CRLS1 (cardiolipin synthase 1, CLS1, formerly C20orf155) is the human cardiolipin synthase of the CDP-alcohol phosphatidyltransferase family. It is a multipass integral protein of the mitochondrial inner membrane that catalyses the final, committed step of de novo cardiolipin synthesis, transferring a phosphatidyl group from CDP-diacylglycerol to phosphatidylglycerol to form cardiolipin and CMP. The enzyme has an alkaline pH optimum and requires a divalent cation. It acts downstream of TAMM41 (CDP-DAG synthesis), PGS1 and PTPMT1 (phosphatidylglycerol synthesis), with which it associates in mitochondrial complexes, and upstream of acyl-chain remodeling by tafazzin. It is unrelated to the phospholipase D-type cardiolipin synthases of bacteria and some protists (2 PG -> CL + glycerol); humans have only the CDP-type enzyme. CRLS1 is most highly expressed in heart, skeletal muscle and liver. Cardiolipin produced by CRLS1 is required for cristae structure, respiratory chain organization and mitochondrial biogenesis: Crls1 null mice die around implantation, tissue-specific knockouts cause neurodegeneration or neonatal heart failure, and biallelic human variants cause an autosomal recessive multisystem mitochondrial encephalopathy (COXPD57) with reduced cardiolipin and accumulated phosphatidylglycerol. A single study has reported an additional acyl-CoA-dependent lysophosphatidylglycerol acyltransferase activity, which has not been independently confirmed.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003841 1-acylglycerol-3-phosphate O-acyltransferase activity | TAS Reactome:R-HSA-1482689 | REMOVE | Summary: Reactome 1-acyl-LPG acylation event mapped to 1-acylglycerol-3-phosphate (LPA) O-acyltransferase activity; wrong substrate and doubtful underlying activity. Reason: This Reactome-derived TAS asserts lysophosphatidic acid (LPA) acyltransferase activity (acyl-CoA + acyl-sn-glycerol-3-phosphate -> phosphatidate). The Reactome event it comes from describes acylation of lysophosphatidylglycerol (LPG) to phosphatidylglycerol, not of LPA; LPA and LPG differ in head group, so the mapped GO term names a reaction that has never been reported for CRLS1. The underlying LPG acyltransferase claim itself rests on a single report from one laboratory (Nie et al. 2010, PMID:20025994), has not been independently replicated, is mechanistically unusual for a CDP-alcohol phosphatidyltransferase-fold enzyme that has no acyltransferase motif, and used LPGAT1 as its positive control - a protein whose LPG acyltransferase assignment has since been questioned (see the human LPGAT1 review). Because the annotation is a curator-statement (TAS) mapping onto the wrong substrate class rather than an experimental assertion, removal is appropriate. Whether CRLS1 should instead carry a lysophospholipid acyltransferase term is raised as a suggested question rather than proposed as a replacement. Supporting Evidence: PMID:20025994 In this report, we identified a novel function of the hCLS1 enzyme as an acyl-CoA dependent LPG acyltransferase. file:human/CRLS1/CRLS1-uniprot.txt Belongs to the CDP-alcohol phosphatidyltransferase class-I |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: CRLS1 detected in the high-confidence human mitochondrial proteome (MitoCoP). Reason: CRLS1 is a mitochondrial inner membrane enzyme; mitochondrion is a correct, if less specific, location. Recombinant hCLS1 localizes to mitochondria by immunofluorescence and subcellular fractionation, and the protein has five predicted transmembrane helices consistent with the UniProt inner-membrane assignment. The HTP proteomic detection is consistent with the targeted studies. Supporting Evidence: PMID:34800366 it is crucial to establish a high-confidence inventory of the human mitochondrial proteome PMID:16716149 recombinant hCLS1 protein was localized to the mitochondria when transiently |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of mitochondrial localization