SLC27A5 (bile acyl-CoA synthetase, BACS; also fatty acid transport protein 5, FATP5; very-long-chain acyl-CoA synthetase homolog 2, VLCS-H2 / VLACS-related) is a liver-specific, endoplasmic-reticulum-membrane enzyme of the ATP-dependent AMP-binding (acyl-CoA synthetase) family. Its principal role is the ATP-dependent activation of C24 bile acids (cholate, chenodeoxycholate, and the secondary bile acids deoxycholate and lithocholate) to their CoA thioesters (bile-acyl-CoA), the obligatory step preceding amino-acid (glycine/taurine) conjugation by BAAT. It thereby re-activates and re-conjugates bile acids returning to the liver via the enterohepatic circulation rather than participating in de novo bile acid synthesis. The enzyme also has broad long-chain and very-long-chain fatty-acyl-CoA synthetase activity (C18:0-C26:0; EC 6.2.1.3 and 6.2.1.7) and contributes to hepatic long-chain fatty-acid uptake. It is a multi-pass membrane protein anchored in the endoplasmic reticulum membrane with a large cytoplasmic catalytic domain, with a minor plasma-membrane pool associated with fatty-acid uptake.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004467 long-chain fatty acid-CoA ligase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (PAN-GO) inference of long-chain fatty acid-CoA ligase activity. This is a well-supported core molecular function for SLC27A5, which activates C18:0, C20:0, C24:0 and C26:0 fatty acids to their CoA thioesters and carries EC 6.2.1.3. Reason: Consistent with direct biochemical characterization of the human protein as a long-/very-long-chain acyl-CoA synthetase; represents a core catalytic function of the FATP/ACSVL family. Supporting Evidence: PMID:10479480 For all substrates tested (C18:0, C20:0, C24:0, C26:0) |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic inference of plasma-membrane localization, reflecting the FATP family role in fatty-acid uptake at the cell surface. A minor plasma-membrane pool is plausible for hepatic LCFA uptake, but the experimentally documented localization of SLC27A5 is the endoplasmic reticulum membrane. Reason: A plasma-membrane fraction is consistent with the FATP fatty-acid-uptake role, but the principal, experimentally established site of SLC27A5 action is the ER membrane; retain as non-core. Supporting Evidence: PMID:20530735 a plasma membrane-associated long-chain fatty acid |
| GO:0001676 long-chain fatty acid metabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference that SLC27A5 participates in long-chain fatty acid metabolism, consistent with its LCFA-CoA ligase activity that primes fatty acids for downstream metabolism. Reason: Directly supported by demonstrated LCFA activation activity in the human enzyme. Supporting Evidence: PMID:10479480 For all substrates tested (C18:0, C20:0, C24:0, C26:0) |
| GO:0005789 endoplasmic reticulum membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of ER-membrane localization, matching the experimentally determined subcellular location of the human enzyme. Reason: The human protein localizes to the ER (not peroxisomes) and its topology places the catalytic domain on the cytosolic face of the ER membrane; this is the core site of action. Supporting Evidence: PMID:10479480 the protein was associated with the endoplasmic reticulum but not with |
| GO:0008206 bile acid metabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference that SLC27A5 participates in bile acid metabolism. This is strongly supported experimentally, as the enzyme activates C24 bile acids to their CoA thioesters for recycling and re-conjugation. Reason: Bile acid metabolism is a core biological process for SLC27A5; supported by direct enzymatic studies. Supporting Evidence: PMID:11980911 this enzyme also activates chenodeoxycholate, the secondary bile acids |
| GO:0044539 long-chain fatty acid import into cell | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic inference of a role in cellular LCFA import, reflecting the FATP-family fatty-acid uptake function. FATP5 contributes to hepatic fatty-acid uptake; note that FATP-mediated uptake is widely interpreted as vectorial acylation driven by the synthetase activity rather than a channel-type transporter. Reason: A role in hepatic LCFA uptake is supported for FATP5, but is secondary to the bile-acid/fatty-acyl-CoA ligase activity that is the enzyme's characterized core function; retain as non-core. Supporting Evidence: PMID:20530735 a plasma membrane-associated long-chain fatty acid |
