Acaa (also called Yip2, "Yippee interacting protein 2"; CG4600; FBgn0040064) is the Drosophila melanogaster ortholog of human ACAA2, a mitochondrial 3-ketoacyl-CoA thiolase (acetyl-CoA acyltransferase; EC 2.3.1.16). It is a 398-residue member of the thiolase family within the thiolase-like superfamily, built from a Thiolase N-terminal and a Thiolase C-terminal domain and carrying the conserved catalytic cysteine (acyl-thioester intermediate) and proton-acceptor residues typical of degradative thiolases. The enzyme is predicted to act in the mitochondrial matrix, where it catalyzes the fourth and final, thiolytic step of each cycle of the fatty acid beta-oxidation spiral: using free coenzyme A it cleaves a 3-ketoacyl-CoA (3-oxoacyl-CoA) into acetyl-CoA and a fatty acyl-CoA shortened by two carbons. By the reversibility of the thiolase reaction it can also condense two acetyl-CoA units into acetoacetyl-CoA (acetyl-CoA C-acetyltransferase activity, EC 2.3.1.9), a secondary/biosynthetic capability. In Drosophila, Yip2 is part of the nuclear-receptor dHNF4-regulated mitochondrial beta-oxidation gene program that supports lipid mobilization and survival during starvation. The gene name "Yip2" reflects a historical yeast-two-hybrid interaction with the Yippee protein and does not denote its metabolic activity.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003985 acetyl-CoA C-acetyltransferase activity | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic (IBA) propagation of acetyl-CoA C-acetyltransferase activity (EC 2.3.1.9), the acetoacetyl-CoA-forming/cleaving reaction. This activity is a genuine capability of thiolase-family enzymes (via reaction reversibility) and is documented for the human ortholog ACAA2, but it is a secondary/biosynthetic side of the enzyme; the core physiological role of Acaa is the chain-shortening C-acyltransferase (thiolase) reaction on longer 3-oxoacyl-CoAs (GO:0003988). Keep, but mark as non-core. |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic propagation of mitochondrial localization. Correct and consistent with the conserved mitochondrial thiolase identity and predicted mitochondrial targeting signal; a more precise term (mitochondrial matrix, GO:0005759) is also annotated. Keep as non-core relative to the specific matrix location. |
| GO:0006635 fatty acid beta-oxidation | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic propagation of the core biological process. Acaa catalyzes the final (thiolytic) step of each beta-oxidation cycle. Independently supported in the fly by membership of the dHNF4-regulated beta-oxidation gene program (PMID:19254568). Core process for this gene. Accept. Supporting Evidence: PMID:19254568 yip2, CG9577, CG6178, and Acox57D-d, many of which are predicted to act in Ξ²-oxidation |
| GO:0003985 acetyl-CoA C-acetyltransferase activity | IEA GO_REF:0000003 | KEEP AS NON CORE | Summary: Electronic (EC 2.3.1.9) assertion of the same biosynthetic acetoacetyl-CoA C-acetyltransferase activity captured by the IBA and ISS annotations. Consistent with the UniProt EC assignment, but secondary to the core beta-oxidation thiolase reaction. Keep as non-core. |
| GO:0003988 acetyl-CoA C-acyltransferase activity | IEA GO_REF:0000117 | ACCEPT | Summary: Electronic (ARBA / EC 2.3.1.16) assertion of acetyl-CoA C-acyltransferase (3-ketoacyl-CoA thiolase) activity. This is the core molecular function of Acaa in beta-oxidation, consistent with the UniProt EC assignment, the conserved thiolase domains and active-site residues, and 14/14 DIOPT orthology to human ACAA2. Accept. |
| GO:0006629 lipid metabolic process | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: Electronic (ARBA) assertion of the very general parent process "lipid metabolic process". Correct in direction but an uninformative ancestor of the specific and already-annotated fatty acid beta-oxidation (GO:0006635). Over-general. Reason: Non-informative ancestor of GO:0006635 (fatty acid beta-oxidation), which is the specific process already annotated. |
| GO:0016746 acyltransferase activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: InterPro2GO mapping to the high-level parent term acyltransferase activity. Correct in direction but far less informative than the specific thiolase MF (GO:0003988) already annotated. Over-general. Reason: Redundant generic ancestor of GO:0003988; carries no information beyond the specific thiolase activity term. |
