COASY is the human bifunctional coenzyme A synthase, a single polypeptide that carries out the last two of the five steps of de novo coenzyme A (CoA) biosynthesis from pantothenate (vitamin B5). Its N-terminal/central phosphopantetheine adenylyltransferase (PPAT) domain adenylylates (R)-4'-phosphopantetheine using ATP to form 3'-dephospho-CoA, and its C-terminal dephospho-CoA kinase (DPCK) domain then phosphorylates 3'-dephospho-CoA using ATP to generate CoA. CoA and its acyl-CoA thioesters are ubiquitous acyl-group carriers essential for fatty acid metabolism, the TCA cycle, and many other pathways. The enzyme functions predominantly in the cytosol, where the bulk of de novo CoA synthesis occurs, with a minor pool associated with mitochondria. It is expressed in essentially all tissues, with a brain-enriched splice isoform. Loss-of-function mutations in COASY cause neurodegeneration with brain iron accumulation (COASY protein-associated neurodegeneration, CoPAN/NBIA6) and pontocerebellar hypoplasia type 12.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004140 dephospho-CoA kinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Dephospho-CoA kinase (DPCK) is one of the two well-established catalytic activities of COASY, corresponding to the fifth/final step of CoA biosynthesis (EC 2.7.1.24). The phylogenetic (IBA) inference is fully consistent with direct experimental evidence for the human protein. Core molecular function. Supporting Evidence: file:human/COASY/COASY-uniprot.txt Reaction=3'-dephospho-CoA + ATP = ADP + CoA + H(+); file:human/COASY/COASY-uniprot.txt the fifth step, the phosphorylation of dephospho-CoA to CoA. |
| GO:0015937 coenzyme A biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: Coenzyme A biosynthetic process is the core biological process for COASY, which catalyzes the last two steps of this pathway. IBA inference is consistent with experimental evidence. Core process. Supporting Evidence: file:human/COASY/COASY-uniprot.txt Bifunctional enzyme that catalyzes the fourth step of the PMID:11923312 The biosynthesis of CoA from pantothenic acid (vitamin B5) is an essential |
| GO:0004595 pantetheine-phosphate adenylyltransferase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Pantetheine-phosphate (phosphopantetheine) adenylyltransferase (PPAT) is the second of COASY's two catalytic activities, corresponding to the fourth step of CoA biosynthesis (EC 2.7.7.3). The IBA inference matches direct experimental evidence. Core molecular function. Supporting Evidence: file:human/COASY/COASY-uniprot.txt Reaction=(R)-4'-phosphopantetheine + ATP + H(+) = 3'-dephospho-CoA + diphosphate file:human/COASY/COASY-uniprot.txt the fourth step of the coenzyme A biosynthetic pathway, the adenylation of 4'-phosphopantetheine |
| GO:0003824 catalytic activity | IEA GO_REF:0000002 | MODIFY | Summary: Root-level catalytic activity is an uninformative parent of the two specific activities of COASY, PPAT (GO:0004595) and DPCK (GO:0004140), both experimentally established. Reason: The generic InterPro2GO term is correct but uninformative; both specific activities are experimentally established and already carried by this gene, so both are proposed. Proposed replacements: pantetheine-phosphate adenylyltransferase activity dephospho-CoA kinase activity Supporting Evidence: file:human/COASY/COASY-uniprot.txt Bifunctional enzyme that catalyzes the fourth step of the coenzyme A biosynthetic pathway, the adenylation of 4'- phosphopantetheine, and the fifth step, the phosphorylation of dephospho-CoA to CoA. |
| GO:0004140 dephospho-CoA kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (ARBA/RHEA/EC) inference of the DPCK activity. Correct and consistent with the experimental annotations; redundant with the IDA/EXP evidence for the same term but not wrong. Core molecular function captured by better evidence elsewhere. Supporting Evidence: file:human/COASY/COASY-uniprot.txt Bifunctional enzyme that catalyzes the fourth step of the coenzyme A biosynthetic pathway, the adenylation of 4'- phosphopantetheine, and the fifth step, the phosphorylation of dephospho-CoA to CoA. |
| GO:0004595 pantetheine-phosphate adenylyltransferase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (ARBA/RHEA/EC) inference of the PPAT activity. Correct and consistent with the experimental annotations; redundant with the IDA/EXP evidence for the same term. Core molecular function captured by better evidence elsewhere. Supporting Evidence: file:human/COASY/COASY-uniprot.txt Bifunctional enzyme that catalyzes the fourth step of the coenzyme A biosynthetic pathway, the adenylation of 4'- phosphopantetheine, and the fifth step, the phosphorylation of dephospho-CoA to CoA. |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Both catalytic domains use ATP as a co-substrate (ATP -> AMP/PPi transfer in PPAT; ATP -> ADP transfer in DPCK), and UniProt annotates an ATP-binding P-loop in the DPCK domain. ATP binding is a real molecular feature but is a supporting activity of the two catalytic functions rather than an independent core function. Supporting Evidence: file:human/COASY/COASY-uniprot.txt /ligand="ATP" |
