CPOX is an oxygen-dependent coproporphyrinogen-III oxidase that catalyzes successive oxidative decarboxylations of two propionate side chains to form protoporphyrinogen IX in heme biosynthesis. The characterized human enzyme is a homodimer and does not require a metal or organic cofactor. Its mitochondrial precursor is processed to a mature enzyme in the intermembrane space; rat fractionation additionally identifies a loosely inner-membrane-associated fraction. Pathogenic variants cause hereditary coproporphyria or harderoporphyria.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | MODIFY | Summary: The inherited cytoplasm annotation is compatible with mitochondrial localization but can be made more specific. Reason: Current GO:0005737 includes organelles, so mitochondrial targeting does not contradict this IBA. The actual current PTN000079415 IBD lies on the human target path and its aligned sequence exactly matches the canonical product. Refine the broad location to the established mitochondrial intermembrane space, without claiming it is the sole possible location or treating the target among its own extant evidence as circular. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000079415 SUPPORTS TRANSFER The current ancestral cytoplasm assertion is real and compatible with the target; the replacement adds target-specific compartment precision. Proposed replacements: mitochondrial intermembrane space Supporting Evidence: file:human/CPOX/CPOX-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion intermembrane space PMID:31872 The enzyme was found in the intermembrane space with a fraction loosely bound to the inner membrane. file:human/CPOX/CPOX-uniprot.txt PANTHER; PTHR10755; COPROPORPHYRINOGEN III OXIDASE, MITOCHONDRIAL; 1. |
| GO:0006783 heme biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: CPOX performs a catalytic step in heme biosynthesis. Reason: PAINT IBA (GO_REF:0000033) from PANTHER family PTHR10755 (node PTN000079415). CPOX performs the oxidative decarboxylation of coproporphyrinogen III to protoporphyrinogen IX itself, so this is catalytic participation in heme biosynthesis, corroborated by functional expression of the human enzyme. Core process. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000079415 SUPPORTS TRANSFER The actual current PTN000079415 IBD is on the target path, the 454-residue human MSA is exact, and extant target/ortholog experimental records provide positive context. Historical placement is not reconstructed. Supporting Evidence: PMID:8159699 Coproporphyrinogen oxidase (EC 1.3.3.3) catalyzes the sixth step in the heme biosynthetic pathway, the oxidation of coproporphyrinogen III to protoporphyrinogen IX. file:human/CPOX/CPOX-uniprot.txt Catalyzes the aerobic oxidative decarboxylation of propionate groups of rings A and B of coproporphyrinogen-III to yield the vinyl groups in protoporphyrinogen-IX and participates to the sixth step in the heme biosynthetic pathway. file:human/CPOX/CPOX-uniprot.txt PANTHER; PTHR10755; COPROPORPHYRINOGEN III OXIDASE, MITOCHONDRIAL; 1. |
| GO:0004109 coproporphyrinogen oxidase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Coproporphyrinogen oxidase is the defining catalytic activity of CPOX. Reason: The actual current PTN000079415 catalytic IBD lies on the human target path, and the 454-residue target alignment matches the canonical protein. Its descendant evidence includes direct human and ortholog activity records; target self-evidence is legitimate grounding of an inherited ancestral function. Human functional expression in PMID:8159699 and solution/structural work in PMID:16176984 independently corroborate the reaction. This accepts the phylogenetic catalytic assertion without claiming to reconstruct the historical PAINT session. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000079415 SUPPORTS TRANSFER The actual current PTN000079415 IBD is on the target path, the 454-residue human MSA is exact, and extant target/ortholog experimental records provide positive context. Historical placement is not reconstructed. Supporting Evidence: PMID:8159699 Expression of the cDNA coding for the putative mature human coproporphyrinogen oxidase in Escherichia coli resulted in a 17-fold increase in coproporphyrinogen activity over endogenous activity. file:human/CPOX/CPOX-uniprot.txt Reaction=coproporphyrinogen III + O2 + 2 H(+) = protoporphyrinogen IX + 2 CO2 + 2 H2O file:human/CPOX/CPOX-uniprot.txt PANTHER; PTHR10755; COPROPORPHYRINOGEN III OXIDASE, MITOCHONDRIAL; 1. |
| GO:0004109 coproporphyrinogen oxidase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Coproporphyrinogen oxidase is the defining catalytic activity of CPOX. Reason: The combined electronic assertion has distinct, traceable premises: current ARBA00087102 branch 0 matches the official FunFam and Metazoa predicates; three InterPro signatures identify the enzyme family; EC 1.3.3.3 and RHEA:18257 specify its oxidative-decarboxylation reaction; and the two ortholog identifiers map to actual mouse and rat records. These premises converge on GO:0004109 and agree with direct human activity. The source-specific comments separate rule matching, family recognition, chemistry and ortholog evidence. