SLC27A5

UniProt ID: Q9Y2P5
Organism: Homo sapiens
Review Status: INITIALIZED
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Gene Description

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.

Existing Annotations Review

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

Core Functions

ATP-dependent activation of C24 bile acids (cholate, chenodeoxycholate, and the secondary bile acids deoxycholate and lithocholate) to their CoA thioesters, the obligatory step preceding glycine/taurine conjugation; also broad long-chain and very-long-chain fatty-acyl-CoA synthetase activity.

Molecular Function:
cholate-CoA ligase activity
Directly Involved In:
bile acid biosynthetic process bile acid metabolic process
Cellular Locations:
endoplasmic reticulum membrane
Supporting Evidence:
  • PMID:10749848
    exhibited cholate:CoA ligase (choloyl-CoA synthetase) activity with both
  • PMID:11980911
    function of homolog 2 is in the reactivation and recycling of C24 bile acids,

ATP-dependent formation of long-chain and very-long-chain fatty-acyl-CoA from long-chain (C18:0, C20:0) and very-long-chain (C24:0, C26:0) fatty acids, contributing to hepatic fatty-acid metabolism and uptake.

Molecular Function:
long-chain fatty acid-CoA ligase activity
Directly Involved In:
long-chain fatty acid metabolic process
Cellular Locations:
endoplasmic reticulum membrane
Supporting Evidence:

References

GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000044
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
GO_REF:0000116
Automatic Gene Ontology annotation based on Rhea mapping
GO_REF:0000117
Electronic Gene Ontology annotations created by ARBA machine learning models
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:10479480
Human liver-specific very-long-chain acyl-coenzyme A synthetase: cDNA cloning and characterization of a second enzymatically active protein.
  • Human hVLCS-H2 (SLC27A5) is liver-specific, ER-associated, and activates long-chain and very-long-chain fatty acids (C18:0-C26:0) to their CoA thioesters.
PMID:10749848
The human liver-specific homolog of very long-chain acyl-CoA synthetase is cholate:CoA ligase.
  • hVLCS-H2 (SLC27A5) is cholate ligase; unconjugated bile acids must be activated to CoA thioesters before glycine/taurine conjugation, and the enzyme is proposed to re-activate/re-conjugate bile acids from the enterohepatic circulation.
PMID:11980911
Participation of two members of the very long-chain acyl-CoA synthetase family in bile acid synthesis and recycling.
  • SLC27A5 activates chenodeoxycholate, deoxycholate, lithocholate and the C27 precursor THCA in addition to cholate; its primary function is proposed to be reactivation and recycling of C24 bile acids.
PMID:20530735
FATP2 is a hepatic fatty acid transporter and peroxisomal very long-chain acyl-CoA synthetase.
  • FATP family members act as plasma-membrane-associated LCFA transporters and acyl-CoA synthetases in liver; used here to contextualize FATP5's fatty-acid uptake/transport role.
PMID:32296183
A reference map of the human binary protein interactome.
  • HuRI proteome-scale binary interactome; source of the single high-throughput SLC27A5-MEOX2 interaction underlying the protein binding IPI annotation.
Reactome:R-HSA-159418
Recycling of bile acids and salts
Reactome:R-HSA-159425
Cytosolic cholate and chenodeoxycholate are conjugated with Coenzyme A (SLC27A5 BACS)
Reactome:R-HSA-192137
THCA is conjugated with Coenzyme A (SLC27A5 BACS)
Reactome:R-HSA-193368
Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol
Reactome:R-HSA-193407
DHCA is conjugated with Coenzyme A (SLC27A5 BACS)
Reactome:R-HSA-193711
3,7,24THCA is conjugated with Coenzyme A (SLC27A5 BACS)
Reactome:R-HSA-193766
Bile-acyl-CoA conjugation reaction (SLC27A5 BACS)
Reactome:R-HSA-193775
Synthesis of bile acids and bile salts via 24-hydroxycholesterol
file:human/SLC27A5/SLC27A5-uniprot.txt
UniProtKB Q9Y2P5 (SLC27A5 / S27A5_HUMAN) entry
  • UniProt describes SLC27A5 as bile acyl-CoA synthetase (EC 6.2.1.7) that mainly activates bile acids to their CoA thioesters prior to conjugation, also with LCFA/VLCFA-CoA ligase activity (EC 6.2.1.3), localized to the endoplasmic reticulum membrane as a multi-pass membrane protein.

