Enzyme specificity

Right enzyme class, wrong substrate, cofactor, donor or reaction

AI Gene Review · projects/ENZYME_SPECIFICITY · 2026

Bottom line

  • A GO MF term can name the right kind of enzyme and still get the substrate, cofactor or reaction wrong.
  • We reviewed 14 genes: four exemplars (LPL1, GND1, PHYKPL, EryCIII) and all ten human β-oxidation enzymes, where chain length decides the term.
  • Errors caught: too-narrow substrate, wrong reaction, wrong donor, wrong chain length, wrong subunit, a nickname collision. GND1 was a negative control. Complete.

Why specificity

  • Specificity errors survive because the fold and enzyme class are right; nothing looks wrong until someone checks the substrate.
  • They mislead pathway reconstruction and propagate by IBA.
  • Four categories: substrate, reaction mechanism, cofactor, non-enzymatic homolog (e.g. Epe1).
  • Principle: use the specific term where one exists, fall back to the general term where GO has none.

Four exemplars

β-oxidation: specificity inside a paralog set

Proposing the missing terms

PHYKPL review: GO has no term for its reaction, so the review proposes 5-phosphooxy-L-lysine phospho-lyase activity and a matching catabolic process, and adds the general GO:0016838 carbon-oxygen lyase activity, acting on phosphates, as NEW.

Findings

  1. Family membership is the usual culprit: PHYKPL (aminotransferase III), EryCIII (IEA UDP-GT), GND1 D-gluconate (UniProt keyword via ARBA rule).
  2. Wrong subunit or paralog errors cluster in complexes and families: HADHA thiolase, HADH long-chain, ACADVL mouse-LCAD transfers.
  3. Name collisions create errors no sequence check finds: "ACAT1" = SOAT1 vs mitochondrial T2.
  4. A GO → RHEA gap: hydratase GO:0004300 maps to RHEA:20724 (3E), not the canonical (2E) RHEA:16105.

Status and next steps

  • ✅ 14/14 reviews complete; MODULE:fatty_acid_beta_oxidation built.
  • ⬜ If extended: keyword-derived substrate terms on other PPP enzymes (ZWF1); NAD vs NADP dehydrogenase pairs.

Read more: projects/ENZYME_SPECIFICITY.md · modules/fatty_acid_beta_oxidation.yaml · projects/RHEA/RHEA-EC-SPECIFICITY.md