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00087102 SUPPORTS TRANSFER Current ARBA00087102 zero-based branch 0 matches both FunFam 3.40.1500.10:FF:000002 and Metazoa (33208) in the official human record. This is a current predicate trace, not reconstruction of an earlier rule release. UniProtKB:P36552 SUPPORTS TRANSFER The exact mouse P36552 source has same-term IDA records including PMID:8407975, whose recombinant mouse activity was read in the independent original-source consultation. No direct human experiment is attributed to this mouse donor. ensembl:ENSMUSP00000055455 SUPPORTS TRANSFER The official mouse cross-reference resolves this Ensembl protein to P36552. It is an alternative identifier of that donor, not an independent experiment; the P36552 source comment states the actual assay scope. UniProtKB:Q3B7D0 SUPPORTS TRANSFER The rat Q3B7D0 query contains the exact same-term experimental record(s), PMID:11079369 (IDA) and PMID:666752 (EXP). Those donor records were inspected; their original full papers were not independently read here. The transfer is corroborated by human catalysis, not by an invented ARBA match on this donor. ensembl:ENSRNOP00000002257 SUPPORTS TRANSFER The official rat cross-reference resolves this Ensembl protein to Q3B7D0. It is an alternative identifier of that donor, not an additional assay; the Q3B7D0 source comment distinguishes record inspection from primary-paper access. InterPro:IPR001260 SUPPORTS TRANSFER The official human record contains InterPro:IPR001260, representing the coproporphyrinogen III oxidase family. This family/signature premise is consistent with direct catalytic evidence; it is distinct from an ARBA branch or direct assay. InterPro:IPR018375 SUPPORTS TRANSFER The official human record contains InterPro:IPR018375, representing the conserved coproporphyrinogen III oxidase site. This family/signature premise is consistent with direct catalytic evidence; it is distinct from an ARBA branch or direct assay. InterPro:IPR036406 SUPPORTS TRANSFER The official human record contains InterPro:IPR036406, representing the coproporphyrinogen III oxidase structural superfamily. This family/signature premise is consistent with direct catalytic evidence; it is distinct from an ARBA branch or direct assay. RHEA:18257 SUPPORTS TRANSFER RHEA:18257 specifies coproporphyrinogen III oxidation to protoporphyrinogen IX with oxygen and release of carbon dioxide and water. The official catalytic annotation and current GO:0004109 describe the same net reaction; this is reaction mapping, not a FunFam predicate. EC:1.3.3.3 SUPPORTS TRANSFER EC 1.3.3.3 is the coproporphyrinogen oxidase catalytic classification recorded for the human protein. It agrees with GO:0004109 and direct human expression evidence; the enzyme-class mapping is not a taxonomic or ARBA condition. Supporting Evidence: file:human/CPOX/CPOX-uniprot.txt Reaction=coproporphyrinogen III + O2 + 2 H(+) = protoporphyrinogen IX + 2 CO2 + 2 H2O file:human/CPOX/CPOX-uniprot.txt Catalyzes the aerobic oxidative decarboxylation of propionate groups of rings A and B of coproporphyrinogen-III to yield the vinyl groups in protoporphyrinogen-IX and participates to the sixth step in the heme biosynthetic pathway. file:human/CPOX/CPOX-uniprot.txt InterPro; IPR001260; Coprogen_oxidase_aer. |
| GO:0005758 mitochondrial intermembrane space | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location vocabulary mapping (GO_REF:0000044) to the mitochondrial intermembrane space; this source row is no longer in the current GOA file, where the same location is carried by combined IEA, ISS and TAS rows. Reason: This biological location remains supported. The row is retired only because its old GO_REF:0000044 source assertion is absent from the current GOA and the same location is now represented by combined IEA provenance; retirement does not mean biological removal. Propagation Review Root cause: NO FAILURE CORE Sources checked: GO_REF:0000044 SUPPORTS TRANSFER Retired source grouping only; the biological IMS location is retained by the current combined source and primary ortholog evidence. Supporting Evidence: file:human/CPOX/CPOX-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion intermembrane space PMID:31872 The enzyme was found in the intermembrane space with a fraction loosely bound to the inner membrane. |
| GO:0006779 porphyrin-containing compound biosynthetic process | IEA GO_REF:0000120 | MODIFY | Summary: Combined electronic annotation (GO_REF:0000120; InterPro family signatures and rat ortholog transfer) to the broad porphyrin-containing compound biosynthetic process. Reason: Correct but more general than the evidence supports. CPOX's product, protoporphyrinogen IX, is committed to heme in human cells, and the specific descendant heme biosynthetic process (GO:0006783), which the gene already carries by IBA, IEA and TAS, is the appropriate replacement. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q3B7D0 SUPPORTS TRANSFER The rat Q3B7D0 query contains the exact same-term experimental record(s), PMID:3814086 (IDA). Those donor records were inspected; their original full papers were not independently read here. The transfer is corroborated by human catalysis, not by an invented ARBA match on this donor. ensembl:ENSRNOP00000002257 SUPPORTS TRANSFER The official rat cross-reference resolves this Ensembl protein to Q3B7D0. It is an alternative identifier of that donor, not an additional assay; the Q3B7D0 source comment distinguishes record inspection from primary-paper access. InterPro:IPR001260 SUPPORTS TRANSFER The official human record contains InterPro:IPR001260, representing the coproporphyrinogen III oxidase family. This family/signature premise is consistent with direct catalytic evidence; it is distinct from an ARBA branch or direct assay. InterPro:IPR018375 SUPPORTS TRANSFER The official human record contains InterPro:IPR018375, representing the conserved coproporphyrinogen III oxidase site. This family/signature premise is consistent with direct catalytic evidence; it is distinct from an ARBA branch or direct assay. InterPro:IPR036406 SUPPORTS TRANSFER The official human record contains InterPro:IPR036406, representing the coproporphyrinogen III oxidase structural superfamily. This family/signature premise is consistent with direct catalytic evidence; it is distinct from an ARBA branch or direct assay. Proposed replacements: heme biosynthetic process Supporting Evidence: PMID:8159699 Coproporphyrinogen oxidase (EC 1.3.3.3) catalyzes the sixth step in the heme biosynthetic pathway, the oxidation of coproporphyrinogen III to protoporphyrinogen IX. file:human/CPOX/CPOX-uniprot.txt PATHWAY: Porphyrin-containing compound metabolism; protoporphyrin-IX biosynthesis; protoporphyrinogen-IX from coproporphyrinogen-III (O2 route): step 1/1. file:human/CPOX/CPOX-uniprot.txt InterPro; IPR001260; Coprogen_oxidase_aer. |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Rat fractionation supports a loosely inner-membrane-associated CPOX fraction. Reason: The exact rat Q3B7D0 donor has IDA GO:0005743 from PMID:31872. Original rat-liver fractionation, alkaline/salt release and sonication data support a peripheral association on the intermembrane-space side; they do not establish a transmembrane protein or direct human topology. Human MitoCoP classifies the target group as soluble under its extraction conditions, which does not erase the rat association result. The authors could not retain binding on isolated inner membranes; this limits the inferred association to their biochemical fractionation conditions. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q3B7D0 SUPPORTS TRANSFER The exact rat Q3B7D0 same-term IDA record cites PMID:31872; the Ensembl identifier resolves to the same rat protein. The review reason preserves the source-specific exposure or fractionation result and its limits, without a direct human-assay claim. ensembl:ENSRNOP00000002257 SUPPORTS TRANSFER The exact rat Q3B7D0 same-term IDA record cites PMID:31872; the Ensembl identifier resolves to the same rat protein. The review reason preserves the source-specific exposure or fractionation result and its limits, without a direct human-assay claim. Supporting Evidence: PMID:31872 The enzyme was found in the intermembrane space with a fraction loosely bound to the inner membrane. PMID:31872 This fraction was released by washing the inner-membrane-matrix complex with alkaline solutions or solutions of high ionic strength. |
| GO:0006783 heme biosynthetic process | IEA GO_REF:0000120 | ACCEPT | Summary: CPOX performs a catalytic step in heme biosynthesis. Reason: Current ARBA00027909 branch 4 matches FunFam 3.40.1500.10:FF:000002 and Metazoa in the official human record. The combined source also contains rat Q3B7D0 and its exact Ensembl protein identifier, with an independently curated same-term IDA record. CPOX performs the pathway reaction itself, so the broad heme-biosynthesis assertion is compatible with direct human functional expression and the existing catalytic GO-CAM. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00027909 SUPPORTS TRANSFER Current ARBA00027909 zero-based branch 4 matches both FunFam 3.40.1500.10:FF:000002 and Metazoa (33208) in the official human record. This is a current predicate trace, not reconstruction of an earlier rule release. UniProtKB:Q3B7D0 SUPPORTS TRANSFER The rat Q3B7D0 query contains the exact same-term experimental record(s), PMID:3955059 (IDA). Those donor records were inspected; their original full papers were not independently read here. The transfer is corroborated by human catalysis, not by an invented ARBA match on this donor. ensembl:ENSRNOP00000002257 SUPPORTS TRANSFER The official rat cross-reference resolves this Ensembl protein to Q3B7D0. It is an alternative identifier of that donor, not an additional assay; the Q3B7D0 source comment distinguishes record inspection from primary-paper access. Supporting Evidence: PMID:8159699 Coproporphyrinogen oxidase (EC 1.3.3.3) catalyzes the sixth step in the heme biosynthetic pathway, the oxidation of coproporphyrinogen III to protoporphyrinogen IX. file:human/CPOX/CPOX-uniprot.txt PATHWAY: Porphyrin-containing compound metabolism; protoporphyrin-IX biosynthesis; protoporphyrinogen-IX from coproporphyrinogen-III (O2 route): step 1/1. |
| GO:0010039 response to iron ion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The rat donor supports a contextual enzyme response to iron ion. Reason: Chronic carbonyl-iron feeding in rats decreased liver CPOX activity; the cached abstract distinguishes this from the ethanol condition. The current response definition includes changes in enzyme activity. Retain the existing ortholog transfer at this exposure-associated scope, without asserting a human experiment, a dedicated sensor, or a regulatory detoxification mechanism. The complete cached abstract and exact current donor row were read; the full original was not recovered. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q3B7D0 SUPPORTS TRANSFER The exact rat Q3B7D0 same-term IEP record cites PMID:2289051; the Ensembl identifier resolves to the same rat protein. The review reason preserves the source-specific exposure or fractionation result and its limits, without a direct human-assay claim. ensembl:ENSRNOP00000002257 SUPPORTS TRANSFER The exact rat Q3B7D0 same-term IEP record cites PMID:2289051; the Ensembl identifier resolves to the same rat protein. The review reason preserves the source-specific exposure or fractionation result and its limits, without a direct human-assay claim. Supporting Evidence: PMID:2289051 Decreased coproporphyrinogen oxidase activity was found in chronically carbonyliron-fed rats |
