LPCAT4, also called LPEAT2 or LPLAT10, is an integral endoplasmic-reticulum membrane lysophospholipid acyltransferase that reacylates lysophospholipids in phospholipid remodeling. Human-enzyme assays establish activity toward lysophosphatidylcholine, lysophosphatidylethanolamine, and lysophosphatidylserine, with particularly prominent LPE acylation in the original study. Position-resolved assays show that LPCAT4 can acylate sn-2 lysophospholipids selectively at the sn-1 position and favors unsaturated fatty-acyl-CoA donors. Oleoyl- and docosahexaenoyl-CoA are effective donors, while palmitoyl- and stearoyl-CoA also support activity. These activities remodel phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine and generate minor phospholipid species bearing an unsaturated fatty acid at sn-1. The older assay supports acylation of 1-acyl LPG at its free sn-2 position, whereas position-resolved assays found no activity toward 2-acyl LPG at its free sn-1 position. Thus phosphatidylglycerol remodeling depends on acceptor position. Despite the historical name AGPAT7 and membership in an acyltransferase family, direct studies found no appreciable activity toward lysophosphatidic acid or glycerol 3-phosphate; LPCAT4 is therefore not supported as a lysophosphatidic-acid acyltransferase or phosphatidic-acid biosynthetic enzyme. Lplat10-deficient mouse brain loses phospholipids with unsaturated sn-1 chains, providing in-vivo support for the remodeling chemistry while leaving the functions of these minor lipids unresolved in humans. Mouse liver overexpression effects on insulin secretion and an LPCAT4-WNT-beta-catenin-c-JUN-ACSL3 axis reported in hepatocellular carcinoma are context-specific outcomes rather than additional core catalytic activities. No functionally distinct protein isoforms or stable LPCAT4-containing complex has been established.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | MODIFY | Summary: The endoplasmic-reticulum assignment is valid but should be refined to the membrane where this multi-pass enzyme acts. Reason: Human LPCAT4 is an integral endoplasmic-reticulum membrane acyltransferase; PMID:18458083 reports ER localization after expression in mammalian cells, and UniProt records multi-pass topology. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:2384812 SUPPORTS TRANSFER Exact WITH/FROM source; it supports the related activity or location, while direct LPCAT4 evidence supports the more informative replacement. MGI:MGI:3606214 SUPPORTS TRANSFER Exact WITH/FROM source; it supports the related activity or location, while direct LPCAT4 evidence supports the more informative replacement. PANTHER:PTN001128751 SUPPORTS TRANSFER Exact WITH/FROM source; it supports the related activity or location, while direct LPCAT4 evidence supports the more informative replacement. UniProtKB:Q643R3 SUPPORTS TRANSFER Self-reference: the target is its own IBD seed, which is expected rather than circular -- its own IDA annotation to this term is one of the descendant evidences behind the IBD. The IBA then asserts the additional claim that the function is inherited rather than lineage-specific. UniProtKB:Q7L5N7 SUPPORTS TRANSFER Exact WITH/FROM source; it supports the related activity or location, while direct LPCAT4 evidence supports the more informative replacement. UniProtKB:Q8NF37 SUPPORTS TRANSFER Exact WITH/FROM source; it supports the related activity or location, while direct LPCAT4 evidence supports the more informative replacement. Proposed replacements: endoplasmic reticulum membrane |
| GO:0042171 lysophosphatidic acid acyltransferase activity | IBA GO_REF:0000033 | REMOVE | Summary: The inferred lysophosphatidic-acid acyltransferase activity is contradicted by direct human LPCAT4 substrate testing. Reason: PMID:18458083 found prominent LPE acylation and several other lysophospholipid substrates but explicitly reported no appreciable activity toward lysophosphatidic acid or glycerol 3-phosphate. The phylogenetic family assignment should not override the target-specific biochemical result. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN001128751 SUPPORTS SOURCE BUT NOT TARGET Exact WITH/FROM source; family or rule provenance does not override direct evidence that human LPCAT4 lacks appreciable lysophosphatidic-acid acyltransferase activity. RGD:1311599 SUPPORTS SOURCE BUT NOT TARGET Exact WITH/FROM source; family or rule provenance does not override direct evidence that human LPCAT4 lacks appreciable lysophosphatidic-acid acyltransferase activity. UniProtKB:Q7L5N7 SUPPORTS SOURCE BUT NOT TARGET Exact WITH/FROM source; family or rule provenance does not override direct evidence that human LPCAT4 lacks appreciable lysophosphatidic-acid acyltransferase activity. |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Accepted as the experimentally supported membrane location of LPCAT4. Reason: The UniProt subcellular-location mapping agrees with PMID:18458083, which localized overexpressed human LPEAT2/LPCAT4 to the endoplasmic reticulum, and with its multi-pass membrane topology. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0097 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPCAT4 biochemical or localization evidence. |