across the CDP-type cardiolipin synthase clade. Reason: The PANTHER node covers eukaryotic CDP-type cardiolipin synthases (yeast Crd1-like, plant, fission yeast and animal orthologs), all of which act in mitochondria. Human CRLS1 lies inside this clade and has its own direct localization evidence, which is why it appears among the descendant evidence. No evidence of lineage-specific relocation. CRLS1 is a mitochondrial inner membrane enzyme; mitochondrion is a correct, if less specific, location. Recombinant hCLS1 localizes to mitochondria by immunofluorescence and subcellular fractionation, and the protein has five predicted transmembrane helices consistent with the UniProt inner-membrane assignment. Supporting Evidence: PMID:16716149 recombinant hCLS1 protein was localized to the mitochondria when transiently file:human/CRLS1/CRLS1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0005739 mitochondrion | IDA PMID:16716149 Identification and functional characterization of hCLS1, a h... | ACCEPT | Summary: Recombinant hCLS1 localized to mitochondria by immunostaining and subcellular fractionation in COS-7 cells. Reason: CRLS1 is a mitochondrial inner membrane enzyme; mitochondrion is a correct, if less specific, location. Recombinant hCLS1 localizes to mitochondria by immunofluorescence and subcellular fractionation, and the protein has five predicted transmembrane helices consistent with the UniProt inner-membrane assignment. Supporting Evidence: PMID:16716149 recombinant hCLS1 protein was localized to the mitochondria when transiently PMID:16716149 subcellular fractionation analyses of the recombinant hCLS1 protein. |
| GO:0005739 mitochondrion | IDA PMID:38322995 Mieap forms membrane-less organelles involved in cardiolipin... | ACCEPT | Summary: EGFP-CRLS1 imaged in mitochondria (inner membrane, Mieap-depleted phase of Mieap condensates). Reason: CRLS1 is a mitochondrial inner membrane enzyme; mitochondrion is a correct, if less specific, location. Recombinant hCLS1 localizes to mitochondria by immunofluorescence and subcellular fractionation, and the protein has five predicted transmembrane helices consistent with the UniProt inner-membrane assignment. Ikari et al. use EGFP-CRLS1 as an inner mitochondrial membrane marker in live-cell imaging; the 'is_active_in' qualifier is appropriate for the site of cardiolipin synthesis. Supporting Evidence: PMID:38322995 EGFP-CRLS1 (the inner mitochondrial membrane) PMID:38322995 Mi-BCs compartmentalize and concentrate all four sequential enzymes for CL biosynthesis (TAMM41, PGS1, PTPMT1, and CRLS1) |
| GO:0005743 mitochondrial inner membrane | EXP PMID:16547353 Cloning and characterization of a cDNA encoding human cardio... | ACCEPT | Summary: Inner mitochondrial membrane localization of hCLS1 (UniProt cites this paper for the IM assignment). Reason: CRLS1 is a multipass integral protein of the mitochondrial inner membrane, where de novo cardiolipin synthesis occurs; this is the most specific well-supported cellular component and is a core location. The cached record is abstract-only; the abstract establishes mitochondrial CL synthesis, and the curator-assigned inner-membrane localization from the full text is consistent with all other evidence, so the annotation is accepted. Supporting Evidence: PMID:16547353 These results demonstrate that hCLS1 encodes an enzyme that synthesizes CL. file:human/CRLS1/CRLS1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane PMID:38322995 EGFP-CRLS1 (the inner mitochondrial membrane) |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular location keyword mapping (Mitochondrion inner membrane). Reason: CRLS1 is a multipass integral protein of the mitochondrial inner membrane, where de novo cardiolipin synthesis occurs; this is the most specific well-supported cellular component and is a core location. Supporting Evidence: file:human/CRLS1/CRLS1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Transfer from Arabidopsis