 does not act on oxalate directly; rather, its dysfunction perturbs glyoxylate/oxalate handling and causes hyperoxaluria (PH3). This is a disease-level/physiological link rather than the enzyme's direct catalytic role, so keep as non-core. Supporting Evidence: PMID:21896830 hypothesized to cause a gain of mitochondrial 4-hydroxy-2-oxoglutarate aldolase PMID:21896830 HOGA1 may be a predisposing factor for this
GO:0042803 protein homodimerization activity	IDA PMID:21998747 Structural and biochemical studies of human 4-hydroxy-2-oxog...	ACCEPT	Summary: Structural study shows HOGA1 assembles via a "tight" dimer interface into a homotetramer (dimer of dimers); the active site lies at the dimer interface. Reason: The crystal structure directly demonstrates self-association. The biological assembly is a homotetramer, but it is built as a dimer of dimers, and the active site is formed at the tight dimer interface (a residue from the adjacent monomer, Tyr140', contributes to the active site), so homodimerization is a genuine, structurally-supported self-association activity. UniProt records the assembly as a homotetramer. Supporting Evidence: PMID:21998747 reveal a tetrameric structure composed of a dimer of dimers file:human/HOGA1/HOGA1-uniprot.txt SUBUNIT: Homotetramer
GO:0042866 pyruvate biosynthetic process	IDA PMID:21998747 Structural and biochemical studies of human 4-hydroxy-2-oxog...	KEEP AS NON CORE	Summary: Pyruvate is a co-product of the HOGA1-catalyzed cleavage of HOG (HOG -> glyoxylate + pyruvate). Reason: Pyruvate is genuinely produced by the HOGA1 reaction, so this annotation is factually correct. However, pyruvate is a minor co-product of hydroxyproline catabolism and HOGA1 is not a dedicated pyruvate-biosynthetic enzyme; keep as a non-core annotation rather than a core function. Supporting Evidence: PMID:21998747 In the terminal reaction, HOG is cleaved by HOGA to produce pyruvate and glyoxylate.
GO:0046487 glyoxylate metabolic process	IDA PMID:21998747 Structural and biochemical studies of human 4-hydroxy-2-oxog...	KEEP AS NON CORE	Summary: HOGA1 produces glyoxylate as a product of HOG cleavage, participating in mitochondrial glyoxylate metabolism. Reason: Correct - HOGA1 generates glyoxylate, so it participates in glyoxylate metabolic process. This is a more accurate parent than "glyoxylate catabolic process" (since HOGA1 makes, not degrades, glyoxylate), but it is a downstream/pathway annotation rather than the core hydroxyproline-catabolic function; keep as non-core. Supporting Evidence: PMID:21998747 In the terminal reaction, HOG is cleaved by HOGA to produce pyruvate and glyoxylate.
GO:0009436 glyoxylate catabolic process	IMP PMID:20797690 Mutations in DHDPSL are responsible for primary hyperoxaluri...	KEEP AS NON CORE	Summary: Mutations in HOGA1 (DHDPSL) cause primary hyperoxaluria type 3, establishing HOGA1's role in the glyoxylate/hydroxyproline pathway by loss of function. Reason: The disease-based IMP correctly places HOGA1 in the glyoxylate pathway, but "glyoxylate catabolic process" is an imperfect descriptor since HOGA1 produces rather than degrades glyoxylate; the core BP is hydroxyproline catabolism. Retain as a non-core pathway-participation annotation. Supporting Evidence: PMID:20797690 cause a third type of PH (PH III) PMID:20797690 the gene encoding 4-hydroxy-2-oxoglutarate
GO:0008700 (R,S)-4-hydroxy-2-oxoglutarate aldolase activity	ISS GO_REF:0000024	ACCEPT	Summary: Sequence-similarity transfer of the core aldolase activity from the bovine ortholog (Q0P5I5), which shares ~90% identity with human HOGA1. Reason: Correct core molecular function, redundant with the direct experimental (IDA) annotation to the same term. The bovine ortholog is 90.2% identical and functionally characterized. Supporting Evidence: PMID:21998747 Sequence comparison of human HOGA with bovine HOGA (90.2% identity)

Gene Description

Existing Annotations Review

Core Functions

Catalyzes the terminal step of the mitochondrial 4-hydroxyproline degradation pathway, the retro-aldol cleavage of 4-hydroxy-2-oxoglutarate (HOG) into glyoxylate and pyruvate, via a Schiff-base (type I aldolase) mechanism using Lys196 as the catalytic nucleophile.

References

Suggested Questions for Experts

Suggested Experiments

📚 Additional Documentation

Notes

📄 View Raw YAML