| GO:0016746 acyltransferase activity | IEA GO_REF:0000002 | MODIFY | Summary: The broad acyltransferase assignment should be replaced by the experimentally established lysophospholipid acyltransferase activity. Reason: The acyltransferase-domain mapping is correct but uninformative. PMID:18458083 directly establishes acyl-CoA-dependent activity toward a selective set of lysophospholipid acceptors. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: InterPro:IPR002123 SUPPORTS TRANSFER Exact WITH/FROM source; it supports the related activity or location, while direct LPCAT4 evidence supports the more informative replacement. Proposed replacements: lysophospholipid acyltransferase activity |
| GO:0016747 acyltransferase activity, transferring groups other than amino-acyl groups | IEA GO_REF:0000002 | MODIFY | Summary: The broad non-amino-acyl transferase assignment should be replaced by the experimentally established lysophospholipid acyltransferase activity. Reason: The family mapping captures the transferase chemistry but not the substrate class. Direct assays in PMID:18458083 support the more informative lysophospholipid acyltransferase term. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: InterPro:IPR045252 SUPPORTS TRANSFER Exact WITH/FROM source; it supports the related activity or location, while direct LPCAT4 evidence supports the more informative replacement. Proposed replacements: lysophospholipid acyltransferase activity |
| GO:0042171 lysophosphatidic acid acyltransferase activity | IEA GO_REF:0000117 | REMOVE | Summary: The rule-derived lysophosphatidic-acid acyltransferase activity is contradicted by direct LPCAT4 biochemistry. Reason: PMID:18458083 explicitly reports no appreciable lysophosphatidic-acid or glycerol-3-phosphate acylation by human LPCAT4. The ARBA assignment appears to over-transfer a family-associated activity. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE Sources checked: ARBA:ARBA00027459 SUPPORTS SOURCE BUT NOT TARGET Exact WITH/FROM source; family or rule provenance does not override direct evidence that human LPCAT4 lacks appreciable lysophosphatidic-acid acyltransferase activity. |
| GO:0047166 1-alkenylglycerophosphoethanolamine O-acyltransferase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Accepted as a directly supported plasmalogen-LPE acyltransferase activity. Reason: PMID:18458083 reports significant acyl-CoA-dependent activity toward 1-O-alkenyl-lysophosphatidylethanolamine, matching this reaction-specific term. Propagation Review Root cause: NO FAILURE CORE Sources checked: RHEA:16245 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPCAT4 biochemical or localization evidence. RHEA:37631 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPCAT4 biochemical or localization evidence. RHEA:37635 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPCAT4 biochemical or localization evidence. RHEA:37755 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPCAT4 biochemical or localization evidence. RHEA:37759 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPCAT4 biochemical or localization evidence. RHEA:37763 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPCAT4 biochemical or localization evidence. EC:2.3.1.121 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPCAT4 biochemical or localization evidence. |
| GO:0047184 1-acylglycerophosphocholine O-acyltransferase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Accepted as directly supported sn-1-acyl LPC acyltransferase activity. Reason: PMID:18458083 demonstrates acyl-CoA-dependent lysophosphatidylcholine acylation, and PMID:41740885 independently resolves activity with sn-position-defined LPC substrates. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q6NVG1 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPCAT4 biochemical or localization evidence. ensembl:ENSMUSP00000028554 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPCAT4 biochemical or localization evidence. RHEA:12937 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPCAT4 biochemical or localization evidence. RHEA:33359 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPCAT4 biochemical or localization evidence. RHEA:37387 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPCAT4 biochemical or localization evidence. RHEA:37475 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPCAT4 biochemical or localization evidence. RHEA:37803 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPCAT4 biochemical or localization evidence. EC:2.3.1.23 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPCAT4 biochemical or localization evidence. |
