COQ4 (YDR204W) encodes a mitochondrial protein of the COQ4 family that is required for coenzyme Q6 biosynthesis. Coq4 is a peripheral membrane protein on the matrix face of the inner mitochondrial membrane and is a central organizer of the CoQ synthome (the multi-subunit complex of Coq3, Coq4, Coq5, Coq6, Coq7 and Coq9), being needed for the steady-state levels of several other Coq polypeptides. Catalytically, Coq4 carries out the C1 oxidative decarboxylation of the polyprenylated ring intermediate, a single oxygen-dependent step that replaces both the bacterial UbiD/UbiX decarboxylase and the UbiH C1 hydroxylase; yeast Coq4 shows this activity when expressed in Escherichia coli ubiD and ubiD ubiH mutants and in Corynebacterium glutamicum. The protein carries the conserved HDxxH(x)11E metal-binding motif, and the human ortholog binds zinc. coq4 null mutants make no CoQ and accumulate 3-hexaprenyl-4-hydroxybenzoate.
Definition: Catalysis of the O2-dependent oxidative decarboxylation of a ring-carboxylated polyprenyl benzoate intermediate of coenzyme Q biosynthesis (such as 4-hydroxy-3-methoxy-5-polyprenylbenzoate), removing the C1 carboxyl group and introducing the C1 hydroxyl group in a single step.
Justification: GO:0120539 is defined as a non-oxidative decarboxylation to 2-methoxy-6-polyprenylphenol, and GO:0120538 assigns the C1 hydroxylation to a separate ferredoxin-dependent enzyme (Coq6), but Pelosi et al. show that COQ4 performs both C1 reactions as one oxidative decarboxylation. COQ4 reviews (yeast, S. pombe, human) and ubiquinone_biosynthesis use GO:0120539 for want of a matching term.
Parent term: carboxy-lyase activity
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003674 molecular_function | ND GO_REF:0000015 | REMOVE | Summary: Root molecular function ND annotation from SGD, made when no molecular function had been curated for Coq4 from the literature. Reason: Stale. The 2024 Pelosi et al. paper (PMID:38295803, full text checked) assays the S. cerevisiae protein itself: yeast COQ4 restores CoQ8 synthesis in E. coli ubiD and ubiD ubiH mutants, in an O2-dependent manner, and converts polyprenyl-4-hydroxybenzoates into polyprenyl-1,4-benzoquinones when expressed in C. glutamicum. That is literature on this gene product in this species identifying a molecular function (C1 oxidative decarboxylase, closest GO term GO:0120539), so the "no data" claim no longer holds. The activity is already carried by the IBA and EC-mapping GO:0120539 rows. Supporting Evidence: PMID:38295803 Heterologous expression of both yeast COQ4 (yCOQ4) and hCOQ4 increased the respiratory growth of ΞubiD cells, whereas the functionally inactive D164A mutant did not PMID:38295803 Interestingly, 9PP or 10PP were not detected in the strain expressing yCOQ4 (Fig 4E), strongly suggesting that the conversion of 9-10P-HB into PBQ9-10 occurred in a single step, via an oxidative decarboxylation. |
| GO:0005739 mitochondrion | HDA PMID:24769239 Quantitative variations of the mitochondrial proteome and ph... | ACCEPT | Summary: Detected in the quantitative proteome of isolated yeast mitochondria. Reason: Root organelle term from an organelle-proteomics assay that cannot resolve the sub-compartment; per the organelle policy this is ACCEPTed. It agrees with the Western-blot fractionation that places Coq4p on the matrix face of the inner membrane, where the CoQ synthome acts. Supporting Evidence: PMID:11469793 Coq4p was shown to peripherally associate with the matrix face of the mitochondrial inner membrane |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: IBA mitochondrion from the COQ4 family node (PTN000308948) including S. pombe coq4 and SGD COQ4, with human COQ4 as the third seed. Reason: PAINT places the mitochondrial location at PTN000308948 (PTHR12922), seeded by experimental data on yeast, fission yeast and human COQ4; yeast Coq4 is inside that clade and carries a predicted N-terminal transit peptide and direct import and fractionation data. The organelle claim holds; the row stops at the organelle because the seeds include organelle-level assays. The sub-compartment is given by the separate inner-membrane and extrinsic-component rows. Supporting Evidence: PMID:11469793 The putative mitochondrial-targeting sequence present at the amino-terminus of the polypeptide efficiently imported it to mitochondria in a membrane-potential-dependent manner. |
| GO:0005743 mitochondrial inner membrane | IDA PMID:11469793 Yeast COQ4 encodes a mitochondrial protein required for coen... | ACCEPT | Summary: Fractionation shows Coq4p peripherally associated with the matrix face of the inner membrane. Reason: Directly supported. The more precise GO:0031314 (extrinsic component of mitochondrial inner membrane) is annotated from the same paper; inner membrane remains an informative, true statement of where the protein and its complex reside. Supporting Evidence: PMID:11469793 Coq4p was shown to peripherally associate with the matrix face of the mitochondrial inner membrane |