| GO:0005324 long-chain fatty acid transmembrane transporter activity | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic inference of LCFA transmembrane transporter activity for the FATP family. The transporter interpretation of FATPs is debated (vectorial acylation vs. bona fide transport), but a fatty-acid transport function is documented for FATP5. Reason: Transport-type activity is retained as a non-core function; the enzyme's well-established core molecular function is acyl-CoA ligase activity. Supporting Evidence: PMID:20530735 a plasma membrane-associated long-chain fatty acid |
| GO:0004467 long-chain fatty acid-CoA ligase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Automated (multi-method IEA) assignment of LCFA-CoA ligase activity, mapped from Rhea/EC 6.2.1.3. Redundant with, and consistent with, the experimentally supported core function. Reason: Correct EC/Rhea-based mapping; the human enzyme carries EC 6.2.1.3 and activates long-chain fatty acids. Supporting Evidence: PMID:10479480 For all substrates tested (C18:0, C20:0, C24:0, C26:0) |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Automated mapping from the UniProt subcellular-location keyword to ER membrane, matching the experimentally determined localization. Reason: Consistent with IDA evidence for ER-membrane localization of the human enzyme. Supporting Evidence: PMID:10479480 the protein was associated with the endoplasmic reticulum but not with |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Automated mapping from the UniProt cell-membrane subcellular-location keyword. A plasma-membrane pool is plausible for fatty-acid uptake but is non-core relative to the ER-membrane enzymatic role. Reason: UniProt lists a cell-membrane location (by similarity); retain as non-core given the principal ER-membrane site of action. Supporting Evidence: PMID:20530735 a plasma membrane-associated long-chain fatty acid |
| GO:0006631 fatty acid metabolic process | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA machine-learning assignment of the general fatty acid metabolic process term. Correct but less specific than the long-chain fatty acid metabolic process and bile-acid process terms already annotated. Reason: Generic parent term; the more specific long-chain fatty acid metabolic process (GO:0001676) and bile acid metabolic process (GO:0008206) annotations capture the function more precisely. Supporting Evidence: PMID:10479480 For all substrates tested (C18:0, C20:0, C24:0, C26:0) |
| GO:0015245 fatty acid transmembrane transporter activity | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA machine-learning assignment of a generic fatty-acid transmembrane transporter activity. Less precise than the long-chain fatty acid transmembrane transporter activity (GO:0005324) already annotated, and the transporter interpretation of FATPs is itself debated. Reason: Redundant generic transporter term; the specific LCFA transporter term is already present, and this activity is non-core relative to the acyl-CoA ligase function. Supporting Evidence: PMID:20530735 a plasma membrane-associated long-chain fatty acid |
| GO:0015909 long-chain fatty acid transport | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA machine-learning assignment of long-chain fatty acid transport, consistent with the FATP-family hepatic LCFA-uptake role. Non-core relative to the enzymatic function. Reason: LCFA transport is a documented but secondary function of FATP5; retain as non-core. Supporting Evidence: PMID:20530735 LCFA uptake was reduced by 40% |
| GO:0031957 very long-chain fatty acid-CoA ligase activity | IEA GO_REF:0000116 | ACCEPT | Summary: Rhea-based automated assignment of very-long-chain fatty acid-CoA ligase activity, matching direct assays showing activation of C24:0 (lignocerate) and C26:0. Reason: Supported by direct biochemical assays of VLCFA (C24:0, C26:0) activation by the human enzyme. Supporting Evidence: PMID:10479480 activated the very-long-chain fatty acid |
