UniProt: Q9W3N9 (unreviewed / TrEMBL). Gene: Acat1 / CG10932 / FBgn0029969, X chromosome.
Protein: 410 aa, thiolase-like superfamily (Thiolase family). EC 2.3.1.9 asserted.
Ortholog of human ACAT1 (P24752), mitochondrial acetoacetyl-CoA thiolase ("T2").
This is the only substantive functional study in Drosophila. It uses fly Acat1 (CG10932) directly:
IMPORTANT curation note: In this paper, ketone-body synthesis (ketogenesis) in cortex glia is
attributed to "the successive actions of a thiolase, the HMGS and the HMG-CoA lyase" — the thiolase
step of ketogenesis is described generically, and the gene tested/assayed as ACAT1/CG10932 is the
NEURONAL KB-OXIDATION (catabolism) enzyme, not a demonstrated ketogenic enzyme. So the GOA NAS
annotations (PMID:35177854) to "ketone body biosynthetic process" (GO:0046951) and "ketone
biosynthetic process" (GO:0042181) are, if anything, the LESS well-supported reading of this paper for
Acat1; the paper's direct evidence for CG10932 is ketone-body OXIDATION/catabolism. (Thiolase chemistry
is reversible, so the enzyme can in principle act in both ketogenesis and ketolysis, as in mammals; but
the fly experimental evidence here is for the catabolic/oxidation role.)
MF:
- GO:0003985 acetyl-CoA C-acetyltransferase activity — IBA (GO_REF:0000033); IEA (EC:2.3.1.9,
GO_REF:0000003); ISS from human P24752 (GO_REF:0000024). CORE. Multiple concordant lines.
- GO:0016453 C-acetyltransferase activity — ISS (parent of GO:0003985). Non-core (less specific).
- GO:0016746 acyltransferase activity — IEA InterPro (broad parent). Non-core.
- GO:0016747 acyltransferase activity, transferring groups other than amino-acyl groups — IEA InterPro.
Non-core.
(metal ion binding GO:0046872 IEA-UniProtKB-KW appears in the UniProt DR block but NOT in goa.tsv, so
it is not in existing_annotations to review. T2 is K+-activated; a "potassium ion binding" would be more
apt than generic metal binding, but neither is in the GOA set here.)
CC:
- GO:0005739 mitochondrion — IBA (is_active_in), HDA (PMID:19317464 LOPIT organelle proteomics), ISM
(PMID:22758915 peroxisome-inventory prediction). CORE localization. Human T2 is mitochondrial matrix;
fly ortholog expected same. LOPIT (PMID:19317464) is direct MS-based organelle mapping in embryos.
- GO:0005777 peroxisome — ISM (PMID:22758915). This is a computational targeting-signal prediction from
a Drosophila peroxisomal-proteome inventory. The human ortholog is exclusively mitochondrial matrix;
no experimental support for peroxisomal Acat1 in fly. Some thiolases (ACAA1) are peroxisomal, but the
ACAT1/T2 subfamily is mitochondrial. Treat as low-confidence prediction -> KEEP_AS_NON_CORE or
MARK_AS_OVER_ANNOTATED. The paper is abstract-only; it says "The subcellular localization of five of
these predicted peroxisomal proteins was confirmed" — not stated whether Acat1 was among the confirmed
five, so verification is not possible from cache -> lean UNDECIDED/over-annotated. Choosing
MARK_AS_OVER_ANNOTATED given strong contrary evidence for mitochondrial matrix localization of the T2
subfamily.
BP:
- GO:0042182 ketone catabolic process — ISS from P24752. Correct direction (ketolysis). Non-core parent
of ketone body catabolic process.
- GO:0046952 ketone body catabolic process — ISS from P24752. CORE (ketolysis; matches Silva 2022 neuronal
KB oxidation).
- GO:0006550 L-isoleucine catabolic process — ISS from P24752. CORE (T2 uniquely cleaves 2-methyl-branched
2-methylacetoacetyl-CoA, final step of Ile catabolism).
- GO:0006085 acetyl-CoA biosynthetic process — ISS from P24752. Reaction-level product (thiolysis yields
acetyl-CoA); non-core. Matches Silva 2022 "to generate acetyl-CoA".
- GO:0046951 ketone body biosynthetic process — NAS (PMID:35177854). Ketogenesis direction. Weakly
supported for Acat1 specifically by this paper (see note above); thiolase can act in ketogenesis in
mammals. KEEP_AS_NON_CORE (plausible but not the direct evidence).
- GO:0042181 ketone biosynthetic process — NAS (PMID:35177854). Broad parent of GO:0046951. Same as above,
KEEP_AS_NON_CORE.
Acat1 (CG10932) is the single Drosophila ortholog of human mitochondrial acetoacetyl-CoA thiolase (T2,
ACAT1, EC 2.3.1.9). It is a thiolase-family enzyme with the canonical Cys-His-Cys catalytic triad,
predicted mitochondrial, that catalyzes the reversible acetoacetyl-CoA <-> 2 acetyl-CoA thiolysis/
condensation at the heart of ketone-body metabolism and the final thiolytic step of L-isoleucine
catabolism. Direct fly evidence (Silva et al. 2022) shows it is required in mushroom body neurons for
ketone-body oxidation to generate acetyl-CoA for energy, sustaining memory under starvation.
It is NOT the cholesterol-esterifying sterol O-acyltransferase (SOAT1/SOAT2, EC 2.3.1.26, "ACAT" in the
cholesterol-metabolism literature). No cholesterol/sterol O-acyltransferase or ER-localization
annotations are present in the fly GOA set (unlike the human record, where a SOAT1 name-collision
mis-annotation had to be removed) — so no SOAT/cholesterol flag is needed here, but I note the distinction
in the description per the ortholog convention.
Core functions:
1. MF GO:0003985 acetyl-CoA C-acetyltransferase activity; directly_involved_in GO:0046952 ketone body
catabolic process; location GO:0005739 mitochondrion.
2. MF GO:0003985; directly_involved_in GO:0006550 L-isoleucine catabolic process; location GO:0005739.