CLS (Q93YW7), an inner-membrane CDP-type cardiolipin synthase. Reason: CRLS1 is a multipass integral protein of the mitochondrial inner membrane, where de novo cardiolipin synthesis occurs; this is the most specific well-supported cellular component and is a core location. Sequence similarity transfer from the plant ortholog is consistent with direct human evidence. Supporting Evidence: file:human/CRLS1/CRLS1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane PMID:38322995 EGFP-CRLS1 (the inner mitochondrial membrane) |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-1482546 | ACCEPT | Summary: Reactome LPG-acylation event places CRLS1 in the inner mitochondrial membrane. Reason: CRLS1 is a multipass integral protein of the mitochondrial inner membrane, where de novo cardiolipin synthesis occurs; this is the most specific well-supported cellular component and is a core location. The location is correct even though the specific Reactome reaction (LPG acylation) is doubtful; the location claim is independent of that reaction. Supporting Evidence: file:human/CRLS1/CRLS1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane PMID:38322995 EGFP-CRLS1 (the inner mitochondrial membrane) |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-1482689 | ACCEPT | Summary: Reactome LPG-acylation event places CRLS1 in the inner mitochondrial membrane. Reason: CRLS1 is a multipass integral protein of the mitochondrial inner membrane, where de novo cardiolipin synthesis occurs; this is the most specific well-supported cellular component and is a core location. The location is correct even though the specific Reactome reaction (LPG acylation) is doubtful; the location claim is independent of that reaction. Supporting Evidence: file:human/CRLS1/CRLS1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane PMID:38322995 EGFP-CRLS1 (the inner mitochondrial membrane) |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-1483063 | ACCEPT | Summary: Reactome cardiolipin synthesis event (PG + CDP-DAG -> CL) at the inner mitochondrial membrane. Reason: CRLS1 is a multipass integral protein of the mitochondrial inner membrane, where de novo cardiolipin synthesis occurs; this is the most specific well-supported cellular component and is a core location. Supporting Evidence: Reactome:R-HSA-1483063 converts phosphatidylglycerol (PG) and cytidine diphosphate-diacylglycerol (CDP-DAG) into cardiolipin (CL) file:human/CRLS1/CRLS1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0008654 phospholipid biosynthetic process | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO (IPR000462, CDP-alcohol phosphatidyltransferase) mapping to phospholipid biosynthesis. Reason: Correct but general: all CDP-alcohol phosphatidyltransferases make phospholipids, and CRLS1 makes cardiolipin. The more specific cardiolipin biosynthetic process (GO:0032049) is already annotated, so this broad IEA is harmless and consistent with the CDP-type mechanism. Supporting Evidence: file:human/CRLS1/CRLS1-uniprot.txt Belongs to the CDP-alcohol phosphatidyltransferase class-I PMID:16716149 cardiolipin in vitro using CDP-DAG and PG as substrates. |
| GO:0016020 membrane | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO mapping to membrane. Reason: Correct but very general; CRLS1 is an integral inner mitochondrial membrane protein (GO:0005743 is the informative term). Supporting Evidence: file:human/CRLS1/CRLS1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0016780 phosphotransferase activity, for other substituted phosphate groups | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO (IPR000462) mapping to phosphotransferase activity, for other substituted phosphate groups. Reason: This is an is_a ancestor of cardiolipin synthase (CMP-forming) activity (GO:0043337, via phosphatidyltransferase activity GO:0030572) and correctly reflects the CDP-alcohol phosphatidyltransferase mechanism, in which a phosphatidyl group is transferred from CDP-DAG to an alcohol acceptor with release of CMP. Importantly it is on the CDP-type branch, not the phospholipase D-type cardiolipin synthase activity (GO:0008808, 2 PG -> CL + glycerol), which humans lack. Correct but general; GO:0043337 is the informative term. Supporting Evidence: file:human/CRLS1/CRLS1-uniprot.txt Belongs to the CDP-alcohol phosphatidyltransferase class-I PMID:16716149 cardiolipin in vitro using CDP-DAG and PG as substrates. |
