SLC27A5 (bile acyl-CoA synthetase, BACS; fatty acid transport protein 5, FATP5) is a liver-enriched member of the FATP subfamily of ATP-dependent AMP-binding (ANL superfamily) acyl-CoA synthetases. The 700-residue horse protein has an N-terminal hydrophobic membrane anchor, a large AMP-binding catalytic domain and the conserved AMP-binding C-terminal subdomain. By orthology to the experimentally characterised human and mouse enzymes, it is an endoplasmic reticulum membrane enzyme whose main role is the ATP-dependent activation of C24 bile acids (cholate, chenodeoxycholate and the secondary bile acids deoxycholate and lithocholate) to their CoA thioesters, the first step of bile acid conjugation with glycine or taurine, so that bile acids returning to the liver through the enterohepatic circulation are re-conjugated. It also activates long-chain and very-long-chain fatty acids (C18 to C26) to acyl-CoAs, and a pool at the basal (sinusoidal) plasma membrane of hepatocytes contributes to hepatic long-chain fatty acid uptake. None of these functions has been tested on the horse protein itself.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000038 very long-chain fatty acid metabolic process | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara projection from human SLC27A5 (IDA). Human SLC27A5 activates the very-long-chain fatty acids lignocerate (C24:0) and hexacosanoate (C26:0) to acyl-CoAs, the activation step of their metabolism. Reason: The enzyme itself catalyses the activation step of very-long-chain fatty acid metabolism in the human ortholog. Horse A0A5F5PXH2 is in the same PANTHER subfamily (PTHR43107:SF25) as human SLC27A5, is 80.9% identical over its full length and retains the AMP-binding motif, so the projection is evolutionarily grounded. Not tested in horse. Supporting Evidence: PMID:10479480 activated the very-long-chain fatty acid file:HORSE/SLC27A5__A0A5F5PXH2/SLC27A5__A0A5F5PXH2-bioinformatics/RESULTS.md The horse protein is a full-length SLC27A5 ortholog |
| GO:0001676 long-chain fatty acid metabolic process | IEA GO_REF:0000108 | ACCEPT | Summary: Inferred from the long-chain fatty acid-CoA ligase activity annotation by inter-ontology link. Activation of long-chain fatty acids to acyl-CoA is the entry step of their metabolism. The same term is carried by human SLC27A5 by IBA from the family-wide PAINT node PTN001945407, from which horse SF25 descends. Reason: The enzyme performs a step of the process (fatty acid activation); consistent with the PAINT placement at the FATP family root node and with direct assays of C18:0 and C20:0 activation by human SLC27A5. Supporting Evidence: PMID:10479480 For all substrates tested (C18:0, C20:0, C24:0, C26:0) |
| GO:0004467 long-chain fatty acid-CoA ligase activity | IEA GO_REF:0000003 | ACCEPT | Summary: EC 6.2.1.3 mapping. The EC number on the horse record is an ARBA rule assignment, but the activity is independently grounded by the PAINT IBD for GO:0004467 at the FATP family root node PTN001945407 and by direct assays of the human SF25 ortholog. Reason: Long-chain fatty acid-CoA ligase activity is a family-wide, ancestral FATP activity placed by PAINT at the family root, demonstrated for human SLC27A5; horse retains the AMP-binding motif and full-length conservation. Not assayed in horse. Supporting Evidence: PMID:10479480 For all substrates tested (C18:0, C20:0, C24:0, C26:0) file:HORSE/SLC27A5__A0A5F5PXH2/SLC27A5__A0A5F5PXH2-bioinformatics/RESULTS.md The AMP-binding motif annotated on human SLC27A5 (residues 292-303, FIYTSGTTGLPK) is identical in horse |