| GO:0047747 cholate-CoA ligase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Automated (multi-method IEA) assignment of cholate-CoA ligase activity (EC 6.2.1.7). This is the defining, experimentally established core molecular function of SLC27A5 (BACS). Reason: The human enzyme was directly shown to be cholate ligase; the EC/Rhea-based mapping is correct. Supporting Evidence: PMID:10749848 exhibited cholate:CoA ligase (choloyl-CoA synthetase) activity with both |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Single high-throughput yeast two-hybrid interaction (with MEOX2) from the HuRI human binary interactome map. This is an uninformative bare protein binding annotation with no functional context relevant to SLC27A5's characterized enzymatic role. Reason: Bare protein binding from a proteome-scale interactome screen; provides no molecular-function information and is not corroborated by a directed study of SLC27A5. Per curation policy, retained (not removed) but flagged as over-annotated. Supporting Evidence: PMID:32296183 With approximately 53,000 protein-protein interactions, HuRI has approximately four |
| GO:0008206 bile acid metabolic process | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl-Compara ortholog projection (from rat Slc27a5, Q9ES38) of bile acid metabolic process. Consistent with the experimentally established bile-acid role of the human enzyme. Reason: Ortholog-projected but biologically correct; bile acid metabolism is a core process for SLC27A5. Supporting Evidence: PMID:11980911 this enzyme also activates chenodeoxycholate, the secondary bile acids |
| GO:0032991 protein-containing complex | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl-Compara ortholog projection asserting the protein is part of a protein-containing complex. There is no evidence that SLC27A5 acts as part of a stable complex; it is characterized as a monofunctional membrane-bound enzyme. Reason: Uninformative, ortholog-projected complex annotation with no supporting evidence for a defined SLC27A5 complex; not a core aspect of its function. Supporting Evidence: PMID:11980911 Activation by thioesterification to CoA is required |
| GO:0044877 protein-containing complex binding | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl-Compara ortholog projection of protein-containing complex binding. Like the generic protein binding annotation, this is uninformative and unsupported by directed study of SLC27A5. Reason: Ortholog-projected, non-specific binding term with no functional interpretation for SLC27A5; over-annotation. Supporting Evidence: PMID:11980911 Activation by thioesterification to CoA is required |
| GO:0006699 bile acid biosynthetic process | TAS Reactome:R-HSA-193368 | ACCEPT | Summary: Reactome (TAS) placement of SLC27A5 within bile acid/bile salt synthesis (via 7alpha-hydroxycholesterol). SLC27A5 contributes the CoA-activation step that primes bile acids for conjugation within the biosynthetic pathway. Reason: The CoA-thioester activation catalyzed by SLC27A5 is a required step in the bile acid biosynthetic/conjugation pathway represented by Reactome. Supporting Evidence: PMID:11980911 Activation by thioesterification to CoA is required |
| GO:0006699 bile acid biosynthetic process | TAS Reactome:R-HSA-193775 | ACCEPT | Summary: Reactome (TAS) placement of SLC27A5 within bile acid/bile salt synthesis (via 24-hydroxycholesterol). As above, SLC27A5 provides the CoA-activation step for bile acid conjugation. Reason: Duplicate-pathway TAS assignment consistent with the enzyme's role in bile-acid CoA activation preceding conjugation. Supporting Evidence: PMID:11980911 Activation by thioesterification to CoA is required |
| GO:0015721 bile acid and bile salt transport | TAS Reactome:R-HSA-159418 | KEEP AS NON CORE | Summary: Reactome (TAS) placement within recycling of bile acids and salts. SLC27A5 re-activates C24 bile acids returning via the enterohepatic circulation, functioning within the recycling pathway rather than as a bile-acid transporter per se. Reason: The enzyme's contribution to bile-acid recycling is via CoA re-activation (its enzymatic function), not membrane transport; retain the pathway context as non-core. Supporting Evidence: PMID:11980911 function of homolog 2 is in the reactivation and recycling of C24 bile acids, |
| GO:0004467 long-chain fatty acid-CoA ligase activity | TAS Reactome:R-HSA-159425 | ACCEPT | Summary: Reactome (TAS) molecular-function assignment for the BACS reaction conjugating cytosolic cholate/chenodeoxycholate with CoA on the ER membrane. Correct core catalytic function. Reason: Reactome represents SLC27A5 (BACS) catalyzing bile-acid CoA thioester formation; consistent with the experimentally established ligase activity. Supporting Evidence: PMID:10749848 exhibited cholate:CoA ligase (choloyl-CoA synthetase) activity with both |