| GO:0010288 response to lead ion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The rat donor supports a contextual enzyme response to lead ion. Reason: Original rat-liver Methods and Results show reduced CPOX activity after lead treatment; the authors did not statistically test the small pooled-sample CPOX series. The current response definition includes changes in enzyme activity. Retain the existing ortholog transfer at this exposure-associated scope, without asserting a human experiment, a dedicated sensor, or a regulatory detoxification mechanism. The original main text was read. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q3B7D0 SUPPORTS TRANSFER The exact rat Q3B7D0 same-term IEP record cites PMID:656697; the Ensembl identifier resolves to the same rat protein. The review reason preserves the source-specific exposure or fractionation result and its limits, without a direct human-assay claim. ensembl:ENSRNOP00000002257 SUPPORTS TRANSFER The exact rat Q3B7D0 same-term IEP record cites PMID:656697; the Ensembl identifier resolves to the same rat protein. The review reason preserves the source-specific exposure or fractionation result and its limits, without a direct human-assay claim. Supporting Evidence: PMID:656697 coproporphyrinogen oxidase and ferrochelatase were decreased by increasing lead pretreatment. |
| GO:0016020 membrane | IEA GO_REF:0000107 | MODIFY | Summary: Ensembl Compara projection (GO_REF:0000107) of generic membrane localization from mouse P36552. Reason: Correct but general. The only membrane association supported for CPOX is the loose, salt- and alkali-releasable attachment of a fraction of the enzyme to the mitochondrial inner membrane on the intermembrane-space side (rat liver fractionation); the mouse erythrocyte-ghost source does not discriminate membrane attachment from retained mitochondria. The specific term the evidence supports is mitochondrial inner membrane (GO:0005743), which the gene already carries (kept as non-core); no integral or plasma-membrane location is implied. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P36552 UNRESOLVED The exact mouse IMP donor and its Ensembl alias are real, and original Table 1 positively detects P36552. This ghost-fraction assay does not resolve membrane attachment versus retained mitochondrial material. The retained biological judgment additionally uses independent rat peripheral-association evidence, not this donor assay alone. ensembl:ENSMUSP00000055455 UNRESOLVED The exact mouse IMP donor and its Ensembl alias are real, and original Table 1 positively detects P36552. This ghost-fraction assay does not resolve membrane attachment versus retained mitochondrial material. The retained biological judgment additionally uses independent rat peripheral-association evidence, not this donor assay alone. Proposed replacements: mitochondrial inner membrane Supporting Evidence: PMID:31872 The enzyme was found in the intermembrane space with a fraction loosely bound to the inner membrane. PMID:31872 This fraction was released by washing the inner-membrane-matrix complex with alkaline solutions or solutions of high ionic strength. |
| GO:0017085 response to insecticide | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The rat donor supports a contextual enzyme response to insecticide. Reason: The rat experiment used diazinon with isodiazinon for 100 days; CPOX activity fell in that condition, whereas stabilized diazinon alone did not produce the same effect. The current response definition includes changes in enzyme activity. Retain the existing ortholog transfer at this exposure-associated scope, without asserting a human experiment, a dedicated sensor, or a regulatory detoxification mechanism. The complete cached abstract and exact current donor row were read; the full original was not recovered. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q3B7D0 SUPPORTS TRANSFER The exact rat Q3B7D0 same-term IEP record cites PMID:6626236; the Ensembl identifier resolves to the same rat protein. The review reason preserves the source-specific exposure or fractionation result and its limits, without a direct human-assay claim. ensembl:ENSRNOP00000002257 SUPPORTS TRANSFER The exact rat Q3B7D0 same-term IEP record cites PMID:6626236; the Ensembl identifier resolves to the same rat protein. The review reason preserves the source-specific exposure or fractionation result and its limits, without a direct human-assay claim. Supporting Evidence: PMID:6626236 a decrease in the activity of coproporphyrinogen oxidase. |
| GO:0042802 identical protein binding | IEA GO_REF:0000107 | MODIFY | Summary: The positive identical-protein association can be specified as homodimerization. Reason: Human CPOX analytical ultracentrifugation and crystallography establish a homodimer, and exon-6 deletion disrupts dimerization. GO:0042803 captures this more precisely than generic identical-protein binding. This refinement does not imply that the shorter alternative product forms the same dimer. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q3B7D0 SUPPORTS TRANSFER Positive same-protein association agrees with the direct human homodimer assay; the replacement is a specificity refinement. ensembl:ENSRNOP00000002257 SUPPORTS TRANSFER Positive same-protein association agrees with the direct human homodimer assay; the replacement is a specificity refinement. Proposed replacements: protein homodimerization activity Supporting Evidence: file:human/CPOX/CPOX-uniprot.txt SUBUNIT: Homodimer. PMID:16176984 We show that deletion of residues (392-418) encoded by exon six disrupts dimerization. |