| GO:0005324 long-chain fatty acid transmembrane transporter activity | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara projection from human SLC27A5. FATP5 overexpression increases long-chain fatty acid uptake and knockout reduces hepatocyte LCFA uptake in mouse; PAINT also places GO:0005324 at the FATP family root node. Whether FATPs translocate fatty acids or drive uptake by vectorial acylation remains unresolved. Reason: A fatty acid uptake role is supported for the SF25 subfamily (mouse knockout), but the transporter interpretation is debated and secondary to the acyl-CoA ligase activity; retained as non-core, consistent with the human SLC27A5 review. Supporting Evidence: PMID:16618416 FATP5 deletion significantly reduced LCFA uptake by hepatocytes isolated from FATP5 knockout animals |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000107 | MODIFY | Summary: Ensembl Compara projection of ER localisation from human SLC27A5. Correct but less specific than ER membrane (GO:0005789), which this gene also carries; the protein is an integral membrane enzyme with a cytoplasmic catalytic domain. Reason: True but general; the specific supported location is endoplasmic reticulum membrane, already annotated to this gene. Proposed replacements: endoplasmic reticulum membrane Supporting Evidence: PMID:10479480 the protein was associated with the endoplasmic reticulum but not with |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara projection from human SLC27A5 (IDA). Also placed by PAINT (IBD) at the eumetazoan node PTN001186241, whose seeds include human SLC27A5. Horse has the N-terminal hydrophobic anchor (SignalP calls residues 1-31 a signal peptide, which in human corresponds to the first transmembrane segment). Reason: ER membrane is the experimentally established site of the human ortholog and is supported by the PAINT placement; core location. Supporting Evidence: PMID:10479480 the protein was associated with the endoplasmic reticulum but not with PMID:10749848 liver specificity and an endoplasmic reticulum subcellular localization |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | MODIFY | Summary: Mapping from the UniProt "Cell membrane" subcellular location, which on this record rests only on an ARBA rule. A plasma-membrane pool is supported for mouse Slc27a5 (same subfamily SF25), specifically the basal plasma membrane of hepatocytes, which is also annotated to this gene. Reason: True but general; the specific supported location is basal plasma membrane (GO:0009925, is_a plasma membrane), already annotated to this gene. Non-core relative to the ER membrane. Proposed replacements: basal plasma membrane Supporting Evidence: PMID:16618416 localized to the basal plasma membrane of hepatocytes |
| GO:0006699 bile acid biosynthetic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara projection from human SLC27A5 (IDA). Human SLC27A5 activates THCA, the C27 precursor of cholate, in vitro, which is a step of de novo synthesis; but the physiological role argued by the same group and supported by the mouse knockout (total bile acid levels unchanged, conjugation defective) is re-activation and re-conjugation of recycled C24 bile acids rather than de novo synthesis. Reason: Deferring to the human curators' IDA for the in vitro THCA activity, but the core process is bile acid conjugation/recycling, not de novo bile acid synthesis; retained as non-core. Supporting Evidence: PMID:11980911 deoxycholate and lithocholate, and 3alpha,7alpha,12alpha-trihydroxy-5beta-cholestanoic acid PMID:10749848 rather than in de novo bile acid synthesis |
| GO:0009925 basal plasma membrane | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara projection from mouse Slc27a5 (Q4LDG0, PTHR43107:SF25). Mouse FATP5 localises to the basal (sinusoidal) plasma membrane of hepatocytes, consistent with a role in LCFA uptake from the circulation. Reason: Supported for the mouse SF25 ortholog by immunolocalisation; a secondary location relative to the ER membrane where the bile acid activation function is executed. Not tested in horse. Supporting Evidence: PMID:16618416 localized to the basal plasma membrane of hepatocytes, congruent with a role in LCFA uptake from the circulation |
