Acadl (mouse LCAD) — curation notes

Gene: Acadl (long-chain specific acyl-CoA dehydrogenase, LCAD), Mus musculus
UniProt: P51174 · EC: 1.3.8.8 · Family: acyl-CoA dehydrogenase (ACAD), PANTHER PTHR48083

Why this gene was curated

Mouse Acadl is the home for a cluster of annotations that were mis-transferred
onto human ACADVL by Ensembl Compara orthology and that we removed in the
human ACADVL review (8 REMOVE calls). Human and rodent long-chain FAO are wired
differently: in humans VLCAD (ACADVL) dominates long-chain β-oxidation and LCAD
(ACADL) is a minor/near-vestigial activity, whereas in rodents LCAD is a
functionally important long-chain dehydrogenase. So the whole-organism knockout
phenotypes belong to mouse Acadl, not human ACADVL.

Function

LCAD catalyzes the first (FAD-dependent, α,β-dehydrogenation) step of each mitochondrial
FAO cycle, forming (2E)-enoyl-CoA and passing electrons to ETF. Its long-chain specific
activity overlaps with ACADVL and ACAD9, acting on saturated and unsaturated acyl-CoAs
of ~C6–C24 [file:mouse/Acadl/Acadl-uniprot.txt "long-chain specific / acyl-CoA dehydrogenase
activity overlaps with that of ACADV and ACAD9, acting on saturated and unsaturated acyl-CoAs
with 6 to 24 carbons"]. Mature enzyme is a homotetramer in the mitochondrial matrix,
one FAD per subunit. LCAD is notably the principal dehydrogenase for unsaturated and
branched/methyl-branched long-chain substrates and for some C22–C24 species.

The LCAD-knockout phenotypes (the mis-transfer source)

The mouse Acadl-null has been extensively characterized, and its phenotypes are annotated
here with experimental IMP evidence — these are exactly the terms removed from human ACADVL:

The classic LCAD-KO mouse (Kurtz/Guerra and successors) shows cold intolerance / impaired
non-shivering thermogenesis, gestational loss, hepatic and cardiac lipidosis, and altered
lipid homeostasis — the phenotypic basis of the thermoregulation and lipid-regulation terms
above. (PMIDs recorded as leads from GOA; not yet cached for verbatim supporting_text
verification — anchor quotes to the in-repo UniProt record, or fetch these publications before
citing them in supported_by.)

Core molecular function

• GO:0004466 long-chain fatty acyl-CoA dehydrogenase activity — core MF, with IDA
  (PMID:9861014) plus IBA/IEA/ISO support. This is the correct chain-length-specific term.
• GO:0050660 FAD binding — cofactor, ACCEPT (flavoenzyme).
• GO:0005759 mitochondrial matrix — core location.

Over-annotation watch

• GO:0017099 very-long-chain acyl-CoA dehydrogenase activity (ECO:0007322) and
  GO:0070991 medium-chain acyl-CoA dehydrogenase activity (IEA/ECO:0000501): LCAD has a
  broad substrate range that overlaps VLCAD (long/very-long) and MCAD (medium), but its
  defining specificity is long-chain. These broader/narrower chain-length MF terms are
  candidates for MARK_AS_OVER_ANNOTATED / KEEP_AS_NON_CORE (parallel to how ACAD9's
  GO:0017099 was handled) rather than core.
• GO:0042803 protein homodimerization activity (ISO): LCAD is a homotetramer; the
  self-association MF term is non-core (cf. the ACADVL/ACADM GO:0042802 treatment).

Cross-reference

This review closes the loop on the human ACADVL cross-paralog cleanup: see the ACADVL
review's 8 REMOVE calls (mouse P50544→P51174 LCAD phenotype transfers) — those annotations
are correctly at home here on mouse Acadl.

Status

Fetched (42 GOA annotations) with notes; full per-annotation review + core_functions to be
completed. Part of the cross-species FAO project (mouse arm).