| GO:0047191 1-alkylglycerophosphocholine O-acyltransferase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Accepted as directly supported alkyl-LPC acyltransferase activity. Reason: PMID:18458083 reports significant acyl-CoA-dependent activity toward 1-O-alkyl-lysophosphatidylcholine, matching this reaction class. Propagation Review Root cause: NO FAILURE CORE Sources checked: RHEA:23992 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPCAT4 biochemical or localization evidence. RHEA:37783 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPCAT4 biochemical or localization evidence. RHEA:37787 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPCAT4 biochemical or localization evidence. EC:2.3.1.63 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPCAT4 biochemical or localization evidence. |
| GO:0106262 1-acylglycerophosphoethanolamine O-acyltransferase activity | IEA GO_REF:0000116 | ACCEPT | Summary: Accepted as the prominent directly measured LPE acyltransferase activity of LPCAT4. Reason: PMID:18458083 reports up to ninefold increased LPE acyltransferase activity after expression of human LPCAT4 and identifies LPE as its prominent acceptor. Propagation Review Root cause: NO FAILURE CORE Sources checked: RHEA:32995 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPCAT4 biochemical or localization evidence. RHEA:37575 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPCAT4 biochemical or localization evidence. RHEA:37731 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPCAT4 biochemical or localization evidence. RHEA:37767 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPCAT4 biochemical or localization evidence. RHEA:37771 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPCAT4 biochemical or localization evidence. RHEA:37775 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPCAT4 biochemical or localization evidence. |
| GO:0106263 1-acylglycerophosphoserine O-acyltransferase activity | IEA GO_REF:0000116 | ACCEPT | Summary: Accepted as directly supported lysophosphatidylserine acyltransferase activity. Reason: PMID:18458083 reports significant acyl-CoA-dependent activity toward lysophosphatidylserine. Propagation Review Root cause: NO FAILURE CORE Sources checked: RHEA:33191 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPCAT4 biochemical or localization evidence. RHEA:37531 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPCAT4 biochemical or localization evidence. |
| GO:0036151 phosphatidylcholine acyl-chain remodeling | IEA GO_REF:0000107 | ACCEPT | Summary: Accepted as a core phosphatidylcholine-remodeling process. Reason: LPC acylation directly remodels phosphatidylcholine, and the orthology-based inference is independently supported by human LPCAT4 assays in PMID:18458083 and PMID:41740885. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q6NVG1 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPCAT4 biochemical or localization evidence. ensembl:ENSMUSP00000028554 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPCAT4 biochemical or localization evidence. |
| GO:0047190 2-acylglycerophosphocholine O-acyltransferase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Accepted as directly supported sn-2-acyl LPC acyltransferase activity. Reason: PMID:41740885 directly tested position-defined lysophospholipids and found LPCAT4 incorporates fatty acids selectively at the sn-1 position, which corresponds to acylation of 2-acyl LPC. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q6NVG1 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPCAT4 biochemical or localization evidence. ensembl:ENSMUSP00000028554 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPCAT4 biochemical or localization evidence. RHEA:74799 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPCAT4 biochemical or localization evidence. RHEA:74811 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPCAT4 biochemical or localization evidence. |
| GO:0036151 phosphatidylcholine acyl-chain remodeling | IDA PMID:41740885 LPLAT10/LPEAT2 produces atypical phospholipids with an unsat... | ACCEPT | Summary: Accepted as direct evidence that LPCAT4 participates in phosphatidylcholine acyl-chain remodeling. Reason: The now-cached full text of PMID:41740885 directly demonstrates LPCAT4-dependent incorporation into position-defined LPC and depletion of atypical sn-1-unsaturated phosphatidylcholine species in Lplat10-deficient mouse brain. The human enzyme assay supports the activity, while the in vivo lipidomic consequence is mouse evidence. |
| GO:0047184 1-acylglycerophosphocholine O-acyltransferase activity | IDA PMID:41740885 LPLAT10/LPEAT2 produces atypical phospholipids with an unsat... | ACCEPT | Summary: Accepted as direct sn-1-acyl LPC acyltransferase activity. Reason: PMID:41740885 directly assays human LPLAT10/LPCAT4 with position-defined LPC substrates and confirms acyl-CoA-dependent phosphatidylcholine production. |
| GO:0047190 2-acylglycerophosphocholine O-acyltransferase activity | IDA PMID:41740885 LPLAT10/LPEAT2 produces atypical phospholipids with an unsat... | ACCEPT | Summary: Accepted as direct sn-2-acyl LPC acyltransferase activity. Reason: PMID:41740885 developed stabilized sn-2 LPC substrates and directly shows LPCAT4 incorporation at the sn-1 position, supporting this position-specific activity. |
