HOGA1 (Q86XE5) review notes

Summary

HOGA1 = 4-hydroxy-2-oxoglutarate aldolase, mitochondrial (EC 4.1.3.16; formerly DHDPSL /
C10orf65). Mitochondrial matrix enzyme catalysing the terminal step of the hydroxyproline
(4-Hyp) degradation pathway: retro-aldol cleavage of 4-hydroxy-2-oxoglutarate (HOG) into
glyoxylate + pyruvate. Belongs to the DapA (dihydrodipicolinate synthase, DHDPS) family;
Schiff-base type I aldolase using Lys196 as the catalytic nucleophile. Forms a homotetramer
(dimer of dimers). Loss-of-function mutations cause primary hyperoxaluria type 3 (PH3 /
HP3, MIM 613616).

Key point on directionality of disease: HOGA1 itself produces glyoxylate (a precursor of
oxalate), yet its loss causes hyperoxaluria. Mechanism is debated (loss-of-function with
accumulation of HOG/upstream intermediates that dysregulate glyoxylate detoxification /
possible dominant-negative effect), but the enzymatic reaction and the disease association
are both firmly established.

Molecular function

• EC 4.1.3.16; Rhea:35639 [(4S)-HOG = glyoxylate + pyruvate] and Rhea:30687 [(4R)-HOG].
  Enzyme cleaves both R- and S-forms of HOG (racemic-active), consistent with GO:0008700
  "(R,S)-4-hydroxy-2-oxoglutarate aldolase activity". GO:0106009 is the (4S)-specific term
  from the Rhea:35639 mapping; GOA carries both.
• PMID:21998747
• PMID:21998747
• Catalytic residues (mutagenesis): Lys196 nucleophile (K196A dead), Tyr168 (Y168F dead),
  Ser77/Asn78/Ser198 modulate substrate binding PMID:21998747.
• Homotetramer: PMID:21998747.
  UniProt SUBUNIT = Homotetramer; the GOA GO:0042803 "protein homodimerization activity"
  (IDA, PMID:21998747) captures the tight-dimer interface but tetramer is the biological
  assembly; homodimerization is a real, structurally-supported sub-assembly.

Biological process

• Terminal step of hydroxyproline catabolism PMID:21998747
  -> GO:0019470 trans-4-hydroxy-L-proline catabolic process (IDA). CORE BP.
• UniProt FUNCTION: "Catalyzes the final step in the metabolic pathway of hydroxyproline."
• Glyoxylate metabolic/catabolic process (GO:0046487 / GO:0009436): HOGA produces glyoxylate.
  Note glyoxylate is a product, so "glyoxylate metabolic process" (0046487) fits well;
  "glyoxylate catabolic process" (0009436) is arguably a stretch (HOGA makes glyoxylate, it
  does not itself degrade it) but is the standard IBA/IMP call for this pathway and is not
  wrong at the pathway level -> keep, non-core-ish but accept as pathway participation.
• Pyruvate biosynthetic process (GO:0042866, IDA): pyruvate is the co-product -> accept.
• Oxalate metabolic process (GO:0033609, IMP, PMID:21896830): HOGA1 loss/variants influence
  urine oxalate; disease connection to oxalate. Keep as non-core (regulatory/disease-level
  link, not the direct catalysed reaction).

Localization

• Mitochondrion (GO:0005739) / mitochondrial matrix (GO:0005759). N-terminal transit peptide
  (1..25). Multiple orthogonal lines: IBA, IEA(SubCell), ISS from bovine Q0P5I5, HTP
  mito-proteome (PMID:34800366), TAS Reactome matrix. All consistent. Accept mitochondrion;
  mitochondrial matrix is the more precise CC.

protein binding IPIs

Four IPI GO:0005515 "protein binding" annotations from high-throughput interactome / mito
protein-interaction screens (PMID:27499296 STARD7; PMID:28514442 & 33961781 USP47;
PMID:32296183 CIMAP1A). Bare "protein binding" is uninformative and these are HT screens;
per policy -> MARK_AS_OVER_ANNOTATED (do NOT REMOVE bare protein-binding IPIs). No evidence
these interactions are functionally relevant to the aldolase activity.

lyase activity (GO:0016829, IEA InterPro)

Correct but very general parent of the specific aldolase MF -> MARK_AS_OVER_ANNOTATED
(redundant with GO:0008700). Not wrong.

Core functions

1. MF: GO:0008700 (R,S)-4-hydroxy-2-oxoglutarate aldolase activity
2. BP: GO:0019470 trans-4-hydroxy-L-proline catabolic process
3. CC: GO:0005759 mitochondrial matrix (mitochondrion GO:0005739 also correct)

Disease

PH3 / HP3 (MIM 613616): PMID:20797690. Loss-of-function mechanism supported
PMID:21896830.

Deep research note

falcon deep-research provider is out of credits (HTTP 402); no -deep-research-falcon.md
generated. Review grounded in UniProt Q86XE5, seeded GOA, and cached publications
(PMID:20797690, 21896830, 21998747) plus Reactome R-HSA-6784423.