CA5A encodes carbonic anhydrase VA, a zinc-dependent enzyme imported into the mitochondrial matrix after cleavage of an N-terminal targeting peptide. It catalyzes reversible interconversion of carbon dioxide and bicarbonate. Its bicarbonate production supplies mitochondrial carbamoyl-phosphate synthetase 1 and biotin-dependent carboxylases, linking this reaction to nitrogen disposal and intermediary metabolism without catalyzing their downstream reactions. Human loss-of-function variants can impair enzyme activity or stability and cause episodes of hyperammonemia and associated metabolic disturbances, particularly early in life.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004089 carbonate dehydratase activity | EXP PMID:18618712 Crystal structure of human carbonic anhydrase XIII and its c... | ACCEPT | Summary: CA5A has carbonate dehydratase activity; the original comparative assay remains incompletely accessible. Reason: The PMID18618712 abstract foregrounds the structure of human CA XIII and comparisons among other isoforms; its CA5A-specific assay table was not inspected. That title is not evidence of a wrong-gene annotation. Retain the curator-assigned EXP assertion because direct expression of human CA5A and independently characterized human CA5A mutants establish exactly this activity. This acceptance does not claim that the original CA5A measurement was independently recovered. |
| GO:0004089 carbonate dehydratase activity | IBA GO_REF:0000033 | ACCEPT | Summary: The inherited catalytic activity is directly corroborated in human CA5A. Reason: PAINT places carbonate dehydratase activity at PTN001055728. Human CA5A expression and mutant enzyme assays independently corroborate the inherited activity. P35218 among descendant evidence is legitimate target experimental grounding, not circularity. The local family export lacks the ancestral tree/IBD record, so the precise node placement was not re-adjudicated and no inference is based on the number of listed donors. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN001055728 UNRESOLVED The normal family export does not include this ancestral IBD tree/node record. Target-specific human evidence supports the biological assertion; the narrower localization recommendation does not claim an incorrect inherited placement or criticize donor count/self-source inclusion. |
| GO:0004089 carbonate dehydratase activity | IDA PMID:16686544 Carbonic anhydrase activators. Activation of isoforms I, II,... | ACCEPT | Summary: Human CA VA activity is measured in the phenylalanine activation panel. Reason: The abstract explicitly includes human CA VA among six kinetically assayed isoforms and reports its activation by both phenylalanine stereoisomers. The crystal structures concern CA II, and their individual binding contacts are not transferred to CA5A. The kinetic target panel supports the existing catalytic activity. Supporting Evidence: PMID:16686544 a weaker activator of hCA VA and VII |
| GO:0004089 carbonate dehydratase activity | IDA PMID:16807956 Carbonic anhydrase activators. Activation of isozymes I, II,... | ACCEPT | Summary: Human CA VA is a catalytically active member of the histidine activation panel. Reason: The abstract explicitly reports kinetic activation of human CA VA by histidine. Atomic ligand contacts were characterized for CA II rather than CA VA; the annotation is retained on the target-specific kinetic result without transferring that structural detail. Supporting Evidence: PMID:16807956 l-His was a potent activator of isozymes I, VA, VII, and XIV |
| GO:0004089 carbonate dehydratase activity | IDA PMID:17127057 Carbonic anhydrase activators: L-Adrenaline plugs the active... | ACCEPT | Summary: CA VA catalytic activity responds to adrenaline in the reported isoform panel. Reason: The abstract identifies CA VA among the activated isoforms. The crystallographic adduct is CA II and does not establish an identical CA5A binding mode. The measured CA VA activation nevertheless supports carbonate dehydratase activity. Supporting Evidence: PMID:17127057 Isoforms CA IV, VA, VII, and XIV were activated |
| GO:0004089 carbonate dehydratase activity | IDA PMID:17314045 Phosph(on)ate as a zinc-binding group in metalloenzyme inhib... | ACCEPT | Summary: The eleven-isoform kinetic study is consistent with established CA5A catalysis. Reason: The abstract describes kinetics across eleven carbonic-anhydrase isozymes, although its structure is a CA I complex and the individual CA5A kinetic entry is not visible. UniProt assigns this paper to human CA5A catalysis and regulation; retain the curator-supported activity with independent human CA5A expression evidence, without claiming inspection of the original target table or transferring the CA I structure. Supporting Evidence: PMID:17314045 with 11 CA isozymes has been investigated kinetically |