| GO:0006654 phosphatidic acid biosynthetic process | TAS Reactome:R-HSA-1483166 | REMOVE | Summary: The phosphatidic-acid biosynthesis assignment is contradicted by direct LPCAT4 substrate testing. Reason: This Reactome pathway includes the conversion of LPA to phosphatidic acid, but PMID:18458083 explicitly found no appreciable LPCAT4 activity toward lysophosphatidic acid or glycerol 3-phosphate. LPCAT4 should not be retained as a PA-biosynthetic enzyme. |
| GO:0036148 phosphatidylglycerol acyl-chain remodeling | TAS Reactome:R-HSA-1482925 | KEEP AS NON CORE | Summary: Phosphatidylglycerol remodeling is retained as a position-dependent, non-core activity. Reason: PMID:18458083 reported human LPCAT4 activity toward LPG without resolving the glycerol position, consistent with acylation of 1-acyl LPG at free sn-2. PMID:41740885 directly found no activity toward sn-2-dominant 2-acyl LPG at free sn-1. PG remodeling is therefore retained as a position-dependent non-core process rather than an unqualified activity across LPG isomers. |
| GO:0036150 phosphatidylserine acyl-chain remodeling | TAS Reactome:R-HSA-1482801 | ACCEPT | Summary: Accepted as phosphatidylserine acyl-chain remodeling by an ER lysophospholipid acyltransferase. Reason: The Reactome pathway placement is consistent with direct human LPCAT4 activity toward the corresponding lysophospholipid acceptor in PMID:18458083. It represents substrate-class remodeling rather than a separate catalytic mechanism. |
| GO:0036151 phosphatidylcholine acyl-chain remodeling | TAS Reactome:R-HSA-1482788 | ACCEPT | Summary: Accepted as phosphatidylcholine acyl-chain remodeling by an ER lysophospholipid acyltransferase. Reason: The Reactome pathway placement is consistent with direct human LPCAT4 activity toward the corresponding lysophospholipid acceptor in PMID:18458083. It represents substrate-class remodeling rather than a separate catalytic mechanism. |
| GO:0036152 phosphatidylethanolamine acyl-chain remodeling | TAS Reactome:R-HSA-1482839 | ACCEPT | Summary: Accepted as phosphatidylethanolamine acyl-chain remodeling by an ER lysophospholipid acyltransferase. Reason: The Reactome pathway placement is consistent with direct human LPCAT4 activity toward the corresponding lysophospholipid acceptor in PMID:18458083. It represents substrate-class remodeling rather than a separate catalytic mechanism. |
| GO:0006644 phospholipid metabolic process | IEA GO_REF:0000041 | ACCEPT | Summary: Accepted as a broad process encompassing LPCAT4-dependent phospholipid remodeling. Reason: Although broad, phospholipid metabolism accurately encompasses the directly demonstrated conversion of multiple lysophospholipids to phospholipids in PMID:18458083. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniPathway:UPA00085 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPCAT4 biochemical or localization evidence. |
| GO:0003841 1-acylglycerol-3-phosphate O-acyltransferase activity | TAS Reactome:R-HSA-1482539 | MODIFY | Summary: The Reactome event supports 1-acyl LPG acylation, but the seeded glycerol-3-phosphate term names the wrong substrate. Reason: Reactome explicitly describes LPCAT4 in the 1-acyl LPG-to-phospholipid reaction. Direct assays support this lysophospholipid class, whereas PMID:18458083 reports no appreciable glycerol-3-phosphate or LPA acylation; the reaction-appropriate term should replace the seeded term. Proposed replacements: lysophospholipid acyltransferase activity |
| GO:0003841 1-acylglycerol-3-phosphate O-acyltransferase activity | TAS Reactome:R-HSA-1482547 | MODIFY | Summary: The Reactome event supports 1-acyl LPC acylation, but the seeded glycerol-3-phosphate term names the wrong substrate. Reason: Reactome explicitly describes LPCAT4 in the 1-acyl LPC-to-phospholipid reaction. Direct assays support this lysophospholipid class, whereas PMID:18458083 reports no appreciable glycerol-3-phosphate or LPA acylation; the reaction-appropriate term should replace the seeded term. Proposed replacements: 1-acylglycerophosphocholine O-acyltransferase activity |
| GO:0003841 1-acylglycerol-3-phosphate O-acyltransferase activity | TAS Reactome:R-HSA-1482636 | MODIFY | Summary: The Reactome event supports 1-acyl LPS acylation, but the seeded glycerol-3-phosphate term names the wrong substrate. Reason: Reactome explicitly describes LPCAT4 in the 1-acyl LPS-to-phospholipid reaction. Direct assays support this lysophospholipid class, whereas PMID:18458083 reports no appreciable glycerol-3-phosphate or LPA acylation; the reaction-appropriate term should replace the seeded term. Proposed replacements: 1-acylglycerophosphoserine O-acyltransferase activity |
| GO:0003841 1-acylglycerol-3-phosphate O-acyltransferase activity | TAS Reactome:R-HSA-1482667 | MODIFY | Summary: The Reactome event supports 1-acyl LPE acylation, but the seeded glycerol-3-phosphate term names the wrong substrate. Reason: Reactome explicitly describes LPCAT4 in the 1-acyl LPE-to-phospholipid reaction. Direct assays support this lysophospholipid class, whereas PMID:18458083 reports no appreciable glycerol-3-phosphate or LPA acylation; the reaction-appropriate term should replace the seeded term. Proposed replacements: 1-acylglycerophosphoethanolamine O-acyltransferase activity |