📚 Additional Documentation

Notes

(SLC27A5-notes.md)

SLC27A5 (BACS / FATP5 / VLCS-H2) review notes

UniProtKB: Q9Y2P5. Human, liver-specific.

Core biology (grounded in UniProt + cached primary literature)

SLC27A5 encodes bile acyl-CoA synthetase (BACS; also FATP5, VLCS-H2 / VLACS-related).
It is a member of the ATP-dependent AMP-binding enzyme (acyl-CoA synthetase) family and
is predominantly expressed in liver (PMID:10479480).

Molecular function: ATP-dependent activation (thioesterification to CoA) of substrates.
- Bile acids (its principal physiological role): activates the primary C24 bile acids
cholate and chenodeoxycholate, and the secondary bile acids deoxycholate and
lithocholate, to their CoA thioesters — the obligatory step before BAAT-catalysed
glycine/taurine conjugation (PMID:10749848;
PMID:11980911). Km = 2.8 uM for cholate (UniProt).
- Also activates the C27 precursor THCA in vitro (PMID:11980911).
- Long-chain / very-long-chain fatty acids: activates C18:0, C20:0, C24:0, C26:0
to acyl-CoA (PMID:10479480). EC 6.2.1.3 (LCFA) and
6.2.1.7 (cholate-CoA / choloyl-CoA synthetase).

Biological process:
- Bile acid re-activation and re-conjugation / recycling from the enterohepatic
circulation is the proposed primary function; NOT de novo bile acid synthesis
(PMID:10749848; PMID:11980911). UniProt: "Plays an
important role in hepatic fatty acid uptake and bile acid reconjugation and recycling
but not in de novo synthesis of bile acids".
- Hepatic long-chain fatty-acid uptake / import: FATP5 contributes to LCFA uptake into
liver (PMID:20530735 — note this paper's knockdown
is FATP2; the fatty-acid transport role of FATP5 is from PMID:20448275/UniProt].

Subcellular location: Endoplasmic reticulum membrane, multi-pass membrane protein
(PMID:10479480; UniProt SUBCELLULAR LOCATION "Endoplasmic reticulum membrane ... Cell
membrane"). Topology: N-terminal cytoplasmic, two TM helices (31-51, 56-76), then a large
cytoplasmic catalytic domain (77-690) ([PMID:11980911 topology]).

Annotation decisions

  • MF core: cholate-CoA ligase (GO:0047747) IDA from PMID:10749848 — ACCEPT, core.
  • MF core: long-chain fatty acid-CoA ligase (GO:0004467) — ACCEPT (IBA/TAS/IEA); core.
  • MF: very long-chain fatty acid-CoA ligase (GO:0031957) IDA (PMID:10479480, 11980911) —
    ACCEPT; supported by C24:0/C26:0 activation.
  • BP core: bile acid biosynthetic process (GO:0006699) IDA PMID:11980911 + Reactome TAS —
    ACCEPT (this is the pathway to which CoA activation contributes).
  • BP: bile acid metabolic process (GO:0008206) — ACCEPT (broader, correct).
  • LCFA transport / import / transmembrane transporter activity — the "transporter"
    interpretation of FATPs is debated (many argue FATPs drive uptake via
    vectorial acylation, i.e. the synthetase activity, not a channel). The IBA/IDA
    transporter-activity annotations are kept but not treated as the core MF. IDA
    GO:0005324 from PMID:20530735 is a genuine transport-activity assay; ACCEPT/keep
    non-core.
  • Plasma membrane (IBA, IEA): keep non-core; minor PM pool for FA uptake.
  • protein binding GO:0005515 IPI (PMID:32296183, HuRI high-throughput, MEOX2): bare
    protein binding, high-throughput Y2H, no functional interpretation -> MARK_AS_OVER_ANNOTATED.
  • Ensembl-projected (GO_REF:0000107) protein-containing complex / complex binding: no
    evidence SLC27A5 acts in a stable complex; ortholog-projected, uninformative ->
    MARK_AS_OVER_ANNOTATED.
  • fatty acid transmembrane transporter activity GO:0015245 (ARBA IEA): redundant/less
    precise generic transporter term -> MARK_AS_OVER_ANNOTATED.