| GO:0005743 mitochondrial inner membrane | IDA PMID:24406904 Coenzyme Q supplementation or over-expression of the yeast C... | ACCEPT | Summary: ComplexPortal annotation of the CoQ-synthome to the inner membrane, citing He et al. 2014, which analysed Coq polypeptide complexes in digitonin extracts of mitochondria. Reason: The paper's model places all Coq polypeptides of the synthome peripherally on the matrix side of the inner membrane, consistent with the fractionation data. Supporting Evidence: PMID:24406904 The model is consistent with the peripheral association of each of the Coq polypeptides to the matrix side of the mitochondrial inner membrane, with the exception of Coq2 |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000120 | ACCEPT | Summary: UniProt combined IEA (InterPro IPR027540 Coq4_euk and SubCell SL-0168). Reason: The electronic mapping agrees with the experimental location of this protein; consistent with the two IDA rows for the same term. Supporting Evidence: file:yeast/COQ4/COQ4-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0006744 ubiquinone biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from the COQ4 family node (PTN000308947) supported by yeast, S. pombe and human experimental data, together with C. elegans coq-4. Reason: PTN000308947 is the eukaryotic COQ4 node (taxon:2759); yeast Coq4 is a member and is itself one of the experimental seeds, which marks experimental grounding on the target rather than circularity. Coq4 catalyses the C1 oxidative decarboxylation step, so it does work within the process. Supporting Evidence: PMID:9266513 Q mutant strains harboring mutations in the coq3, coq4, coq5, coq6, coq7, or coq8 genes were unable to produce Q PMID:38295803 these two reactions occur in a single oxidative decarboxylation step catalyzed by COQ4 |
| GO:0006744 ubiquinone biosynthetic process | IEA GO_REF:0000120 | ACCEPT | Summary: UniProt combined IEA from InterPro IPR007715/IPR027540, UniRule and UniPathway. Reason: Correct; consistent with the experimental and IBA rows for the core process. Supporting Evidence: file:yeast/COQ4/COQ4-uniprot.txt PATHWAY: Cofactor biosynthesis; ubiquinone biosynthesis. |
| GO:0006744 ubiquinone biosynthetic process | IMP PMID:11469793 Yeast COQ4 encodes a mitochondrial protein required for coen... | ACCEPT | Summary: COQ4 complements a Q-deficient coq4 mutant, restoring Q6 synthesis and respiration. Reason: Necessity shown by complementation; participation is established by the catalytic C1 step (PMID:38295803) and the scaffolding role in the synthome. Supporting Evidence: PMID:11469793 Yeast coq4 mutant strains harboring the COQ4 gene on either single- or multicopy plasmids acquired the ability to grow on media containing a nonfermentable carbon source, synthesize Q(6), and respire. |
| GO:0006744 ubiquinone biosynthetic process | IMP PMID:9266513 Sensitivity to treatment with polyunsaturated fatty acids is... | ACCEPT | Summary: coq4 mutants are unable to produce Q and accumulate the early intermediate 3-hexaprenyl-4-hydroxybenzoate. Reason: Accumulation of HHB places the coq4 block after prenylation and before the ring modifications, consistent with Coq4 acting in the ring-modification sequence. Supporting Evidence: PMID:9266513 Q mutant strains harboring mutations in the coq3, coq4, coq5, coq6, coq7, or coq8 genes were unable to produce Q |
| GO:0006744 ubiquinone biosynthetic process | NAS PMID:24406904 Coenzyme Q supplementation or over-expression of the yeast C... | ACCEPT | Summary: ComplexPortal NAS for the CoQ-synthome, citing He et al. 2014. Reason: Correct; consistent with the experimental rows for the same term. Supporting Evidence: PMID:24406904 indicating that Coq4 is a central organizer of the Coq complex |
| GO:0008270 zinc ion binding | IEA GO_REF:0000104 | ACCEPT | Summary: UniRule (HAMAP MF_03111) zinc ion binding; UniProt lists Zn2+ as a cofactor of the COQ4 family by similarity. Reason: COQ4 proteins share the HDxxH(x)11E motif; purified human COQ4 binds about two zinc ions and the motif D164A mutant loses zinc binding and cannot complement yeast coq4 null cells. Zinc has not been measured on the yeast protein, but the cofactor is part of the catalytic mechanism of the family and the human COQ4 review treats it the same way, so the row is kept as supporting the core activity. Supporting Evidence: file:yeast/COQ4/COQ4-uniprot.txt Name=Zn(2+); Xref=ChEBI:CHEBI:29105 PMID:38295803 The D164A mutant was unable to complement respiratory growth in ΞCOQ4 yeast (Fig S2E) and the protein was virtually unable to bind zinc (Fig 2A). |