| GO:0003841 1-acylglycerol-3-phosphate O-acyltransferase activity | TAS Reactome:R-HSA-75885 | REMOVE | Summary: The Reactome LPA-to-PA activity is contradicted by direct human LPCAT4 biochemistry. Reason: This event and GO term specifically require lysophosphatidic-acid acylation, but PMID:18458083 explicitly reports that human LPCAT4 lacks appreciable activity toward lysophosphatidic acid and glycerol 3-phosphate. |
| GO:0047144 2-acylglycerol-3-phosphate O-acyltransferase activity | TAS Reactome:R-HSA-1482533 | MODIFY | Summary: The Reactome event supports 2-acyl LPC acylation, but the seeded glycerol-3-phosphate term names the wrong substrate. Reason: Reactome explicitly describes LPCAT4 in the 2-acyl LPC-to-phospholipid reaction. Direct assays support this lysophospholipid class, whereas PMID:18458083 reports no appreciable glycerol-3-phosphate or LPA acylation; the reaction-appropriate term should replace the seeded term. Proposed replacements: 2-acylglycerophosphocholine O-acyltransferase activity |
| GO:0047144 2-acylglycerol-3-phosphate O-acyltransferase activity | TAS Reactome:R-HSA-1482635 | REMOVE | Summary: The 2-acyl LPG reaction is contradicted by position-resolved LPCAT4 substrate testing. Reason: Reactome assigns LPCAT4 to acylation of 2-acyl LPG at the free sn-1 position, but PMID:41740885 directly reports that LPCAT4 did not act on sn-2-dominant LPG. The older non-position-resolved LPG result in PMID:18458083 can support the distinct 1-acyl LPG reaction at free sn-2, but it does not rescue this position-specific assignment. |
| GO:0047144 2-acylglycerol-3-phosphate O-acyltransferase activity | TAS Reactome:R-HSA-1482646 | MODIFY | Summary: The Reactome event supports 2-acyl LPE acylation, but the seeded glycerol-3-phosphate term names the wrong substrate. Reason: Reactome explicitly describes LPCAT4 in the 2-acyl LPE-to-phospholipid reaction. PMID:18458083 directly supports lysophosphatidylethanolamine acylation and reports no appreciable glycerol-3-phosphate or LPA acylation; the headgroup-specific LPE acyltransferase term should replace the seeded term. Proposed replacements: lysophosphatidylethanolamine acyltransferase activity |
| GO:0047144 2-acylglycerol-3-phosphate O-acyltransferase activity | TAS Reactome:R-HSA-1482691 | MODIFY | Summary: The Reactome event supports 2-acyl LPS acylation, but the seeded glycerol-3-phosphate term names the wrong substrate. Reason: Reactome explicitly describes LPCAT4 in the 2-acyl LPS-to-phospholipid reaction. Direct assays support this lysophospholipid class, whereas PMID:18458083 reports no appreciable glycerol-3-phosphate or LPA acylation; the reaction-appropriate term should replace the seeded term. Proposed replacements: lysophospholipid acyltransferase activity |
| GO:0005789 endoplasmic reticulum membrane | EXP PMID:18458083 Molecular identification of a novel mammalian brain isoform ... | ACCEPT | Summary: Accepted as experimental localization of LPCAT4 to the endoplasmic-reticulum membrane. Reason: PMID:18458083 reports that overexpressed human LPEAT2/LPCAT4 localizes to the endoplasmic reticulum; its multi-pass topology supports the membrane-specific term. |
| GO:0006644 phospholipid metabolic process | IDA PMID:18458083 Molecular identification of a novel mammalian brain isoform ... | ACCEPT | Summary: Accepted as direct biochemical evidence for a role in phospholipid metabolism. Reason: Expression of human LPCAT4 increased selective lysophospholipid acylation and generated the corresponding phospholipids in PMID:18458083. |
| GO:0006644 phospholipid metabolic process | IMP PMID:18458083 Molecular identification of a novel mammalian brain isoform ... | ACCEPT | Summary: Accepted as perturbation evidence for a role in phospholipid metabolism. Reason: siRNA knockdown of LPCAT4 in HEK293T cells significantly decreased LPE and 1-alkenyl-LPE acyltransferase activities in PMID:18458083, supporting its contribution to phospholipid metabolism. |
| GO:0071617 lysophospholipid acyltransferase activity | IDA PMID:18458083 Molecular identification of a novel mammalian brain isoform ... | ACCEPT | Summary: Accepted as the direct broad catalytic activity encompassing LPCAT4 substrate classes. Reason: PMID:18458083 directly demonstrates acyl-CoA-dependent acylation of a selective set of lysophospholipids, with prominent activity toward ethanolamine-containing substrates. |
| GO:0071617 lysophospholipid acyltransferase activity | IMP PMID:18458083 Molecular identification of a novel mammalian brain isoform ... | ACCEPT | Summary: Accepted with curator deference as perturbation support for lysophospholipid acyltransferase activity. Reason: The IMP annotation is consistent with the reported reduction of LPE and 1-alkenyl-LPE acylating activities after LPCAT4 knockdown in PMID:18458083; it complements the direct enzyme assays. |
| GO:0036150 phosphatidylserine acyl-chain remodeling | IDA PMID:18458083 Molecular identification of a novel mammalian brain isoform ... | ACCEPT | Summary: Accepted as direct evidence for phosphatidylserine acyl-chain remodeling. Reason: PMID:18458083 directly demonstrates LPCAT4 activity toward the corresponding lysophospholipid, supporting reacylation in phosphatidylserine remodeling. |