| GO:0031966 mitochondrial membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Transfer from Arabidopsis CLS (Q93YW7) of mitochondrial membrane. Reason: Correct, though less specific than mitochondrial inner membrane (GO:0005743), which is also annotated. Supporting Evidence: file:human/CRLS1/CRLS1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0032049 cardiolipin biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of cardiolipin biosynthesis across eukaryotic CDP-type cardiolipin synthases. Reason: CRLS1 catalyses the final, committed step of de novo cardiolipin synthesis (CDP-DAG + PG -> CL + CMP), so it directly performs a step of this process. Evidence: complementation of yeast crd1 null, in vitro activity of recombinant enzyme, increased CL on overexpression, and decreased CL with PG accumulation in patient fibroblasts and knockout cells. The PANTHER node unites the yeast, plant, worm, mouse and human CDP-type CLS orthologs; CRLS1 is inside this clade with its own experimental support. Supporting Evidence: PMID:16678169 candidate cDNA in the (cardiolipin synthase-deficient) crd1Delta yeast confirmed PMID:16716149 cardiolipin in vitro using CDP-DAG and PG as substrates. |
| GO:0032049 cardiolipin biosynthetic process | IDA PMID:16678169 Identification and characterization of human cardiolipin syn... | ACCEPT | Summary: Human cardiolipin synthase identified by complementation of yeast crd1 and characterized in purified mitochondria. Reason: CRLS1 catalyses the final, committed step of de novo cardiolipin synthesis (CDP-DAG + PG -> CL + CMP), so it directly performs a step of this process. Evidence: complementation of yeast crd1 null, in vitro activity of recombinant enzyme, increased CL on overexpression, and decreased CL with PG accumulation in patient fibroblasts and knockout cells. Supporting Evidence: PMID:16678169 candidate cDNA in the (cardiolipin synthase-deficient) crd1Delta yeast confirmed PMID:16678169 that it indeed encodes human cardiolipin synthase |
| GO:0032049 cardiolipin biosynthetic process | IDA PMID:16716149 Identification and functional characterization of hCLS1, a h... | ACCEPT | Summary: Recombinant hCLS1 synthesizes CL in vitro and increases CL synthesis in COS-7 cells. Reason: CRLS1 catalyses the final, committed step of de novo cardiolipin synthesis (CDP-DAG + PG -> CL + CMP), so it directly performs a step of this process. Evidence: complementation of yeast crd1 null, in vitro activity of recombinant enzyme, increased CL on overexpression, and decreased CL with PG accumulation in patient fibroblasts and knockout cells. Supporting Evidence: PMID:16716149 hCLS1 enzyme expressed in COS-7 cells catalysed efficiently the synthesis of PMID:16716149 cardiolipin in vitro using CDP-DAG and PG as substrates. |
| GO:0032049 cardiolipin biosynthetic process | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer from mouse Crls1. Reason: CRLS1 catalyses the final, committed step of de novo cardiolipin synthesis (CDP-DAG + PG -> CL + CMP), so it directly performs a step of this process. Evidence: complementation of yeast crd1 null, in vitro activity of recombinant enzyme, increased CL on overexpression, and decreased CL with PG accumulation in patient fibroblasts and knockout cells. Supporting Evidence: PMID:16716149 cardiolipin in vitro using CDP-DAG and PG as substrates. PMID:31914590 embryonic lethality at the peri-implantation stage |