| GO:0046685 response to arsenic-containing substance | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The rat donor supports a contextual enzyme response to arsenic-containing substance. Reason: Sodium arsenate exposure reduced rat kidney CPOX activity and increased porphyrin excretion; the liver response was different. The current response definition includes changes in enzyme activity. Retain the existing ortholog transfer at this exposure-associated scope, without asserting a human experiment, a dedicated sensor, or a regulatory detoxification mechanism. The complete cached abstract and exact current donor row were read; the full original was not recovered. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q3B7D0 SUPPORTS TRANSFER The exact rat Q3B7D0 same-term IEP record cites PMID:2916235; the Ensembl identifier resolves to the same rat protein. The review reason preserves the source-specific exposure or fractionation result and its limits, without a direct human-assay claim. ensembl:ENSRNOP00000002257 SUPPORTS TRANSFER The exact rat Q3B7D0 same-term IEP record cites PMID:2916235; the Ensembl identifier resolves to the same rat protein. The review reason preserves the source-specific exposure or fractionation result and its limits, without a direct human-assay claim. Supporting Evidence: PMID:2916235 decrease in renal, but not hepatic, coproporphyrinogen oxidase activity. |
| GO:0051597 response to methylmercury | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The rat donor supports a contextual enzyme response to methylmercury. Reason: Methylmercury hydroxide exposure reduced rat kidney CPOX activity and increased porphyrin excretion; the liver response was different. The current response definition includes changes in enzyme activity. Retain the existing ortholog transfer at this exposure-associated scope, without asserting a human experiment, a dedicated sensor, or a regulatory detoxification mechanism. The complete cached abstract and exact current donor row were read; the full original was not recovered. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q3B7D0 SUPPORTS TRANSFER The exact rat Q3B7D0 same-term IEP record cites PMID:2916235; the Ensembl identifier resolves to the same rat protein. The review reason preserves the source-specific exposure or fractionation result and its limits, without a direct human-assay claim. ensembl:ENSRNOP00000002257 SUPPORTS TRANSFER The exact rat Q3B7D0 same-term IEP record cites PMID:2916235; the Ensembl identifier resolves to the same rat protein. The review reason preserves the source-specific exposure or fractionation result and its limits, without a direct human-assay claim. Supporting Evidence: PMID:2916235 decrease in renal, but not hepatic, coproporphyrinogen oxidase activity. |
| GO:0006785 heme B biosynthetic process | IDA PMID:7987309 Coproporphyrinogen oxidase: gene organization and descriptio... | ACCEPT | Summary: CPOX catalyzes an upstream step in the heme-B biosynthetic pathway. Reason: This original human IDA cites PMID:7987309. Its full assay details remain unavailable, so that citation-specific evidence is retained with curator deference rather than a claimed fresh verification. Independent human functional expression in PMID:8159699 and the existing curated human GO-CAM establish CPOX as the enzyme performing the coproporphyrinogen-to-protoporphyrinogen step in heme-B biosynthesis. The pathway includes formation through intermediates; this is catalytic participation, not consumption of CPOX as a substrate. Supporting Evidence: PMID:8159699 Coproporphyrinogen oxidase (EC 1.3.3.3) catalyzes the sixth step in the heme biosynthetic pathway, the oxidation of coproporphyrinogen III to protoporphyrinogen IX. file:human/CPOX/CPOX-uniprot.txt Catalyzes the aerobic oxidative decarboxylation of propionate groups of rings A and B of coproporphyrinogen-III to yield the vinyl groups in protoporphyrinogen-IX and participates to the sixth step in the heme biosynthetic pathway. PMID:8407975 Coproporphyrinogen oxidase (EC 1.3.3.3), the enzyme involved in the sixth step of heme biosynthesis, was purified to apparent homogeneity from bovine liver |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: Human Protein Atlas immunofluorescence supports mitochondrial localization. Reason: Human Protein Atlas immunofluorescence (GO_REF:0000052) reports mitochondria as the main location. This organelle-level assay cannot resolve the sub-compartment, so per the root-organelle policy the row is accepted at the organelle; the intermembrane-space location is carried separately. It agrees with the human MitoCoP proteome and with mammalian expression studies. Supporting Evidence: PMID:34800366 human mitochondrial high-confidence proteome (MitoCoP) of 1,134 protein-coding genes PMID:8407975 The cDNA allows for the expression of active coproporphyrinogen oxidase, the activity of which is mainly present in mitochondria of transfected cultured cells, thereby indicating that mammalian coproporphyrinogen oxidase is mitochondrial enzyme. file:human/CPOX/CPOX-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion intermembrane space |
| GO:0005758 mitochondrial intermembrane space | TAS Reactome:R-HSA-189421 | ACCEPT | Summary: The Reactome catalytic entity is placed in the mitochondrial intermembrane space. Reason: Current reaction R-HSA-189421 links catalyst 189416 to the two-copy CPO complex 189485, protein CPOX(111-454) 189448 and reference P36551. Its actual summary explicitly infers human intermembrane-space localization from the rat enzyme; this is curated pathway evidence, not a new human localization experiment. Supporting Evidence: Reactome:R-HSA-189421 The localization of the human enzyme to the mitochondrial intermembrane space is inferred from studies of the homologous rat enzyme (Elder and Evans 1978). Reactome:R-HSA-189421 O2-dependent coproporpyrinogen oxidase (CPO) catalyzes the conversion of coproporphyrinogen III (COPRO3) to protoporphyrinogen IX (PPGEN9) (Martasek et al. 1994). |