| GO:0036151 phosphatidylcholine acyl-chain remodeling | IDA PMID:18458083 Molecular identification of a novel mammalian brain isoform ... | ACCEPT | Summary: Accepted as direct evidence for phosphatidylcholine acyl-chain remodeling. Reason: PMID:18458083 directly demonstrates LPCAT4 activity toward the corresponding lysophospholipid, supporting reacylation in phosphatidylcholine remodeling. |
| GO:0036152 phosphatidylethanolamine acyl-chain remodeling | IDA PMID:18458083 Molecular identification of a novel mammalian brain isoform ... | ACCEPT | Summary: Accepted as direct evidence for phosphatidylethanolamine acyl-chain remodeling. Reason: PMID:18458083 directly demonstrates LPCAT4 activity toward the corresponding lysophospholipid, supporting reacylation in phosphatidylethanolamine remodeling. |
| GO:0047166 1-alkenylglycerophosphoethanolamine O-acyltransferase activity | IDA PMID:18458083 Molecular identification of a novel mammalian brain isoform ... | ACCEPT | Summary: Accepted as direct 1-alkenyl-LPE acyltransferase activity. Reason: PMID:18458083 directly assays human LPCAT4 and reports the corresponding substrate activity; this is an informative catalytic annotation rather than a generic transferase label. |
| GO:0047184 1-acylglycerophosphocholine O-acyltransferase activity | IDA PMID:18458083 Molecular identification of a novel mammalian brain isoform ... | ACCEPT | Summary: Accepted as direct 1-acyl LPC acyltransferase activity. Reason: PMID:18458083 directly assays human LPCAT4 and reports the corresponding substrate activity; this is an informative catalytic annotation rather than a generic transferase label. |
| GO:0047192 1-alkylglycerophosphocholine O-acetyltransferase activity | IDA PMID:18458083 Molecular identification of a novel mammalian brain isoform ... | UNDECIDED | Summary: The cached abstract supports 1-alkyl LPC acylation but does not establish acetyl-CoA use. Reason: PMID:18458083 is available only as an abstract and reports activity toward 1-O-alkyl-lysophosphatidylcholine with medium- and long-chain acyl-CoAs; it does not verify the acetyl-CoA-specific chemistry named by GO:0047192. Defer to the curator's full-text assessment rather than accepting or rejecting this experimental annotation from incomplete evidence. |
| GO:0106262 1-acylglycerophosphoethanolamine O-acyltransferase activity | IDA PMID:18458083 Molecular identification of a novel mammalian brain isoform ... | ACCEPT | Summary: Accepted as direct 1-acyl LPE acyltransferase activity. Reason: PMID:18458083 directly assays human LPCAT4 and reports the corresponding substrate activity; this is an informative catalytic annotation rather than a generic transferase label. |
| GO:0106263 1-acylglycerophosphoserine O-acyltransferase activity | IDA PMID:18458083 Molecular identification of a novel mammalian brain isoform ... | ACCEPT | Summary: Accepted as direct 1-acyl LPS acyltransferase activity. Reason: PMID:18458083 directly assays human LPCAT4 and reports the corresponding substrate activity; this is an informative catalytic annotation rather than a generic transferase label. |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | MODIFY | Summary: The membrane proteomics result is valid but should be refined to the experimentally established ER membrane. Reason: PMID:19946888 identifies LPCAT4 in a large-scale membrane proteome, which supports membrane association but not a specific compartment. Independent direct localization in PMID:18458083 supports the more informative endoplasmic reticulum membrane term. Proposed replacements: endoplasmic reticulum membrane |
| GO:0005783 endoplasmic reticulum | IDA PMID:18458083 Molecular identification of a novel mammalian brain isoform ... | MODIFY | Summary: The endoplasmic-reticulum localization is valid but should be refined to the membrane where LPCAT4 is embedded. Reason: PMID:18458083 reports ER localization, and the protein is an experimentally supported multi-pass membrane enzyme; endoplasmic reticulum membrane is the informative location. Proposed replacements: endoplasmic reticulum membrane |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-1482533 | ACCEPT | Summary: Accepted as the ER-membrane location of the curated lysophospholipid acylation event. Reason: Reactome:R-HSA-1482533 places LPCAT4 in an ER-membrane phospholipid-acylation reaction. This agrees with direct localization and multi-pass topology reported in PMID:18458083. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-1482539 | ACCEPT | Summary: Accepted as the ER-membrane location of the curated lysophospholipid acylation event. Reason: Reactome:R-HSA-1482539 places LPCAT4 in an ER-membrane phospholipid-acylation reaction. This agrees with direct localization and multi-pass topology reported in PMID:18458083. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-1482547 | ACCEPT | Summary: Accepted as the ER-membrane location of the curated lysophospholipid acylation event. Reason: Reactome:R-HSA-1482547 places LPCAT4 in an ER-membrane phospholipid-acylation reaction. This agrees with direct localization and multi-pass topology reported in PMID:18458083. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-1482635 | ACCEPT | Summary: Accepted as the ER-membrane location of the curated lysophospholipid acylation event. Reason: Reactome:R-HSA-1482635 places LPCAT4 in an ER-membrane phospholipid-acylation reaction. This agrees with direct localization and multi-pass topology reported in PMID:18458083. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-1482636 | ACCEPT | Summary: Accepted as the ER-membrane location of the curated lysophospholipid acylation event. Reason: Reactome:R-HSA-1482636 places LPCAT4 in an ER-membrane phospholipid-acylation reaction. This agrees with direct localization and multi-pass topology reported in PMID:18458083. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-1482646 | ACCEPT | Summary: Accepted as the ER-membrane location of the curated lysophospholipid acylation event. Reason: Reactome:R-HSA-1482646 places LPCAT4 in an ER-membrane phospholipid-acylation reaction. This agrees with direct localization and multi-pass topology reported in PMID:18458083. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-1482667 | ACCEPT | Summary: Accepted as the ER-membrane location of the curated lysophospholipid acylation event. Reason: Reactome:R-HSA-1482667 places LPCAT4 in an ER-membrane phospholipid-acylation reaction. This agrees with direct localization and multi-pass topology reported in PMID:18458083. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-1482691 | ACCEPT | Summary: Accepted as the ER-membrane location of the curated lysophospholipid acylation event. Reason: Reactome:R-HSA-1482691 places LPCAT4 in an ER-membrane phospholipid-acylation reaction. This agrees with direct localization and multi-pass topology reported in PMID:18458083. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-75885 | ACCEPT | Summary: Accepted as the ER-membrane location of the curated lysophospholipid acylation event. Reason: Reactome:R-HSA-75885 places LPCAT4 in an ER-membrane phospholipid-acylation reaction. This agrees with direct localization and multi-pass topology reported in PMID:18458083. |
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Download this section (compressed HTML)Q: Which positional LPC, LPE, and LPS species and which saturated or unsaturated acyl-CoAs are the dominant endogenous human LPCAT4 substrates?
Q: Does LPCAT4 acylate endogenous 1-acyl LPG at free sn-2, and does that activity contribute measurably to PG remodeling in vivo?
Q: What functions do LPCAT4-generated sn-1-unsaturated phospholipids serve in human neurons and other high-expression cell types?
Q: How do LPCAT4 membrane topology and active-site architecture determine sn-1, headgroup, and unsaturated-acyl-donor selectivity?
Q: Are liver-endocrine and HCC phenotypes caused by LPCAT4 catalytic products at endogenous expression levels?
Q: Are any endogenous LPCAT4 protein isoforms or stable regulatory partners functionally distinct?
Experiment: Perform endogenous knockout and genomic rescue in human neuronal, epithelial, and hepatic models, using stable-isotope acyl donors and position-resolved lipidomics to quantify acceptor competition, donor kinetics, and PC/PE/PS product flux.
Hypothesis: Endogenous human LPCAT4 preferentially uses sn-2 LPC, LPE, and LPS with unsaturated acyl-CoAs, but substrate ranking differs by cell type.
Type: endogenous positional phospholipid flux profiling
Experiment: Assay matched LPCAT4 preparations against sn-1 and sn-2 LPG panels while varying acyl donor, membrane composition, detergent, enzyme abundance, and time; confirm PG positional products by orthogonal mass spectrometry and compare endogenous PG flux after knockout/rescue.
Hypothesis: LPCAT4 supports 1-acyl LPG acylation at free sn-2 but not 2-acyl LPG acylation at free sn-1, yielding position-dependent rather than universal PG remodeling.
Type: LPG discrepancy resolution
Experiment: Create catalytic-null and rescue human neuronal models, restore individual positional PC/PE/PS species with controlled delivery or orthogonal enzymes, and measure membrane order, organelle dynamics, electrophysiology, and stress responses.
Hypothesis: Selected sn-1-unsaturated phospholipids generated by LPCAT4 alter neuronal membrane organization and signaling.
Type: positional-lipid function dissection
Experiment: Map ER-membrane orientation, determine substrate-bound structures, mutate candidate access-channel and catalytic residues, and test rescue of positional lipid products at the endogenous locus.
Hypothesis: Specific active-site and membrane-facing residues determine LPCAT4 preference for sn-2 lysophospholipids and unsaturated acyl-CoAs.
Type: membrane topology and structure-function analysis
Experiment: Compare endogenous knockout, catalytic-dead rescue, and expression-matched wild-type rescue in primary human hepatocyte/beta-cell co-culture and HCC organoids while measuring positional lipids, insulin secretion, cholesterol flux, WNT-c-JUN activity, and ACSL3 abundance.