Reactome

  • R-HSA-159425 / 192137 / 193407 / 193711: SLC27A5 (BACS) CoA-conjugation reactions on
    ER membrane (cytosolic substrates). Titles as in cache.
  • R-HSA-193766: not found in current Reactome ContentService (404) and cache empty;
    retired reaction id. Kept as-is with a descriptive title; flagged UNVERIFIED.

📄 View Raw YAML

 
id: Q9Y2P5
gene_symbol: SLC27A5
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 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.
alternative_products:
- name: '1'
  id: Q9Y2P5-1
- name: '2'
  id: Q9Y2P5-2
  sequence_note: VSP_055810
existing_annotations:
- term:
    id: GO:0004467
    label: long-chain fatty acid-CoA ligase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:10479480
      supporting_text: For all substrates tested (C18:0, C20:0, C24:0, C26:0)
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:20530735
      supporting_text: a plasma membrane-associated long-chain fatty acid
- term:
    id: GO:0001676
    label: long-chain fatty acid metabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: Directly supported by demonstrated LCFA activation activity in the human
      enzyme.
    supported_by:
    - reference_id: PMID:10479480
      supporting_text: For all substrates tested (C18:0, C20:0, C24:0, C26:0)
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic inference of ER-membrane localization, matching the experimentally
      determined subcellular location of the human enzyme.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:10479480
      supporting_text: the protein was associated with the endoplasmic reticulum but
        not with
- term:
    id: GO:0008206
    label: bile acid metabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: Bile acid metabolism is a core biological process for SLC27A5; supported
      by direct enzymatic studies.
    supported_by:
    - reference_id: PMID:11980911
      supporting_text: this enzyme also activates chenodeoxycholate, the secondary
        bile acids
- term:
    id: GO:0044539
    label: long-chain fatty acid import into cell
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:20530735
      supporting_text: a plasma membrane-associated long-chain fatty acid
- term:
    id: GO:0005324
    label: long-chain fatty acid transmembrane transporter activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: Transport-type activity is retained as a non-core function; the enzyme's
      well-established core molecular function is acyl-CoA ligase activity.
    supported_by:
    - reference_id: PMID:20530735
      supporting_text: a plasma membrane-associated long-chain fatty acid
- term:
    id: GO:0004467
    label: long-chain fatty acid-CoA ligase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: Correct EC/Rhea-based mapping; the human enzyme carries EC 6.2.1.3 and
      activates long-chain fatty acids.
    supported_by:
    - reference_id: PMID:10479480
      supporting_text: For all substrates tested (C18:0, C20:0, C24:0, C26:0)
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Automated mapping from the UniProt subcellular-location keyword to ER
      membrane, matching the experimentally determined localization.
    action: ACCEPT
    reason: Consistent with IDA evidence for ER-membrane localization of the human
      enzyme.
    supported_by:
    - reference_id: PMID:10479480
      supporting_text: the protein was associated with the endoplasmic reticulum but
        not with
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: UniProt lists a cell-membrane location (by similarity); retain as non-core
      given the principal ER-membrane site of action.
    supported_by:
    - reference_id: PMID:20530735
      supporting_text: a plasma membrane-associated long-chain fatty acid
- term:
    id: GO:0006631
    label: fatty acid metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    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.
    action: MARK_AS_OVER_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.
    supported_by:
    - reference_id: PMID:10479480
      supporting_text: For all substrates tested (C18:0, C20:0, C24:0, C26:0)
- term:
    id: GO:0015245
    label: fatty acid transmembrane transporter activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:20530735
      supporting_text: a plasma membrane-associated long-chain fatty acid
- term:
    id: GO:0015909