| GO:0016747 acyltransferase activity, transferring groups other than amino-acyl groups | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: InterPro2GO mapping to an intermediate (still generic) acyltransferase parent. As with GO:0016746, this is a non-informative ancestor of the specific thiolase activity GO:0003988. Over-general. Reason: Over-general ancestor of GO:0003988; the specific thiolase MF term should be used. |
| GO:1902109 negative regulation of mitochondrial membrane permeability involved in apoptotic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity transfer from human ACAA2 (UniProtKB:P42765), where this term rests on a single overexpression study showing ACAA2 attenuates BNIP3-driven apoptosis (PMID:18371312). The role is indirect and single-study even in human, and there is no Drosophila evidence for a BNIP3-type apoptosis-regulation function of Acaa. Keep as non-core/contextual rather than remove, since it is a defensible orthology transfer. Reason: Orthology-transferred from a single human overexpression study; not a core function and unverified in Drosophila. |
| GO:0003988 acetyl-CoA C-acyltransferase activity | ISS GO_REF:0000024 | ACCEPT | Summary: Curator sequence-similarity transfer (from human ACAA2, UniProtKB:P42765) of the core 3-ketoacyl-CoA thiolase activity (EC 2.3.1.16). This is THE core molecular function of Acaa in beta-oxidation and is well supported by conserved thiolase domains and active-site residues. Accept. |
| GO:0003985 acetyl-CoA C-acetyltransferase activity | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Curator sequence-similarity transfer of the biosynthetic acetoacetyl-CoA (EC 2.3.1.9) activity. Genuine capability of the thiolase but secondary to the degradative chain-shortening reaction. Keep as non-core. |
| GO:0005759 mitochondrial matrix | ISS GO_REF:0000024 | ACCEPT | Summary: Curator sequence-similarity transfer of mitochondrial matrix localization from the rat ortholog (UniProtKB:P13437). This is the most precise and correct location for Acaa, a soluble matrix 3-ketoacyl-CoA thiolase (distinct from the inner-membrane MTP thiolase). Accept as core localization. |
| GO:0006635 fatty acid beta-oxidation | ISS GO_REF:0000024 | ACCEPT | Summary: Curator sequence-similarity transfer of the core beta-oxidation process. Redundant with the IBA annotation of the same term and consistent with the fly dHNF4-regulated beta-oxidation program (PMID:19254568). Core process. Accept. Supporting Evidence: PMID:19254568 These include yip2, Acox57D-d, thiolase, scully, and CPTI (carnitine palmitoyltransferase) among the most highly down-regulated genes in fed dHNF4 mutants |
| GO:0005739 mitochondrion | ISM PMID:22758915 An inventory of peroxisomal proteins and pathways in Drosoph... | KEEP AS NON CORE | Summary: Sequence-model (ISM) prediction of mitochondrial localization arising from the Drosophila peroxisomal-proteome inventory study, which screened predicted organellar targeting. CG4600 carries a mitochondrial (not peroxisomal) targeting signal, so the mitochondrial assignment is correct. Consistent with all other localization evidence but less specific than the mitochondrial matrix term. Keep as non-core. The cited paper is abstract-only in the cache and does not describe Acaa individually. |
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Download this section (compressed HTML)Q: Does Drosophila Acaa/Yip2 catalyze the degradative 3-ketoacyl-CoA thiolase reaction directly (as predicted from ACAA2 orthology), and what is its chain-length substrate preference relative to the fly trifunctional-protein thiolase Mtpalpha?
Q: Is the historical Yippee-Yip2 interaction (the source of the gene name) functionally meaningful, or an incidental two-hybrid finding unrelated to its beta-oxidation role?
Q: Does loss of Acaa produce a beta-oxidation / lipid-mobilization phenotype in flies (e.g. starvation sensitivity, TAG accumulation) analogous to the dHNF4 mutant?
Experiment: Assay recombinant Drosophila Acaa in vitro against a panel of straight-chain 3-ketoacyl-CoA substrates (C4-C16) to confirm the EC 2.3.1.16 thiolase activity and define its physiological substrate range.
Experiment: Generate an Acaa loss-of-function allele (or RNAi) and profile acylcarnitines, triacylglycerol levels, and starvation survival to test its in-vivo contribution to mitochondrial beta-oxidation flux.
Experiment: Confirm mitochondrial-matrix localization of endogenous Acaa in Drosophila tissue by fractionation/immunofluorescence, distinguishing it from peroxisomal thiolases.
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