| GO:0004467 long-chain fatty acid-CoA ligase activity | TAS Reactome:R-HSA-192137 | ACCEPT | Summary: Reactome (TAS) molecular-function assignment for the BACS reaction conjugating the C27 precursor THCA with CoA. Consistent with the enzyme's demonstrated ability to activate THCA. Reason: SLC27A5 activates THCA in vitro; the Reactome ligase assignment is correct. Supporting Evidence: PMID:11980911 must be activated to its CoA derivative before side |
| GO:0004467 long-chain fatty acid-CoA ligase activity | TAS Reactome:R-HSA-193407 | ACCEPT | Summary: Reactome (TAS) molecular-function assignment for the BACS reaction conjugating DHCA with CoA. Consistent with the enzyme's acyl-CoA ligase activity toward bile-acid precursors. Reason: Consistent with SLC27A5's characterized CoA-ligase activity on bile-acid intermediates. Supporting Evidence: PMID:11980911 Activation by thioesterification to CoA is required |
| GO:0004467 long-chain fatty acid-CoA ligase activity | TAS Reactome:R-HSA-193711 | ACCEPT | Summary: Reactome (TAS) molecular-function assignment for the BACS reaction conjugating 3,7,24-THCA with CoA. Consistent with the enzyme's acyl-CoA ligase activity. Reason: Consistent with SLC27A5's characterized CoA-ligase activity on bile-acid intermediates. Supporting Evidence: PMID:11980911 Activation by thioesterification to CoA is required |
| GO:0004467 long-chain fatty acid-CoA ligase activity | TAS Reactome:R-HSA-193766 | ACCEPT | Summary: Reactome (TAS) molecular-function assignment (bile-acyl-CoA conjugation reaction). The specific reaction id could not be verified in the current Reactome ContentService (returns 404, likely a retired/renumbered reaction), but the asserted ligase activity is the correct core function of SLC27A5. Reason: The molecular function (acyl-CoA ligase) is correct for SLC27A5; only the specific Reactome reaction id could not be confirmed in the current release. Supporting Evidence: PMID:10749848 exhibited cholate:CoA ligase (choloyl-CoA synthetase) activity with both |
| GO:0005324 long-chain fatty acid transmembrane transporter activity | IDA PMID:20530735 FATP2 is a hepatic fatty acid transporter and peroxisomal ve... | KEEP AS NON CORE | Summary: Direct assay (IDA) of long-chain fatty acid transport activity in the FATP high-throughput uptake system. Supports a fatty-acid uptake/transport role for FATP5, though this is secondary to the enzyme's acyl-CoA ligase function. Reason: Experimentally supported transport activity; retained as a non-core function relative to the characterized bile-acid/fatty-acyl-CoA ligase activity. Supporting Evidence: PMID:20530735 a plasma membrane-associated long-chain fatty acid |
| GO:0047747 cholate-CoA ligase activity | IDA PMID:10749848 The human liver-specific homolog of very long-chain acyl-CoA... | ACCEPT | Summary: Direct biochemical demonstration that human hVLCS-H2 (SLC27A5) is cholate:CoA ligase, activating the primary bile acid cholate to its CoA thioester. This is the defining core molecular function of the gene product. Reason: Gold-standard IDA establishing the cholate-CoA (choloyl-CoA synthetase) activity; the enzyme's central catalytic role in bile-acid CoA activation prior to conjugation. Supporting Evidence: PMID:10749848 exhibited cholate:CoA ligase (choloyl-CoA synthetase) activity with both PMID:10749848 Unconjugated bile acids must be activated |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:11980911 Participation of two members of the very long-chain acyl-CoA... | ACCEPT | Summary: Direct evidence (topology/localization studies) that SLC27A5 is an ER-membrane protein. This is the core subcellular site of the enzyme's action. Reason: Experimentally established ER-membrane localization, consistent with the cloning study and Reactome reaction placement. Supporting Evidence: PMID:10479480 the protein was associated with the endoplasmic reticulum but not with |
| GO:0031957 very long-chain fatty acid-CoA ligase activity | IDA PMID:10479480 Human liver-specific very-long-chain acyl-coenzyme A synthet... | ACCEPT | Summary: Direct assay (IDA) showing activation of the very-long-chain fatty acid lignocerate (C24:0) and other VLCFA by the human enzyme, establishing VLCFA-CoA ligase activity. Reason: Experimentally supported VLCFA-CoA ligase activity of the human protein. Supporting Evidence: PMID:10479480 activated the very-long-chain fatty acid |