| GO:0016831 carboxy-lyase activity | IEA GO_REF:0000104 | MODIFY | Summary: UniRule carboxy-lyase activity; parent of GO:0120539. Reason: Correct but less precise than the specific decarboxylase term GO:0120539 that the gene already carries from IBA and EC mapping. Proposed replacements: 4-hydroxy-3-methoxy-5-polyprenylbenzoate decarboxylase activity Supporting Evidence: PMID:38295803 these two reactions occur in a single oxidative decarboxylation step catalyzed by COQ4 |
| GO:0031314 extrinsic component of mitochondrial inner membrane | IDA PMID:11469793 Yeast COQ4 encodes a mitochondrial protein required for coen... | ACCEPT | Summary: Coq4p is a peripheral membrane protein on the matrix face of the inner membrane. Reason: Most precise location supported by data, and where the CoQ synthome acts. Supporting Evidence: PMID:11469793 Coq4p was shown to peripherally associate with the matrix face of the mitochondrial inner membrane |
| GO:0031314 extrinsic component of mitochondrial inner membrane | IEA GO_REF:0000104 | ACCEPT | Summary: UniRule extrinsic component of mitochondrial inner membrane, matching experimental data. Reason: Consistent with the IDA row for the same term. Supporting Evidence: file:yeast/COQ4/COQ4-uniprot.txt Peripheral membrane protein |
| GO:0120539 4-hydroxy-3-methoxy-5-polyprenylbenzoate decarboxylase activity | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA from PTN000308947 seeded by human COQ4 (Q9Y3A0) experimental annotation of the C1 decarboxylase activity (PMID:38295803). Reason: Yeast Coq4 is inside the eukaryotic COQ4 clade (PTN000308947, taxon:2759) and the same paper shows the yeast protein itself performs the C1 decarboxylation in E. coli and C. glutamicum. The GO term describes a non-oxidative decarboxylation to the phenol, whereas Pelosi et al. show a coupled oxidative decarboxylation; GO:0120539 is the closest existing term and is the one the module and the human COQ4 review use. Supporting Evidence: PMID:38295803 these two reactions occur in a single oxidative decarboxylation step catalyzed by COQ4 PMID:38295803 Finally, we found that the activity of yCOQ4 and hCOQ4 depends on O2 |
| GO:0120539 4-hydroxy-3-methoxy-5-polyprenylbenzoate decarboxylase activity | IEA GO_REF:0000003 | ACCEPT | Summary: EC-to-GO mapping from EC 4.1.1.130 (assigned by UniProt via HAMAP MF_03111). Reason: The EC assignment is by similarity, but the activity is supported by direct data on the yeast protein (PMID:38295803); consistent with the IBA row. Supporting Evidence: file:yeast/COQ4/COQ4-uniprot.txt Reaction=4-hydroxy-3-methoxy-5-(all-trans-hexaprenyl)benzoate + H(+) = PMID:38295803 Heterologous expression of both yeast COQ4 (yCOQ4) and hCOQ4 increased the respiratory growth of ΞubiD cells |
| GO:0110142 ubiquinone biosynthesis complex | IDA PMID:17391640 Saccharomyces cerevisiae Coq9 polypeptide is a subunit of th... | NEW | Summary: Blue-native PAGE shows Coq4p co-migrating with Coq3p and Coq9p in an approximately 1 MDa complex, and Coq4 is described as the central organizer of this CoQ synthome (PMID:24406904). GOA carries only membrane locations, not membership of the complex, although the GO:0110142 definition explicitly lists COQ4. Reason: Coq4 is a physical, structural subunit of the complex (the GO definition names it), so part_of is warranted; this is a cellular-component statement, not a process term, so the participation bar for NEW process terms does not apply. Supporting Evidence: PMID:17391640 Coq9p was found to co-migrate with Coq3p and Coq4p at a molecular mass of approximately 1 MDa PMID:24406904 indicating that Coq4 is a central organizer of the Coq complex |
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Download this section (compressed HTML)Q: GO:0120539 is defined as a non-oxidative decarboxylation to 2-methoxy-6-polyprenylphenol, but Pelosi et al. (PMID:38295803) report an O2-dependent oxidative decarboxylation that yields the C1-hydroxylated product in one step and can act on non-methoxylated polyprenyl-4-hydroxybenzoates. Should GO add an oxidative-decarboxylase term for COQ4, and should GO:0120538 (ferredoxin-dependent C1 hydroxylase) be withdrawn from Coq6 orthologs?
Experiment: Reconstitute purified, zinc-loaded yeast Coq4 with polyprenyl-4-hydroxybenzoate and 4-hydroxy-3-methoxy-5-polyprenylbenzoate in vitro under aerobic and anaerobic conditions to identify the true substrate, product and oxidant of the C1 reaction.
Protein with a role in ubiquinone (Coenzyme Q) biosynthesis; possibly functioning in stabilization of Coq7p; located on matrix face of mitochondrial inner membrane; component of a mitochondrial ubiquinone-synthesizing complex; human homolog COQ4 can complement yeast coq4 null mutant
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