| GO:0032049 cardiolipin biosynthetic process | TAS PMID:38322995 Mieap forms membrane-less organelles involved in cardiolipin... | ACCEPT | Summary: Mieap paper describes CRLS1 as one of the four sequential CL biosynthetic enzymes. Reason: CRLS1 catalyses the final, committed step of de novo cardiolipin synthesis (CDP-DAG + PG -> CL + CMP), so it directly performs a step of this process. Evidence: complementation of yeast crd1 null, in vitro activity of recombinant enzyme, increased CL on overexpression, and decreased CL with PG accumulation in patient fibroblasts and knockout cells. Supporting Evidence: PMID:38322995 Mi-BCs compartmentalize and concentrate all four sequential enzymes for CL biosynthesis (TAMM41, PGS1, PTPMT1, and CRLS1) |
| GO:0032049 cardiolipin biosynthetic process | TAS Reactome:R-HSA-1483076 | ACCEPT | Summary: Reactome 'Synthesis of CL' pathway membership. Reason: CRLS1 catalyses the final, committed step of de novo cardiolipin synthesis (CDP-DAG + PG -> CL + CMP), so it directly performs a step of this process. Evidence: complementation of yeast crd1 null, in vitro activity of recombinant enzyme, increased CL on overexpression, and decreased CL with PG accumulation in patient fibroblasts and knockout cells. Supporting Evidence: Reactome:R-HSA-1483063 converts phosphatidylglycerol (PG) and cytidine diphosphate-diacylglycerol (CDP-DAG) into cardiolipin (CL) |
| GO:0036148 phosphatidylglycerol acyl-chain remodeling | TAS Reactome:R-HSA-1482925 | UNDECIDED | Summary: Reactome places CRLS1 in PG acyl-chain remodeling on the basis of a single report of LPG acyltransferase activity. Reason: The only evidence that CRLS1 participates in phosphatidylglycerol remodeling is Nie et al. 2010 (PMID:20025994), which reported CDP-DAG-independent, acyl-CoA-dependent LPG acyltransferase activity of recombinant and purified hCLS1. The data are internally consistent in that paper, but the activity has not been replicated by other groups, is chemically distinct from the CDP-alcohol phosphatidyltransferase mechanism of the enzyme, and relied on LPGAT1 as a positive control whose own substrate assignment has since been revised. In contrast, CRLS1 is firmly established as a consumer of PG for de novo cardiolipin synthesis (patient cells accumulate PG). Neither accepting nor removing this process is well supported; independent confirmation of the acyltransferase activity is needed. Supporting Evidence: PMID:20025994 In this report, we identified a novel function of the hCLS1 enzyme as an acyl-CoA dependent LPG acyltransferase. PMID:20025994 The LPG acyltransferase activity of the hCLS1 enzyme did not require the presence of CDP-DAG, suggesting that the LPG acyltransferase activity of hCLS1 enzyme is independent from its CL synthase activity. PMID:35147173 levels of phosphatidylglycerol, the substrate of CRLS1 |
| GO:0043337 cardiolipin synthase (CMP-forming) activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of CMP-forming cardiolipin synthase activity. Reason: Core function. CRLS1 is the eukaryotic CDP-alcohol phosphatidyltransferase-type cardiolipin synthase (EC 2.7.8.41), transferring a phosphatidyl group from CDP-diacylglycerol to phosphatidylglycerol with release of CMP. The GO term definition matches exactly this (CDP-type) reaction, not the PLD-type 2 PG -> CL + glycerol reaction. Three independent groups established the activity in 2006. The PAINT node is seeded by experimentally characterized yeast Crd1, Arabidopsis CLS, fission yeast and human CRLS1; CRLS1 is within the clade and retains the CDP-alcohol phosphotransferase motif. Supporting Evidence: PMID:16678169 candidate cDNA in the (cardiolipin synthase-deficient) crd1Delta yeast confirmed PMID:16716149 cardiolipin in vitro using CDP-DAG and PG as substrates. file:human/CRLS1/CRLS1-uniprot.txt Belongs to the CDP-alcohol phosphatidyltransferase class-I |