| GO:0005759 mitochondrial matrix | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Electronic mapping from the UniProt "Mitochondrion matrix" subcellular-location term. A minor mitochondrial pool of COASY exists, but recent evidence shows de novo CoA biosynthesis is primarily cytosolic; the matrix location is a genuine but non-core minor localization. Kept as non-core. Supporting Evidence: file:human/COASY/COASY-uniprot.txt Mitochondrion matrix |
| GO:0005829 cytosol | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic mapping from the UniProt "Cytoplasm, cytosol" subcellular-location term. The cytosol is the primary site of COASY function (bulk of de novo CoA synthesis). Consistent with the experimental is_active_in cytosol annotation. Core location. Supporting Evidence: file:human/COASY/COASY-uniprot.txt Cytoplasm, cytosol |
| GO:0015937 coenzyme A biosynthetic process | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic inference of the core CoA biosynthetic process, redundant with the experimental (IDA) annotation to the same term. Correct. Core process. Supporting Evidence: PMID:11923312 the entire pathway from phosphopantothenate to CoA was successfully reconstituted in vitro using a mixture of purified recombinant enzymes |
| GO:0005515 protein binding | IPI PMID:22982864 EDC4 interacts with and regulates the dephospho-CoA kinase a... | REMOVE | Summary: IPI to EDC4. EDC4 forms a complex with CoAsy and inhibits its dephospho-CoA kinase activity in vitro, but bare protein binding records only the interaction. Removed under the GO:0005515 protein-binding policy as uninformative; the interaction itself is not disputed. Reason: Under the project protein-binding policy GO:0005515 is removed as uninformative. The interaction is regulatory input to COASY rather than a COASY activity, so no more informative COASY molecular-function term applies; removal does not mean the interaction is false. Supporting Evidence: PMID:22982864 EDC4 strongly inhibits the dephospho-CoA kinase activity of CoAsy in vitro. |
| GO:0005515 protein binding | IPI PMID:35156780 CFTR interactome mapping using the mammalian membrane two-hy... | REMOVE | Summary: IPI to CFTR from a high-throughput mammalian membrane two-hybrid CFTR-interactome screen. Bare "protein binding" is uninformative, and the biological significance of a COASY-CFTR interaction for COASY's own function is unclear. Removed under the GO:0005515 protein-binding policy as uninformative; the interaction itself is not disputed. Reason: Bare protein binding to CFTR from interactome screens is uninformative under the project protein-binding policy and identifies no COASY function; removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:36012204 Differential CFTR-Interactome Proximity Labeling Procedures ... | REMOVE | Summary: IPI to CFTR from a CFTR-interactome proximity-labeling study. As with the other CFTR hit, this bare "protein binding" annotation is uninformative and of uncertain relevance to COASY function. Removed under the GO:0005515 protein-binding policy as uninformative; the interaction itself is not disputed. Reason: Bare protein binding to CFTR from interactome screens is uninformative under the project protein-binding policy and identifies no COASY function; removal does not mean the interaction is false. |
| GO:0015937 coenzyme A biosynthetic process | TAS Reactome:R-HSA-196783 | ACCEPT | Summary: Reactome pathway "Coenzyme A biosynthesis" — the core biological process, supported by authoritative pathway curation. Core process. Supporting Evidence: Reactome:R-HSA-196783 It is synthesized from the vitamin pantothenate in a sequence of five reactions |
| GO:0004140 dephospho-CoA kinase activity | TAS Reactome:R-HSA-196773 | ACCEPT | Summary: Reactome reaction "COASY phosphorylates DP-CoA" captures the DPCK activity by authoritative pathway curation. Consistent with the experimental evidence. Core molecular function. Supporting Evidence: Reactome:R-HSA-196773 The kinase activity of CoA synthase (COASY) catalyzes the phosphorylation of dephospho-CoA to form Coenzyme A (CoA-SH). |