| GO:0004109 coproporphyrinogen oxidase activity | EXP PMID:8159699 Molecular cloning, sequencing, and functional expression of ... | ACCEPT | Summary: Human cDNA expression directly increases coproporphyrinogen-oxidase activity. Reason: PMID:8159699 functionally expressed human cDNA coding for the putative mature enzyme in Escherichia coli. The actual original Methods and Table 1 compare sense, antisense and vector conditions and measure increased coproporphyrinogen-oxidase activity. This is direct support for the catalytic activity, with the historical putative-mature construct and uncertain initiation site kept distinct from the current complete 454-residue precursor. Supporting Evidence: PMID:8159699 Expression of the cDNA coding for the putative mature human coproporphyrinogen oxidase in Escherichia coli resulted in a 17-fold increase in coproporphyrinogen activity over endogenous activity. PMID:8159699 Coproporphyrinogen oxidase (EC 1.3.3.3) catalyzes the sixth step in the heme biosynthetic pathway, the oxidation of coproporphyrinogen III to protoporphyrinogen IX. file:human/CPOX/CPOX-uniprot.txt Reaction=coproporphyrinogen III + O2 + 2 H(+) = protoporphyrinogen IX + 2 CO2 + 2 H2O |
| GO:0005758 mitochondrial intermembrane space | ISS GO_REF:0000024 | ACCEPT | Summary: Ortholog evidence supports mitochondrial intermembrane-space localization. Reason: The official human mature-chain annotation and direct rat fractionation agree on the intermembrane-space compartment. The rat work also supports a loosely membrane-associated fraction; it does not require treating the protein as exclusively soluble or as integral membrane. Preserve the distinct ISS and current combined-IEA provenance. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q3B7D0 SUPPORTS TRANSFER Current donor identities and literal records support the conserved location or catalytic pathway role. Available-source and product limits are stated separately; no historical qualifier or support list is rewritten. Supporting Evidence: PMID:31872 The enzyme was found in the intermembrane space with a fraction loosely bound to the inner membrane. file:human/CPOX/CPOX-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion intermembrane space |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: The authentic human MitoCoP dataset identifies CPOX as mitochondrial. Reason: Original Table S1 has CPOX in sheet (A) row 262 and sheet (B) row 237, with subtractive class 1, spatial cluster 1 and importomics class 1. The protein group includes P36551 and P36551-2, so the data do not establish isoform-resolved localization or catalytic equivalence. Its soluble extraction classification and inherited subcompartment annotation columns are separate from the mitochondrial enrichment evidence. Supporting Evidence: PMID:34800366 human mitochondrial high-confidence proteome (MitoCoP) of 1,134 protein-coding genes |
| GO:0004109 coproporphyrinogen oxidase activity | IDA PMID:7987309 Coproporphyrinogen oxidase: gene organization and descriptio... | ACCEPT | Summary: The source-specific human catalytic IDA is retained with curator deference and independent biochemical corroboration. Reason: PMID:7987309 is the exact source of this IDA. Its accessible abstract describes human gene structure and exon skipping, but the full assay sections were not recovered. Retain the experimentally curated activity with explicit curator deference: independent human expression in PMID:8159699 and biochemical/structural work in PMID:16176984 establish this activity. The abstract alone neither verifies this paper's particular assay nor establishes miscitation. Supporting Evidence: PMID:8159699 Expression of the cDNA coding for the putative mature human coproporphyrinogen oxidase in Escherichia coli resulted in a 17-fold increase in coproporphyrinogen activity over endogenous activity. PMID:16176984 In the biologically active dimer (K(D) = 5 x 10(-7) M), one monomer rotates relative to the second by approximately 40 degrees to create an intersubunit interface in close proximity to two independent enzymatic sites. file:human/CPOX/CPOX-uniprot.txt Reaction=coproporphyrinogen III + O2 + 2 H(+) = protoporphyrinogen IX + 2 CO2 + 2 H2O |
| GO:0042803 protein homodimerization activity | IDA PMID:16176984 Structural basis of hereditary coproporphyria. | ACCEPT | Summary: Human CPOX forms a functional homodimer. Reason: The original human crystal structure and solution ultracentrifugation support the dimer, while the exon-6 deletion disrupts it. Retain this experimentally demonstrated molecular association alongside the catalytic core, without treating the proposed radical/carbanion mechanism as experimentally settled. Supporting Evidence: PMID:16176984 In the biologically active dimer (K(D) = 5 x 10(-7) M), one monomer rotates relative to the second by approximately 40 degrees to create an intersubunit interface in close proximity to two independent enzymatic sites. PMID:16176984 We show that deletion of residues (392-418) encoded by exon six disrupts dimerization. file:human/CPOX/CPOX-uniprot.txt SUBUNIT: Homodimer. |
| GO:0004109 coproporphyrinogen oxidase activity | TAS PMID:9888388 Systematic analysis of coproporphyrinogen oxidase gene defec... | ACCEPT | Summary: Human disease-variant expression supports the catalytic activity attributed by this TAS. Reason: The complete PMID:9888388 abstract describes prokaryotic expression of human G197W, W427R and 390delGly variants and loss or marked reduction of CPO activity. That source-specific functional comparison supports the retained catalytic TAS. The full original Methods were not recovered, so assay conditions beyond the abstract are not asserted. Supporting Evidence: PMID:9888388 The pathological significance of the point mutations G197W, W427R, and the in-frame deletion 390delGly were assessed by their respective expression in a prokaryotic system using site-directed mutagenesis. PMID:9888388 These mutations resulted in the absence or a dramatic decrease of CPO activity. |