| GO:0043337 cardiolipin synthase (CMP-forming) activity | IDA PMID:16678169 Identification and characterization of human cardiolipin syn... | ACCEPT | Summary: Activity demonstrated in mitochondria of crd1-null yeast expressing human CLS; pH optimum and cation dependence characterized. Reason: Core function. CRLS1 is the eukaryotic CDP-alcohol phosphatidyltransferase-type cardiolipin synthase (EC 2.7.8.41), transferring a phosphatidyl group from CDP-diacylglycerol to phosphatidylglycerol with release of CMP. The GO term definition matches exactly this (CDP-type) reaction, not the PLD-type 2 PG -> CL + glycerol reaction. Three independent groups established the activity in 2006. Supporting Evidence: PMID:16678169 candidate cDNA in the (cardiolipin synthase-deficient) crd1Delta yeast confirmed PMID:16678169 that it indeed encodes human cardiolipin synthase |
| GO:0043337 cardiolipin synthase (CMP-forming) activity | IDA PMID:16716149 Identification and functional characterization of hCLS1, a h... | ACCEPT | Summary: Recombinant hCLS1 catalyses CL synthesis from CDP-DAG and PG in vitro. Reason: Core function. CRLS1 is the eukaryotic CDP-alcohol phosphatidyltransferase-type cardiolipin synthase (EC 2.7.8.41), transferring a phosphatidyl group from CDP-diacylglycerol to phosphatidylglycerol with release of CMP. The GO term definition matches exactly this (CDP-type) reaction, not the PLD-type 2 PG -> CL + glycerol reaction. Three independent groups established the activity in 2006. Supporting Evidence: PMID:16716149 hCLS1 enzyme expressed in COS-7 cells catalysed efficiently the synthesis of PMID:16716149 cardiolipin in vitro using CDP-DAG and PG as substrates. |
| GO:0043337 cardiolipin synthase (CMP-forming) activity | IEA GO_REF:0000120 | ACCEPT | Summary: Combined IEA from Rhea RHEA:32931 / EC 2.7.8.41. Reason: Core function. CRLS1 is the eukaryotic CDP-alcohol phosphatidyltransferase-type cardiolipin synthase (EC 2.7.8.41), transferring a phosphatidyl group from CDP-diacylglycerol to phosphatidylglycerol with release of CMP. The GO term definition matches exactly this (CDP-type) reaction, not the PLD-type 2 PG -> CL + glycerol reaction. Three independent groups established the activity in 2006. RHEA:32931 is the CDP-diacylglycerol + PG reaction, matching the CDP-type mechanism. Supporting Evidence: PMID:16716149 cardiolipin in vitro using CDP-DAG and PG as substrates. |
| GO:0043337 cardiolipin synthase (CMP-forming) activity | IMP PMID:35147173 Deleterious variants in CRLS1 lead to cardiolipin deficiency... | ACCEPT | Summary: Patient CRLS1 variants reduce CL and raise PG; wild-type CRLS1 rescues mitochondrial morphology. Reason: Core function. CRLS1 is the eukaryotic CDP-alcohol phosphatidyltransferase-type cardiolipin synthase (EC 2.7.8.41), transferring a phosphatidyl group from CDP-diacylglycerol to phosphatidylglycerol with release of CMP. The GO term definition matches exactly this (CDP-type) reaction, not the PLD-type 2 PG -> CL + glycerol reaction. Three independent groups established the activity in 2006. Patient fibroblasts with biallelic variants show reduced CL and increased substrate PG, consistent with loss of the enzyme activity in cells. Supporting Evidence: PMID:35147173 These data functionally validate the pathogenicity of the CRLS1 variants, illustrating that they cause decreased CL levels, altered acyl-chain composition and elevated levels of PG. PMID:35147173 levels of phosphatidylglycerol, the substrate of CRLS1 |
| GO:0043337 cardiolipin synthase (CMP-forming) activity | TAS Reactome:R-HSA-1483063 | ACCEPT | Summary: Reactome reaction: PG and CDP-DAG are converted to CL by CRLS1. Reason: Core function. CRLS1 is the eukaryotic CDP-alcohol phosphatidyltransferase-type cardiolipin synthase (EC 2.7.8.41), transferring a phosphatidyl group from CDP-diacylglycerol to phosphatidylglycerol with release of CMP. The GO term definition matches exactly this (CDP-type) reaction, not the PLD-type 2 PG -> CL + glycerol reaction. Three independent groups established the activity in 2006. Supporting Evidence: Reactome:R-HSA-1483063 converts phosphatidylglycerol (PG) and cytidine diphosphate-diacylglycerol (CDP-DAG) into cardiolipin (CL) PMID:16716149 cardiolipin in vitro using CDP-DAG and PG as substrates. |