| GO:0004595 pantetheine-phosphate adenylyltransferase activity | TAS Reactome:R-HSA-196754 | ACCEPT | Summary: Reactome reaction "COASY transfers an adenylyl group from ATP to PPANT" captures the PPAT activity by authoritative pathway curation. Consistent with the experimental evidence. Core molecular function. Supporting Evidence: Reactome:R-HSA-196754 catalyzes the transfer of an adenylyl group from ATP to pantetheinephosphate (PPANT) to form dephospho-Coenzyme A (DP-CoA) |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: HPA immunofluorescence localizes COASY to mitochondria. A minor mitochondrial pool is well documented, though the primary functional site is the cytosol. Kept as a real but non-core localization (experimental evidence, not removed). Supporting Evidence: file:human/COASY/COASY-uniprot.txt Present in the mitochondrial matrix, probably anchored to the inner mitochondrial membrane (PubMed:24360804). |
| GO:0004140 dephospho-CoA kinase activity | EXP PMID:24360804 Exome sequence reveals mutations in CoA synthase as a cause ... | ACCEPT | Summary: Direct experimental (EXP) evidence for the DPCK activity; the R499C NBIA6 variant specifically abolishes dephospho-CoA kinase activity. Core molecular function. Supporting Evidence: PMID:24360804 coupling phosphopantetheine with ATP to form dephospho-CoA and its subsequent phosphorylation to generate CoA. |
| GO:0004595 pantetheine-phosphate adenylyltransferase activity | EXP PMID:24360804 Exome sequence reveals mutations in CoA synthase as a cause ... | ACCEPT | Summary: Direct experimental (EXP) evidence for the PPAT activity from the NBIA6 disease study, which characterized the bifunctional enzyme and its loss-of-function variants. Core molecular function. Supporting Evidence: PMID:24360804 coupling phosphopantetheine with ATP to form dephospho-CoA and its subsequent phosphorylation to generate CoA. |
| GO:0005829 cytosol | IDA PMID:40925986 Cellular pan-chain acyl-CoA profiling reveals SLC25A42/SLC25... | ACCEPT | Summary: Direct evidence that COASY is active in the cytosol: Liu et al. show that despite a small mitochondria-localized fraction, de novo CoA biosynthesis is primarily cytosolic. This is the core functional location, with the correct is_active_in qualifier. Core location. Supporting Evidence: PMID:40925986 de novo CoA biosynthesis is primarily cytosolic |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | KEEP AS NON CORE | Summary: High-throughput mitochondrial proteome localization to mitochondrion. Corroborates the minor mitochondrial pool documented by other methods. Non-core localization; not the primary functional site. Supporting Evidence: PMID:34800366 We classified >8,000 proteins in mitochondrial preparations of human cells and defined a mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP). file:human/COASY/COASY-uniprot.txt Present in the mitochondrial matrix, probably anchored to the inner mitochondrial membrane (PubMed:24360804). |
| GO:0005759 mitochondrial matrix | IDA PMID:24360804 Exome sequence reveals mutations in CoA synthase as a cause ... | KEEP AS NON CORE | Summary: IDA localization of COASY to the mitochondrial matrix (probably anchored to the inner mitochondrial membrane per UniProt). Represents the minor mitochondrial pool; the exact submitochondrial placement is disputed across sources (Reactome places COASY at the outer membrane). Kept as a real but non-core localization. Supporting Evidence: file:human/COASY/COASY-uniprot.txt probably anchored to the inner mitochondrial |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: Detected by large-scale mass spectrometry of urinary exosomes. This is a proteome-wide catch typical of abundant cytosolic enzymes and does not reflect a site of COASY function. Non-core; retained per policy (experimental HDA, not removed). Supporting Evidence: PMID:19056867 we used LC-MS/MS to profile the proteome of human urinary exosomes |
| GO:0004140 dephospho-CoA kinase activity | IDA PMID:11923312 Complete reconstitution of the human coenzyme A biosynthetic... | ACCEPT | Summary: Direct assay of the DPCK activity of the purified recombinant human bifunctional enzyme, which was kinetically characterized. Foundational experimental evidence for this core molecular function. Supporting Evidence: PMID:11923312 Human recombinant bifunctional phosphopantetheine adenylyltransferase/dephospho-CoA kinase was kinetically characterized. |
| GO:0004595 pantetheine-phosphate adenylyltransferase activity | IDA PMID:11923312 Complete reconstitution of the human coenzyme A biosynthetic... | ACCEPT | Summary: Direct assay of the PPAT activity of the purified recombinant human bifunctional enzyme. Foundational experimental evidence for this core molecular function. Supporting Evidence: PMID:11923312 Human recombinant bifunctional phosphopantetheine adenylyltransferase/dephospho-CoA kinase was kinetically characterized. |