| GO:0004089 carbonate dehydratase activity | IDA PMID:19186056 A thiabendazole sulfonamide shows potent inhibitory activity... | ACCEPT | Summary: The inhibitor panel includes catalytically active mammalian CA V. Reason: The abstract includes mammalian isoforms I-XIV and reports effective inhibition of the IV-VII group, while the crystal structure concerns CA II. This is consistent with the curated CA5A activity; the abstract does not separately resolve every VA/VB measurement, so the target assignment is retained with curator deference and independent human CA5A evidence. |
| GO:0004089 carbonate dehydratase activity | IDA PMID:8356065 Human mitochondrial carbonic anhydrase: cDNA cloning, expres... | ACCEPT | Summary: Expression of human CA5A produces active carbonic anhydrase. Reason: A human liver CA V cDNA was expressed in COS cells and produced active enzyme. This is a direct human gene-product experiment in a heterologous mammalian cell system, not an inference that COS-cell species changes the identity of the expressed enzyme. Supporting Evidence: PMID:8356065 Expression of the cDNA in COS cells produced active enzyme. |
| GO:0004089 carbonate dehydratase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic ortholog, family and reaction mappings agree with direct human CA5A catalysis. Reason: The combined mapping identifies the established carbonic-anhydrase reaction, EC4.2.1.1/RHEA10748, together with rodent ortholog and alpha-carbonic-anhydrase domain evidence. Direct human expression and mutant activity measurements independently establish that CA5A is an active enzyme rather than a catalytically inactive carbonic-anhydrase-related paralog. No individual rodent assay or current domain-family ancestry was re-read for this retention. |
| GO:0004089 carbonate dehydratase activity | IMP PMID:19206230 Non-zinc mediated inhibition of carbonic anhydrases: coumari... | ACCEPT | Summary: The coumarin study is consistent with established CA5A enzymatic activity. Reason: The abstract reports inhibition of all thirteen catalytically active mammalian carbonic-anhydrase isoforms, while its detailed structure concerns CA II. Retain the curated CA5A activity with independent target evidence; the source IMP code is preserved without inventing a CA5A mutant experiment or importing the CA II hydrolysis mechanism as a separate CA5A function. The individual target table was not inspected. Supporting Evidence: PMID:19206230 inhibit all 13 catalytically active mammalian CA isoforms |
| GO:0004089 carbonate dehydratase activity | IMP PMID:24530203 Mitochondrial carbonic anhydrase VA deficiency resulting fro... | ACCEPT | Summary: A human CA5A disease variant reduces enzymatic activity and thermal stability. Reason: The primary main text compares human wild-type and S233P CA VA expressed in COS-7 cells. Mutant-specific activity in total lysates was reduced to about one fifth of wild type, and acetazolamide was used to check assay specificity. Thermal-inactivation experiments provide further functional evidence. These experiments directly substantiate CA5A catalysis beyond the patients' metabolite phenotype; the patients do not establish that CA5A itself catalyzes CPS1 or carboxylase reactions. Supporting Evidence: PMID:24530203 reduced to 20% of wild-type protein activity |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | MODIFY | Summary: The broad cytoplasmic inheritance can be refined to mitochondrial matrix. Reason: GO cytoplasm includes non-nuclear organelles and is not synonymous with cytosol, so the inherited term does not contradict mitochondrial targeting. Human liver/COS-cell mitochondrial localization, mature-protein processing, the matrix assignment in PMID7490083, and curated mitochondrial reaction records support the more precise mitochondrial-matrix location. Refine the term without alleging erroneous PAINT placement; its exact IBD node was unavailable. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: PANTHER:PTN001055728 UNRESOLVED The normal family export does not include this ancestral IBD tree/node record. Target-specific human evidence supports the biological assertion; the narrower localization recommendation does not claim an incorrect inherited placement or criticize donor count/self-source inclusion. Proposed replacements: mitochondrial matrix |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: The mitochondrial proteome assertion correctly places CA5A in mitochondria. Reason: The inspected MitoCoP study combines human-cell fractionation, quantitative mass spectrometry, importomics and curation. Its exact CA5A supplementary-table row was not inspected. Accept the curated mitochondrial detection, corroborated by independent human CA5A localization. Matrix localization is already represented by the separate NAS and TAS annotations; the HTP source is retained at its stated organelle resolution. |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: The mitochondrial PAINT annotation is consistent with established human CA5A localization. Reason: The PTN002708220 assertion agrees with human mitochondrial localization and the 38-residue cleaved targeting peptide. Accept the inherited mitochondrial location; the separate NAS and TAS annotations already capture the matrix compartment. The target in the donor list is valid experimental grounding. The exact ancestral-node placement was not inspected, so no defect in its placement or limitation on PAINT compartment resolution is inferred. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002708220 UNRESOLVED The normal family export does not include this ancestral IBD tree/node record. Direct human evidence corroborates the mitochondrial assertion. The node remains uninspected; no incorrect placement, donor-count weakness or circularity from the target self-source is asserted. |
| GO:0005739 mitochondrion | IDA PMID:8356065 Human mitochondrial carbonic anhydrase: cDNA cloning, expres... | ACCEPT | Summary: The human CA5A localization study supports the mitochondrial annotation. Reason: The original abstract reports the mature protein in normal human liver mitochondria and precursor/mature forms in mitochondria from transfected COS cells. Accept this mitochondrial assertion at the resolution of the inspected evidence, preserving its original part_of relationship and IDA code. The distinct NAS and TAS annotations retain matrix localization; the abstract is not described as a submitochondrial fractionation assay. Supporting Evidence: PMID:8356065 mitochondria isolated from normal human liver Reactome:R-HSA-1475032 |
| GO:0005739 mitochondrion | IEA GO_REF:0000120 | ACCEPT | Summary: The ortholog and subcellular mapping support mitochondrial localization. Reason: The mouse ortholog and UniProt subcellular mapping agree with direct human mitochondrial localization. Accept the mitochondrial assertion while the separate NAS and TAS annotations capture the finer matrix location. The exact mouse donor assay was not inspected; its accession and original electronic evidence remain unchanged. |
| GO:0005759 mitochondrial matrix | NAS PMID:7490083 Genomic organization of the human gene (CA5) and pseudogene ... | ACCEPT | Summary: CA VA is a mitochondrial-matrix enzyme. Reason: The source abstract explicitly places CA V in mitochondrial matrix, although the paper's new experiments concern genomic organization rather than a new compartment-resolution assay. Retain this NAS assignment with the independent human mitochondrial-import evidence and curated matrix-localized CA5A reactions. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-1475028 | ACCEPT | Summary: The bicarbonate-dehydration reaction places CA5A in mitochondrial matrix. Reason: The curated reaction explicitly assigns reversible bicarbonate dehydration to mitochondrial CA VA/CA VB. This agrees with human CA5A targeting and the matrix-specific source annotation; it does not transfer the reaction to a different isozyme or imply membrane transport by CA5A. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-1475032 | ACCEPT | Summary: Matrix CA5A catalyzes carbon-dioxide hydration and generates bicarbonate. Reason: The curated mitochondrial reaction describes zinc-dependent hydration of carbon dioxide, producing bicarbonate and a proton. Its assignment agrees with human CA5A enzymology and matrix localization. Downstream bicarbonate-consuming enzymes perform their own reactions. |
| GO:0008270 zinc ion binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Zinc coordination is a component of CA5A catalysis. Reason: The alpha-carbonic-anhydrase domain mapping supports catalytic zinc binding. UniProt assigns conserved zinc-coordinating positions by similarity, and the human S233P functional study discusses zinc saturation and the zinc-binding region. Keep the cofactor-binding annotation without making a separate zinc-binding core or claiming a human CA5A structure was inspected. |
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Q: Can target-specific primary assay details be recovered for the broad isoform studies and the MitoCoP CA5A entry without treating an abstract-only or supplementary-table access gap as evidence against established CA5A function?
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