| GO:0046474 glycerophospholipid biosynthetic process | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA machine-learning mapping to glycerophospholipid biosynthetic process. Reason: Correct but general ancestor of cardiolipin biosynthetic process (GO:0032049), which is the informative annotation. Supporting Evidence: PMID:16716149 cardiolipin in vitro using CDP-DAG and PG as substrates. |
| GO:0047144 2-acylglycerol-3-phosphate O-acyltransferase activity | TAS Reactome:R-HSA-1482546 | REMOVE | Summary: Reactome 2-acyl-LPG acylation event mapped to 2-acylglycerol-3-phosphate (LPA) O-acyltransferase activity; wrong substrate and doubtful underlying activity. Reason: This Reactome-derived TAS asserts lysophosphatidic acid (LPA) acyltransferase activity (acyl-CoA + acyl-sn-glycerol-3-phosphate -> phosphatidate). The Reactome event it comes from describes acylation of lysophosphatidylglycerol (LPG) to phosphatidylglycerol, not of LPA; LPA and LPG differ in head group, so the mapped GO term names a reaction that has never been reported for CRLS1. The underlying LPG acyltransferase claim itself rests on a single report from one laboratory (Nie et al. 2010, PMID:20025994), has not been independently replicated, is mechanistically unusual for a CDP-alcohol phosphatidyltransferase-fold enzyme that has no acyltransferase motif, and used LPGAT1 as its positive control - a protein whose LPG acyltransferase assignment has since been questioned (see the human LPGAT1 review). Because the annotation is a curator-statement (TAS) mapping onto the wrong substrate class rather than an experimental assertion, removal is appropriate. Whether CRLS1 should instead carry a lysophospholipid acyltransferase term is raised as a suggested question rather than proposed as a replacement. Supporting Evidence: PMID:20025994 In this report, we identified a novel function of the hCLS1 enzyme as an acyl-CoA dependent LPG acyltransferase. file:human/CRLS1/CRLS1-uniprot.txt Belongs to the CDP-alcohol phosphatidyltransferase class-I |
Loading supporting content…
Download this section (compressed HTML)Q: Does CRLS1 really have acyl-CoA-dependent lysophosphatidylglycerol acyltransferase activity (Nie et al. 2010)? If confirmed, the appropriate MF would be a lysophospholipid acyltransferase term rather than the lysophosphatidic acid acyltransferase terms (GO:0003841, GO:0047144) Reactome mapped; if not, the Reactome LPG-acylation and PG remodeling events for CRLS1 should be retired.
Suggested experts: Reactome lipid metabolism curators, Vaz lab, Hatch lab
Q: Is CRLS1 a stable subunit of a defined cardiolipin-synthesizing complex with PGS1 and PTPMT1 (700-800 kDa), and if so, should a protein-containing complex term be created?
Suggested experts: McQuibban lab
Q: Do the PANTHER/InterPro family-level transfers for cardiolipin synthase in protists correctly distinguish CDP-type (PTHR14269/IPR000462) from PLD-type (GO:0008808) enzymes in species that carry both, as reconstructed for LECA?
Suggested experts: PAINT curators
Experiment: Assay purified wild-type CRLS1 and a catalytic CDP-alcohol phosphotransferase motif mutant for acyl-CoA:LPG acyltransferase activity in parallel with CMP-forming CL synthase activity, and measure LPG and PG acyl profiles in CRLS1-knockout versus rescued cells by lipidomics.
Hypothesis: The LPG acyltransferase activity reported for hCLS1 is intrinsic to the enzyme rather than a co-purifying activity.
Type: biochemical
Experiment: Express each COXPD57 variant in crd1-null yeast and CRLS1-knockout human cells; measure CL synthase activity in isolated mitochondria, protein abundance and inner-membrane localization.
Hypothesis: Pathogenic CRLS1 variants reduce catalytic activity rather than protein stability or localization.
Type: biochemical
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)