| GO:0031957 very long-chain fatty acid-CoA ligase activity | IDA PMID:11980911 Participation of two members of the very long-chain acyl-CoA... | ACCEPT | Summary: Additional direct evidence for VLCFA-CoA ligase activity, from the bile-acid synthesis/recycling study that also characterized the enzyme's acyl-CoA ligase profile. Reason: Duplicate IDA supporting the VLCFA-CoA ligase activity; retained. Supporting Evidence: PMID:11980911 Activation by thioesterification to CoA is required |
| GO:0006699 bile acid biosynthetic process | IDA PMID:11980911 Participation of two members of the very long-chain acyl-CoA... | ACCEPT | Summary: Direct evidence placing SLC27A5 in bile acid synthesis/recycling. The enzyme provides the required CoA-activation step for bile acids (both the C27 THCA precursor and re-utilized C24 bile acids) prior to conjugation. Reason: The CoA-thioester activation catalyzed by SLC27A5 is an obligatory step in bile-acid conjugation within the biosynthetic/recycling pathway; core biological process. Supporting Evidence: PMID:11980911 Activation by thioesterification to CoA is required PMID:11980911 reutilization of cholate |
| GO:0000038 very long-chain fatty acid metabolic process | IDA PMID:10479480 Human liver-specific very-long-chain acyl-coenzyme A synthet... | ACCEPT | Summary: Direct evidence that SLC27A5 participates in VLCFA metabolism, consistent with its demonstrated activation of C24:0 and C26:0 fatty acids to CoA thioesters. Reason: Supported by direct VLCFA activation assays; a genuine metabolic-process role, though secondary to the bile-acid role in vivo. Supporting Evidence: PMID:10479480 For all substrates tested (C18:0, C20:0, C24:0, C26:0) |
| GO:0005783 endoplasmic reticulum | IDA PMID:10479480 Human liver-specific very-long-chain acyl-coenzyme A synthet... | ACCEPT | Summary: Direct immunofluorescence evidence that the human enzyme associates with the endoplasmic reticulum (and not peroxisomes). Consistent with the more specific ER-membrane annotation. Reason: Experimentally established ER localization; the more specific ER-membrane term is also annotated. Supporting Evidence: PMID:10479480 the protein was associated with the endoplasmic reticulum but not with |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-159425 | ACCEPT | Summary: Reactome (TAS) localization of the BACS reaction to the ER membrane, matching the experimentally determined localization. Reason: Consistent with IDA ER-membrane evidence; correct site of the catalyzed reaction. Supporting Evidence: PMID:10479480 the protein was associated with the endoplasmic reticulum but not with |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-192137 | ACCEPT | Summary: Reactome (TAS) localization of a BACS bile-acid CoA-conjugation reaction to the ER membrane. Reason: Duplicate ER-membrane localization consistent with experimental evidence. Supporting Evidence: PMID:10479480 the protein was associated with the endoplasmic reticulum but not with |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-193407 | ACCEPT | Summary: Reactome (TAS) localization of a BACS bile-acid CoA-conjugation reaction to the ER membrane. Reason: Duplicate ER-membrane localization consistent with experimental evidence. Supporting Evidence: PMID:10479480 the protein was associated with the endoplasmic reticulum but not with |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-193711 | ACCEPT | Summary: Reactome (TAS) localization of a BACS bile-acid CoA-conjugation reaction to the ER membrane. Reason: Duplicate ER-membrane localization consistent with experimental evidence. Supporting Evidence: PMID:10479480 the protein was associated with the endoplasmic reticulum but not with |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-193766 | ACCEPT | Summary: Reactome (TAS) localization of a BACS bile-acid CoA-conjugation reaction to the ER membrane. The specific reaction id could not be confirmed in the current Reactome release, but the ER-membrane localization is experimentally supported. Reason: ER-membrane localization is correct; only the specific Reactome reaction id could not be verified in the current release. Supporting Evidence: PMID:10479480 the protein was associated with the endoplasmic reticulum but not with |
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