| GO:0015937 coenzyme A biosynthetic process | IDA PMID:11923312 Complete reconstitution of the human coenzyme A biosynthetic... | ACCEPT | Summary: The whole CoA biosynthetic pathway from phosphopantothenate to CoA was reconstituted in vitro using the purified recombinant enzymes, including this bifunctional protein. Direct experimental support for the core process. Core process. Supporting Evidence: PMID:11923312 the entire pathway from phosphopantothenate to CoA was successfully reconstituted in vitro |
| GO:0005741 mitochondrial outer membrane | TAS Reactome:R-HSA-196754 | MARK AS OVER ANNOTATED | Summary: Reactome places the COASY reactions at the mitochondrial outer membrane, citing Zhyvoloup et al. 2003; newer direct evidence places COASY mainly in the cytosol with a matrix pool anchored to the inner membrane. Reason: The outer-membrane assignment is contradicted by the later IDA matrix localization and by the finding that COASY is mainly cytosolic and active there. A transient or peripheral association is not excluded, but the outer membrane is not a supported location of COASY function. Supporting Evidence: Reactome:R-HSA-196773 The enzyme is located in the mitochondrial outer membrane file:human/COASY/COASY-uniprot.txt Present in the mitochondrial matrix, probably anchored to the inner mitochondrial membrane (PubMed:24360804). file:human/COASY/COASY-uniprot.txt Note=The protein is mainly cytosolic and active in the cytosol (PubMed:40925986). |
| GO:0005741 mitochondrial outer membrane | TAS Reactome:R-HSA-196773 | MARK AS OVER ANNOTATED | Summary: Reactome places the COASY reactions at the mitochondrial outer membrane, citing Zhyvoloup et al. 2003; newer direct evidence places COASY mainly in the cytosol with a matrix pool anchored to the inner membrane. Reason: The outer-membrane assignment is contradicted by the later IDA matrix localization and by the finding that COASY is mainly cytosolic and active there. A transient or peripheral association is not excluded, but the outer membrane is not a supported location of COASY function. Supporting Evidence: Reactome:R-HSA-196773 The enzyme is located in the mitochondrial outer membrane file:human/COASY/COASY-uniprot.txt Present in the mitochondrial matrix, probably anchored to the inner mitochondrial membrane (PubMed:24360804). file:human/COASY/COASY-uniprot.txt Note=The protein is mainly cytosolic and active in the cytosol (PubMed:40925986). |
| GO:0004140 dephospho-CoA kinase activity | IDA PMID:11994049 Identification and characterization of the gene encoding the... | ACCEPT | Summary: The recombinant 564-aa human protein was shown to possess the associated kinase (DPCK) activity, with kinetics similar to the wild-type pig enzyme. Direct experimental support for this core molecular function. Supporting Evidence: PMID:11994049 The recombinant 564-amino-acid human protein confirmed the associated transferase and kinase activities |
| GO:0004595 pantetheine-phosphate adenylyltransferase activity | IDA PMID:11994049 Identification and characterization of the gene encoding the... | ACCEPT | Summary: The recombinant human protein was shown to possess the associated transferase (PPAT) activity, confirming the bifunctional PPAT/DPCK enzyme. Direct experimental support for this core molecular function. Supporting Evidence: PMID:11994049 The recombinant 564-amino-acid human protein confirmed the associated transferase and kinase activities |
| GO:0015937 coenzyme A biosynthetic process | TAS PMID:11994049 Identification and characterization of the gene encoding the... | ACCEPT | Summary: COASY encodes the bifunctional enzyme catalyzing the final two enzymes of the CoA biosynthetic pathway. Author-statement (TAS) support for the core process. Core process. Supporting Evidence: PMID:11994049 The final two enzymes in the CoA biosynthetic pathway |
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Download this section (compressed HTML)Q: What is the definitive subcellular distribution and submitochondrial topology of COASY (cytosol vs mitochondrial matrix vs inner/outer membrane), and does the mitochondrial pool perform local de novo CoA synthesis or serve another role?
Q: How does EDC4 binding regulate COASY dephospho-CoA kinase activity in vivo, and what is the physiological role of processing-body-associated CoA synthesis regulation?
Experiment: Compartment-resolved metabolic flux analysis (e.g. isotope-labeled pantothenate) combined with organelle fractionation and split-reporter/APEX proximity labeling to quantify the relative contribution of cytosolic vs mitochondrial COASY to the CoA pool.
Experiment: Structure-function analysis of disease variants (e.g. R499C, A214V) measuring PPAT and DPCK activities separately and protein stability, to dissect how NBIA6/PCH12 mutations impair CoA biosynthesis.
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