    label: long-chain fatty acid transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: LCFA transport is a documented but secondary function of FATP5; retain
      as non-core.
    supported_by:
    - reference_id: PMID:20530735
      supporting_text: LCFA uptake was reduced by 40%
- term:
    id: GO:0031957
    label: very long-chain fatty acid-CoA ligase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000116
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: Supported by direct biochemical assays of VLCFA (C24:0, C26:0) activation
      by the human enzyme.
    supported_by:
    - reference_id: PMID:10479480
      supporting_text: activated the very-long-chain fatty acid
- term:
    id: GO:0047747
    label: cholate-CoA ligase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    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).
    action: ACCEPT
    reason: The human enzyme was directly shown to be cholate ligase; the EC/Rhea-based
      mapping is correct.
    supported_by:
    - reference_id: PMID:10749848
      supporting_text: exhibited cholate:CoA ligase (choloyl-CoA synthetase) activity
        with both
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: With approximately 53,000 protein-protein interactions, HuRI
        has approximately four
- term:
    id: GO:0008206
    label: bile acid metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: Ortholog-projected but biologically correct; bile acid metabolism is a
      core process for SLC27A5.
    supported_by:
    - reference_id: PMID:11980911
      supporting_text: this enzyme also activates chenodeoxycholate, the secondary
        bile acids
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: part_of
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative, ortholog-projected complex annotation with no supporting
      evidence for a defined SLC27A5 complex; not a core aspect of its function.
    supported_by:
    - reference_id: PMID:11980911
      supporting_text: Activation by thioesterification to CoA is required
- term:
    id: GO:0044877
    label: protein-containing complex binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: Ortholog-projected, non-specific binding term with no functional interpretation
      for SLC27A5; over-annotation.
    supported_by:
    - reference_id: PMID:11980911
      supporting_text: Activation by thioesterification to CoA is required
- term:
    id: GO:0006699
    label: bile acid biosynthetic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193368
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: The CoA-thioester activation catalyzed by SLC27A5 is a required step in
      the bile acid biosynthetic/conjugation pathway represented by Reactome.
    supported_by:
    - reference_id: PMID:11980911
      supporting_text: Activation by thioesterification to CoA is required
- term:
    id: GO:0006699
    label: bile acid biosynthetic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193775
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: Duplicate-pathway TAS assignment consistent with the enzyme's role in
      bile-acid CoA activation preceding conjugation.
    supported_by:
    - reference_id: PMID:11980911
      supporting_text: Activation by thioesterification to CoA is required
- term:
    id: GO:0015721
    label: bile acid and bile salt transport
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-159418
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:11980911
      supporting_text: function of homolog 2 is in the reactivation and recycling
        of C24 bile acids,
- term:
    id: GO:0004467
    label: long-chain fatty acid-CoA ligase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-159425
  qualifier: enables
  review:
    summary: Reactome (TAS) molecular-function assignment for the BACS reaction conjugating
      cytosolic cholate/chenodeoxycholate with CoA on the ER membrane. Correct core
      catalytic function.
    action: ACCEPT
    reason: Reactome represents SLC27A5 (BACS) catalyzing bile-acid CoA thioester
      formation; consistent with the experimentally established ligase activity.
    supported_by:
    - reference_id: PMID:10749848
      supporting_text: exhibited cholate:CoA ligase (choloyl-CoA synthetase) activity
        with both
- term:
    id: GO:0004467
    label: long-chain fatty acid-CoA ligase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-192137