Hypothesis: Endogenous LPCAT4 catalytic activity, rather than overexpression alone, drives only a subset of the reported liver-endocrine and HCC signaling phenotypes.
Type: context-bounded catalytic causality
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The endogenous acceptor and acyl-CoA usage of human LPCAT4 is not quantitatively resolved across native tissues and cell types.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Heterologous human-enzyme assays support LPC, LPE, and LPS reacylation and favor sn-2 acceptors and unsaturated acyl-CoAs. The in-vivo positional lipidomic validation is from mouse brain, so substrate flux and donor competition in endogenous human cells remain uncertain.
Significance: Native substrate competition determines which PC, PE, and PS species LPCAT4 actually produces and whether the prominent LPE activity observed in one assay dominates physiologically.
What would resolve it: Use isotope-resolved flux lipidomics after endogenous LPCAT4 knockout and genomic rescue in human neuronal and non-neuronal cells, quantifying positional LPC, LPE, and LPS acceptors together with saturated and unsaturated acyl-CoAs.
Gap: The physiological extent of LPCAT4-dependent 1-acyl LPG acylation and phosphatidylglycerol remodeling is unresolved.
OPEN BIOLOGYCURATION
What is known: PMID:18458083 detected LPG activity without resolving acceptor position, consistent with acylation of 1-acyl LPG at free sn-2. PMID:41740885 found no activity toward 2-acyl LPG at free sn-1. Both studies agree on LPC, LPE, and LPS substrates and on absence of LPA acylation.
Significance: Establishing endogenous 1-acyl LPG flux is necessary before PG remodeling can be treated as a physiological LPCAT4 process; the 2-acyl LPG reaction is already contradicted by position-resolved evidence.
What would resolve it: Quantify 1-acyl and 2-acyl LPG separately using purified or matched membrane preparations and endogenous knockout/rescue, with position-resolved products, catalytic-dead controls, and orthogonal mass-spectrometric confirmation.
Gap: The biological roles of LPCAT4-generated phospholipids carrying unsaturated fatty acids at sn-1 are unknown in human cells.
OPEN BIOLOGY
What is known: Lplat10-deficient mouse brain selectively loses sn-1-unsaturated PC, PE, and PS species, but the knockout showed no overt cerebellar histological abnormality and the functional consequences of these low-abundance lipids remain unclear.
Significance: These products may alter membrane physical properties, neuronal signaling, or lipid-mediated communication despite their low abundance.
What would resolve it: Engineer human neuronal models with catalytic LPCAT4 loss and rescue, restore selected positional lipid species independently, and measure membrane order, organelle dynamics, electrophysiology, and stress responses alongside positional lipidomics.
Gap: The membrane orientation and structure-based determinants of LPCAT4 acceptor position, phospholipid headgroup, and acyl-CoA selectivity are not established.
OPEN BIOLOGY
What is known: LPCAT4 is an integral ER-membrane enzyme with two predicted transmembrane helices, but the reviewed primary studies do not resolve its topology, active-site orientation, or substrate-entry routes.
Significance: A mechanistic model is needed to explain sn-1 selectivity, preference for unsaturated donors, and the position-dependent LPG result.
What would resolve it: Determine membrane topology experimentally and solve LPCAT4 structures with acyl-CoA and position-defined lysophospholipid analogs, followed by endogenous mutational rescue and comprehensive substrate profiling.
Gap: The physiological relevance of reported liver-endocrine and hepatocellular-carcinoma phenotypes to endogenous human LPCAT4 activity remains uncertain.
OPEN BIOLOGY
What is known: Increased insulin secretion followed adenoviral LPLAT10 overexpression in mouse liver, where basal expression is low. The WNT-beta-catenin-c-JUN-ACSL3 result is from hepatocellular-carcinoma models and association analyses rather than normal human liver physiology.
Significance: These contexts could reflect specific lipid products or nonphysiological enzyme abundance and should not be generalized without endogenous perturbation.
What would resolve it: Perturb endogenous LPCAT4 in primary human hepatocyte, beta-cell co-culture, and genotype-defined HCC organoid models, then couple positional lipidomics to insulin-secretion, cholesterol-flux, WNT, c-JUN, and ACSL3 measurements with catalytic rescue controls.
Gap: Functionally distinct endogenous LPCAT4 protein isoforms and stable LPCAT4-containing complexes have not been demonstrated.
OPEN BIOLOGYCURATION
What is known: The reviewed UniProt record lists no alternative protein isoforms; old sequence cautions reflect cloning discrepancies. No reviewed evidence establishes a stable complex required for catalysis or localization.
Significance: Unsupported isoform or complex assumptions could obscure regulation of the enzyme and misinterpret transcript or interaction datasets.
What would resolve it: Reconcile full-length transcripts by long-read sequencing and proteomics, and combine endogenous proximity labeling with reciprocal interaction and genetic perturbation to identify reproducible regulatory partners without assuming constitutive complex membership.
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