| GO:0005739 mitochondrion | TAS PMID:8407975 Coproporphyrinogen oxidase. Purification, molecular cloning,... | ACCEPT | Summary: Mammalian CPOX is mitochondrial. Reason: PMID:8407975 purified bovine liver enzyme and cloned mouse MEL-cell cDNA; expressed activity was mainly mitochondrial. This mammalian evidence and independent human HPA/MitoCoP support the organelle-level annotation. Do not describe that historical mouse construct as the complete current human 454-residue precursor. Supporting Evidence: PMID:8407975 The cDNA allows for the expression of active coproporphyrinogen oxidase, the activity of which is mainly present in mitochondria of transfected cultured cells, thereby indicating that mammalian coproporphyrinogen oxidase is mitochondrial enzyme. PMID:16176984 Hereditary coproporphyria is an autosomal dominant disorder resulting from the half-normal activity of coproporphyrinogen oxidase (CPO), a mitochondrial enzyme catalyzing the antepenultimate step in heme biosynthesis. |
| GO:0006783 heme biosynthetic process | TAS PMID:8159699 Molecular cloning, sequencing, and functional expression of ... | ACCEPT | Summary: Traceable author statement from the human cDNA cloning and functional-expression paper: CPOX catalyzes the sixth step of heme biosynthesis. Reason: Correct core process, consistent with the IBA and IEA rows on the same term. The source establishes that CPOX itself forms protoporphyrinogen IX, a performed step of heme biosynthesis; the more specific heme B biosynthetic process is carried separately (IDA, IEA) and is used in core_functions. Supporting Evidence: PMID:8159699 Coproporphyrinogen oxidase (EC 1.3.3.3) catalyzes the sixth step in the heme biosynthetic pathway, the oxidation of coproporphyrinogen III to protoporphyrinogen IX. file:human/CPOX/CPOX-uniprot.txt Catalyzes the aerobic oxidative decarboxylation of propionate groups of rings A and B of coproporphyrinogen-III to yield the vinyl groups in protoporphyrinogen-IX and participates to the sixth step in the heme biosynthetic pathway. |
| GO:0005212 structural constituent of eye lens | IEA GO_REF:0000107 | REMOVE | Summary: Ensembl Compara projection (GO_REF:0000107) from mouse P36552 of structural constituent of eye lens, based on the Nakano cataract (nct) mutant. Reason: The molecular-function claim is not supported. The Nakano cataract is caused by a hypomorphic Cpox allele (p.R380L, about 15% residual activity) with coproporphyrin III accumulating in the lens, and a wild-type Cpox transgene normalizes the phenotype; this establishes that CPOX enzyme activity is needed for lens transparency, not that CPOX is a building block of lens structure. CPOX is a mitochondrial intermembrane-space enzyme, and nothing shows it contributes structurally to the lens. A phenotype has been converted into a structural molecular function in the mouse source, and the electronic projection carries that error to human. The lens involvement remains a suggested question. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:P36552 UNRESOLVED The exact current mouse donor assertion exists. Biological specificity and the original assay scope remain unresolved; this is not evidence that the target or source lacks the function. ensembl:ENSMUSP00000055455 UNRESOLVED The exact current mouse donor assertion exists. Biological specificity and the original assay scope remain unresolved; this is not evidence that the target or source lacks the function. Supporting Evidence: PMID:23631845 Herein, we report that cataracts in the BALB/c-nct/nct mouse are caused by a hypomorphic mutation in the coproporphyrin oxidase gene (Cpox), encoding the enzyme responsible for catalyzing oxidative decarboxylation of the heme precursor, coproporphyrinogen III, in the heme biosynthetic pathway. PMID:23631845 The CPOX isoform with the p.R380L substitution retained only 15% of the activity of the wild type isoform. BALB/c-nct/nct mice had excessive accumulation of coproporphyrin III in the lens. The NCT phenotype was normalized by the introduction of a wild type Cpox transgene. file:human/CPOX/CPOX-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion intermembrane space |
| GO:0005739 mitochondrion | IEA GO_REF:0000107 | ACCEPT | Summary: Mammalian CPOX is mitochondrial. Reason: PMID:8407975 purified bovine liver enzyme and cloned mouse MEL-cell cDNA; expressed activity was mainly mitochondrial. This mammalian evidence and independent human HPA/MitoCoP support the organelle-level annotation. Do not describe that historical mouse construct as the complete current human 454-residue precursor. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P36552 SUPPORTS TRANSFER Current donor identities and literal records support the conserved location or catalytic pathway role. Available-source and product limits are stated separately; no historical qualifier or support list is rewritten. ensembl:ENSMUSP00000055455 SUPPORTS TRANSFER Current donor identities and literal records support the conserved location or catalytic pathway role. Available-source and product limits are stated separately; no historical qualifier or support list is rewritten. Supporting Evidence: PMID:8407975 The cDNA allows for the expression of active coproporphyrinogen oxidase, the activity of which is mainly present in mitochondria of transfected cultured cells, thereby indicating that mammalian coproporphyrinogen oxidase is mitochondrial enzyme. PMID:34800366 human mitochondrial high-confidence proteome (MitoCoP) of 1,134 protein-coding genes |