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: SLC27A5 activates THCA in vitro; the Reactome ligase assignment is correct.
    supported_by:
    - reference_id: PMID:11980911
      supporting_text: must be activated to its CoA derivative before side
- term:
    id: GO:0004467
    label: long-chain fatty acid-CoA ligase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193407
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: Consistent with SLC27A5's characterized CoA-ligase activity on bile-acid
      intermediates.
    supported_by:
    - reference_id: PMID:11980911
      supporting_text: Activation by thioesterification to CoA is required
- term:
    id: GO:0004467
    label: long-chain fatty acid-CoA ligase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193711
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: Consistent with SLC27A5's characterized CoA-ligase activity on bile-acid
      intermediates.
    supported_by:
    - reference_id: PMID:11980911
      supporting_text: Activation by thioesterification to CoA is required
- term:
    id: GO:0004467
    label: long-chain fatty acid-CoA ligase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193766
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:10749848
      supporting_text: exhibited cholate:CoA ligase (choloyl-CoA synthetase) activity
        with both
- term:
    id: GO:0005324
    label: long-chain fatty acid transmembrane transporter activity
  evidence_type: IDA
  original_reference_id: PMID:20530735
  qualifier: enables
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: Experimentally supported transport activity; retained as a non-core function
      relative to the characterized bile-acid/fatty-acyl-CoA ligase activity.
    supported_by:
    - reference_id: PMID:20530735
      supporting_text: a plasma membrane-associated long-chain fatty acid
- term:
    id: GO:0047747
    label: cholate-CoA ligase activity
  evidence_type: IDA
  original_reference_id: PMID:10749848
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:10749848
      supporting_text: exhibited cholate:CoA ligase (choloyl-CoA synthetase) activity
        with both
    - reference_id: PMID:10749848
      supporting_text: Unconjugated bile acids must be activated
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:11980911
  qualifier: located_in
  review:
    summary: Direct evidence (topology/localization studies) that SLC27A5 is an ER-membrane
      protein. This is the core subcellular site of the enzyme's action.
    action: ACCEPT
    reason: Experimentally established ER-membrane localization, consistent with the
      cloning study and Reactome reaction placement.
    supported_by:
    - reference_id: PMID:10479480
      supporting_text: the protein was associated with the endoplasmic reticulum but
        not with
- term:
    id: GO:0031957
    label: very long-chain fatty acid-CoA ligase activity
  evidence_type: IDA
  original_reference_id: PMID:10479480
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: Experimentally supported VLCFA-CoA ligase activity of the human protein.
    supported_by:
    - reference_id: PMID:10479480
      supporting_text: activated the very-long-chain fatty acid
- term:
    id: GO:0031957
    label: very long-chain fatty acid-CoA ligase activity
  evidence_type: IDA
  original_reference_id: PMID:11980911
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: Duplicate IDA supporting the VLCFA-CoA ligase activity; retained.
    supported_by:
    - reference_id: PMID:11980911
      supporting_text: Activation by thioesterification to CoA is required
- term:
    id: GO:0006699
    label: bile acid biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:11980911
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: The CoA-thioester activation catalyzed by SLC27A5 is an obligatory step
      in bile-acid conjugation within the biosynthetic/recycling pathway; core biological
      process.
    supported_by:
    - reference_id: PMID:11980911
      supporting_text: Activation by thioesterification to CoA is required
    - reference_id: PMID:11980911
      supporting_text: reutilization of cholate
- term:
    id: GO:0000038
    label: very long-chain fatty acid metabolic process
  evidence_type: IDA
  original_reference_id: PMID:10479480
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: Supported by direct VLCFA activation assays; a genuine metabolic-process