| GO:0015245 fatty acid transmembrane transporter activity | IEA GO_REF:0000107 | MODIFY | Summary: Ensembl Compara projection from mouse Slc27a5. Less specific than long-chain fatty acid transmembrane transporter activity (GO:0005324), also annotated; the evidence concerns long-chain fatty acids. Reason: True-but-general parent of GO:0005324, which this gene already carries and which matches the LCFA-specific evidence; non-core. Proposed replacements: long-chain fatty acid transmembrane transporter activity Supporting Evidence: PMID:16618416 Overexpression of FATP5 in mammalian cells increased the uptake of 14C-oleate |
| GO:0015908 fatty acid transport | IEA GO_REF:0000108 | MODIFY | Summary: Inter-ontology inference from fatty acid transmembrane transporter activity. Less specific than long-chain fatty acid transport (GO:0015909), also annotated. Reason: True-but-general parent of GO:0015909, which this gene already carries; non-core. Proposed replacements: long-chain fatty acid transport Supporting Evidence: PMID:16618416 FATP5 deletion significantly reduced LCFA uptake by hepatocytes isolated from FATP5 knockout animals |
| GO:0015909 long-chain fatty acid transport | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: Inter-ontology inference from long-chain fatty acid transmembrane transporter activity. Mouse FATP5 contributes to hepatocyte LCFA uptake. Reason: Supported for the SF25 subfamily by the mouse knockout; secondary to the acyl-CoA ligase function and mechanistically debated (transport versus vectorial acylation). Supporting Evidence: PMID:16618416 FATP5 deletion significantly reduced LCFA uptake by hepatocytes isolated from FATP5 knockout animals |
| GO:0031957 very long-chain fatty acid-CoA ligase activity | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara projection from human SLC27A5 (IDA), which activates lignocerate (C24:0) and hexacosanoate (C26:0). PAINT did not propagate GO:0031957 at any node in PTHR43107; the projection here rests on direct one-to-one orthology within SF25 rather than on a phylogenetic node judgement. Reason: Directly assayed for the human SF25 ortholog; horse is a full-length ortholog with the AMP-binding motif conserved. Not assayed in horse. Supporting Evidence: PMID:10479480 activated the very-long-chain fatty acid |
| GO:0047747 cholate-CoA ligase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Combined IEA projection from human SLC27A5 and mouse Slc27a5, both PTHR43107:SF25. Human SLC27A5 has cholate:CoA ligase activity, also with chenodeoxycholate, deoxycholate and lithocholate, whereas other long- and very-long-chain acyl-CoA synthetases, including SLC27A2, do not activate cholate; mouse knockout abolishes most bile acid conjugation. This is the defining activity of the SF25 subfamily. Reason: Defining core activity, established for both human and mouse SF25 orthologs. PAINT did not place GO:0047747 at the SLC27A2+SLC27A5 node (PTN008678717), correctly, because SLC27A2 lacks it; the activity is SF25-specific and horse A0A5F5PXH2 is SF25, so the transfer is justified at subfamily level. Not assayed in horse. Supporting Evidence: PMID:10749848 exhibited cholate:CoA ligase (choloyl-CoA synthetase) activity with both PMID:10749848 Other long- and very long-chain acyl-CoA synthetases were incapable of activating cholate PMID:16618417 the majority of gallbladder bile acids was unconjugated |
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Download this section (compressed HTML)Q: Should GO:0002152 bile acid conjugation be annotated to SLC27A5? The GO term comment names cholate-CoA ligase activity as the first step of the process, the mouse knockout abolishes most conjugation, yet in human only BAAT carries the term.
Q: The horse UniProt record names this gene ZBTB45 (VGNC:25152) with SLC27A5 only as a synonym, although its Ensembl gene, CTD cross-reference (10998, human SLC27A5) and PANTHER subfamily all identify SLC27A5. Is the VGNC assignment a mapping error caused by the adjacent ZBTB45 locus?
Experiment: Express recombinant horse SLC27A5 (A0A5F5PXH2) and assay cholate-, chenodeoxycholate- and lignocerate-CoA ligase activity, with subcellular fractionation of horse liver to confirm ER-membrane localisation.
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