| GO:0005758 mitochondrial intermembrane space | IEA GO_REF:0000120 | ACCEPT | Summary: Ortholog evidence supports mitochondrial intermembrane-space localization. Reason: The official human mature-chain annotation and direct rat fractionation agree on the intermembrane-space compartment. The rat work also supports a loosely membrane-associated fraction; it does not require treating the protein as exclusively soluble or as integral membrane. Preserve the distinct ISS and current combined-IEA provenance. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P36552 SUPPORTS TRANSFER Current donor identities and literal records support the conserved location or catalytic pathway role. Available-source and product limits are stated separately; no historical qualifier or support list is rewritten. ensembl:ENSMUSP00000055455 SUPPORTS TRANSFER Current donor identities and literal records support the conserved location or catalytic pathway role. Available-source and product limits are stated separately; no historical qualifier or support list is rewritten. UniProtKB-SubCell:SL-0169 SUPPORTS TRANSFER Current donor identities and literal records support the conserved location or catalytic pathway role. Available-source and product limits are stated separately; no historical qualifier or support list is rewritten. Supporting Evidence: file:human/CPOX/CPOX-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion intermembrane space PMID:31872 The enzyme was found in the intermembrane space with a fraction loosely bound to the inner membrane. |
| GO:0006784 heme A biosynthetic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: CPOX supplies an upstream catalytic contribution to the heme-A pathway. Reason: The current pathway definition includes reactions leading to heme A, and the exact mouse P36552 IDA cites PMID:8407975. That original measures recombinant mouse coproporphyrinogen-oxidase activity and mitochondrial import, not heme-A production or terminal heme modification. A complete current human/mouse/rat QuickGO query nevertheless shows experimentally annotated upstream comparators including Alad, Hmbs, Uros, Urod, Ppox, Fech and Alas1 alongside Cpox. Thus the annotation convention is not restricted to COX10/COX15. CPOX performs the shared precursor-forming chemistry itself; retain the existing broader downstream contribution as non-core while the compact core remains on the directly characterized heme-B pathway. No human heme-A measurement or terminal synthase activity is claimed. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P36552 SUPPORTS TRANSFER The exact current P36552 IDA GO:0006784 donor is PMID:8407975; the Ensembl identifier resolves to that mouse protein. Its upstream activity and the observed cross-gene pathway convention support this transfer, without inventing a heme-A-specific assay or terminal reaction. ensembl:ENSMUSP00000055455 SUPPORTS TRANSFER The exact current P36552 IDA GO:0006784 donor is PMID:8407975; the Ensembl identifier resolves to that mouse protein. Its upstream activity and the observed cross-gene pathway convention support this transfer, without inventing a heme-A-specific assay or terminal reaction. Supporting Evidence: PMID:8407975 Coproporphyrinogen oxidase (EC 1.3.3.3), the enzyme involved in the sixth step of heme biosynthesis, was purified to apparent homogeneity from bovine liver file:human/CPOX/CPOX-uniprot.txt PATHWAY: Porphyrin-containing compound metabolism; protoporphyrin-IX biosynthesis; protoporphyrinogen-IX from coproporphyrinogen-III (O2 route): step 1/1. |
| GO:0006785 heme B biosynthetic process | IEA GO_REF:0000107 | ACCEPT | Summary: CPOX catalyzes an upstream step in the heme-B biosynthetic pathway. Reason: The exact current mouse P36552 donor carries IDA GO:0006785 from PMID:8407975. Its actual indexed original describes mouse MCPO-1 expression and protoporphyrinogen formation; the human GO-CAM independently places the same catalytic reaction in heme-B biosynthesis. CPOX performs an intermediate-forming step of this pathway, rather than being a consumed substrate. This source-specific transfer does not rely on the separate human PMID:7987309 IDA or imply activity of every human splice product. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P36552 SUPPORTS TRANSFER Current donor identities and literal records support the conserved location or catalytic pathway role. Available-source and product limits are stated separately; no historical qualifier or support list is rewritten. ensembl:ENSMUSP00000055455 SUPPORTS TRANSFER Current donor identities and literal records support the conserved location or catalytic pathway role. Available-source and product limits are stated separately; no historical qualifier or support list is rewritten. Supporting Evidence: PMID:8407975 Coproporphyrinogen oxidase (EC 1.3.3.3), the enzyme involved in the sixth step of heme biosynthesis, was purified to apparent homogeneity from bovine liver PMID:8407975 The cDNA allows for the expression of active coproporphyrinogen oxidase, the activity of which is mainly present in mitochondria of transfected cultured cells, thereby indicating that mammalian coproporphyrinogen oxidase is mitochondrial enzyme. |
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Download this section (compressed HTML)Q: Does the 287-residue alternative product retain measurable activity or form dimers, given its altered 272–287 segment and loss of residues 288–454?
Q: Does CPOX contribute directly to lens structural integrity, or does its metabolic activity protect transparency through control of porphyrin/heme balance, and how does the mouse phenotype translate to humans?
Q: How is flux from the CPOX reaction partitioned into heme A versus other heme products in different human tissues?
Q: How do mitochondrial import, peripheral membrane association and metabolite transfer to PPOX vary across human tissues and assay conditions?
Experiment: Compare purified canonical mature CPOX and the reconstructed alternative product for folding, oligomerization and coproporphyrinogen conversion, with product-specific localization in cells.
Experiment: Separate catalytic rescue from a putative noncatalytic lens role using expression-matched catalytically impaired and structurally intact variants, measuring porphyrin accumulation and lens transparency.
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