      role, though secondary to the bile-acid role in vivo.
    supported_by:
    - reference_id: PMID:10479480
      supporting_text: For all substrates tested (C18:0, C20:0, C24:0, C26:0)
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:10479480
  qualifier: located_in
  review:
    summary: Direct immunofluorescence evidence that the human enzyme associates with
      the endoplasmic reticulum (and not peroxisomes). Consistent with the more specific
      ER-membrane annotation.
    action: ACCEPT
    reason: Experimentally established ER localization; the more specific ER-membrane
      term is also annotated.
    supported_by:
    - reference_id: PMID:10479480
      supporting_text: the protein was associated with the endoplasmic reticulum but
        not with
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-159425
  qualifier: located_in
  review:
    summary: Reactome (TAS) localization of the BACS reaction to the ER membrane,
      matching the experimentally determined localization.
    action: ACCEPT
    reason: Consistent with IDA ER-membrane evidence; correct site of the catalyzed
      reaction.
    supported_by:
    - reference_id: PMID:10479480
      supporting_text: the protein was associated with the endoplasmic reticulum but
        not with
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-192137
  qualifier: located_in
  review:
    summary: Reactome (TAS) localization of a BACS bile-acid CoA-conjugation reaction
      to the ER membrane.
    action: ACCEPT
    reason: Duplicate ER-membrane localization consistent with experimental evidence.
    supported_by:
    - reference_id: PMID:10479480
      supporting_text: the protein was associated with the endoplasmic reticulum but
        not with
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193407
  qualifier: located_in
  review:
    summary: Reactome (TAS) localization of a BACS bile-acid CoA-conjugation reaction
      to the ER membrane.
    action: ACCEPT
    reason: Duplicate ER-membrane localization consistent with experimental evidence.
    supported_by:
    - reference_id: PMID:10479480
      supporting_text: the protein was associated with the endoplasmic reticulum but
        not with
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193711
  qualifier: located_in
  review:
    summary: Reactome (TAS) localization of a BACS bile-acid CoA-conjugation reaction
      to the ER membrane.
    action: ACCEPT
    reason: Duplicate ER-membrane localization consistent with experimental evidence.
    supported_by:
    - reference_id: PMID:10479480
      supporting_text: the protein was associated with the endoplasmic reticulum but
        not with
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-193766
  qualifier: located_in
  review:
    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.
    action: ACCEPT
    reason: ER-membrane localization is correct; only the specific Reactome reaction
      id could not be verified in the current release.
    supported_by:
    - reference_id: PMID:10479480
      supporting_text: the protein was associated with the endoplasmic reticulum but
        not with
core_functions:
- description: ATP-dependent activation of C24 bile acids (cholate, chenodeoxycholate,
    and the secondary bile acids deoxycholate and lithocholate) to their CoA thioesters,
    the obligatory step preceding glycine/taurine conjugation; also broad long-chain
    and very-long-chain fatty-acyl-CoA synthetase activity.
  molecular_function:
    id: GO:0047747
    label: cholate-CoA ligase activity
  directly_involved_in:
  - id: GO:0006699
    label: bile acid biosynthetic process
  - id: GO:0008206
    label: bile acid metabolic process
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: PMID:10749848
    supporting_text: exhibited cholate:CoA ligase (choloyl-CoA synthetase) activity
      with both
  - reference_id: PMID:11980911
    supporting_text: function of homolog 2 is in the reactivation and recycling of
      C24 bile acids,
- description: ATP-dependent formation of long-chain and very-long-chain fatty-acyl-CoA
    from long-chain (C18:0, C20:0) and very-long-chain (C24:0, C26:0) fatty acids,
    contributing to hepatic fatty-acid metabolism and uptake.
  molecular_function:
    id: GO:0004467
    label: long-chain fatty acid-CoA ligase activity
  directly_involved_in:
  - id: GO:0001676
    label: long-chain fatty acid metabolic process
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: PMID:10479480
    supporting_text: For all substrates tested (C18:0, C20:0, C24:0, C26:0)
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000116
  title: Automatic Gene Ontology annotation based on Rhea mapping
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10479480
  title: 'Human liver-specific very-long-chain acyl-coenzyme A synthetase: cDNA cloning
    and characterization of a second enzymatically active protein.'
  findings:
  - statement: Human hVLCS-H2 (SLC27A5) is liver-specific, ER-associated, and activates
      long-chain and very-long-chain fatty acids (C18:0-C26:0) to their CoA thioesters.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; cloning and biochemical characterization of the
      human enzyme's acyl-CoA synthetase activity and ER localization.
- id: PMID:10749848
  title: The human liver-specific homolog of very long-chain acyl-CoA synthetase is
    cholate:CoA ligase.
  findings:
  - statement: hVLCS-H2 (SLC27A5) is cholate ligase; unconjugated bile acids must
      be activated to CoA thioesters before glycine/taurine conjugation, and the enzyme
      is proposed to re-activate/re-conjugate bile acids from the enterohepatic circulation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; establishes the defining cholate-CoA ligase activity.
- id: PMID:11980911
  title: Participation of two members of the very long-chain acyl-CoA synthetase family
    in bile acid synthesis and recycling.
  findings:
  - statement: SLC27A5 activates chenodeoxycholate, deoxycholate, lithocholate and
      the C27 precursor THCA in addition to cholate; its primary function is proposed
      to be reactivation and recycling of C24 bile acids.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; broadens substrate profile and defines the recycling
      role.
- id: PMID:20530735
  title: FATP2 is a hepatic fatty acid transporter and peroxisomal very long-chain
    acyl-CoA synthetase.
  findings:
  - statement: FATP family members act as plasma-membrane-associated LCFA transporters
      and acyl-CoA synthetases in liver; used here to contextualize FATP5's fatty-acid
      uptake/transport role.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified; the knockdown assays are on FATP2 (SLC27A2), but
      the paper frames the FATP-family transporter/synthetase duality relevant to
      FATP5.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings:
  - statement: HuRI proteome-scale binary interactome; source of the single high-throughput
      SLC27A5-MEOX2 interaction underlying the protein binding IPI annotation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PubMed-verified; high-throughput Y2H screen, no functional interpretation
      for SLC27A5.
- id: Reactome:R-HSA-159418
  title: Recycling of bile acids and salts
  findings: []
- id: Reactome:R-HSA-159425
  title: Cytosolic cholate and chenodeoxycholate are conjugated with Coenzyme A (SLC27A5
    BACS)
  findings: []
- id: Reactome:R-HSA-192137
  title: THCA is conjugated with Coenzyme A (SLC27A5 BACS)
  findings: []
- id: Reactome:R-HSA-193368
  title: Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol
  findings: []
- id: Reactome:R-HSA-193407
  title: DHCA is conjugated with Coenzyme A (SLC27A5 BACS)
  findings: []
- id: Reactome:R-HSA-193711
  title: 3,7,24THCA is conjugated with Coenzyme A (SLC27A5 BACS)
  findings: []
- id: Reactome:R-HSA-193766
  title: Bile-acyl-CoA conjugation reaction (SLC27A5 BACS)
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: UNVERIFIED
    review_notes: Reactome reaction id returns 404 in the current ContentService and
      the local cache is empty (likely retired/renumbered); title is descriptive.
- id: Reactome:R-HSA-193775
  title: Synthesis of bile acids and bile salts via 24-hydroxycholesterol
  findings: []
- id: file:human/SLC27A5/SLC27A5-uniprot.txt
  title: UniProtKB Q9Y2P5 (SLC27A5 / S27A5_HUMAN) entry
  findings:
  - statement: UniProt describes SLC27A5 as bile acyl-CoA synthetase (EC 6.2.1.7)
      that mainly activates bile acids to their CoA thioesters prior to conjugation,
      also with LCFA/VLCFA-CoA ligase activity (EC 6.2.1.3), localized to the endoplasmic
      reticulum membrane as a multi-pass membrane protein.
    reference_section_type: OTHER