COQ6 is a mitochondrial FAD-dependent (flavin, class A) monooxygenase of the UbiH/COQ6 family that catalyzes two aromatic-ring hydroxylation steps of coenzyme Q10 (ubiquinone) biosynthesis. It performs the conserved C5-ring hydroxylation of 4-hydroxy-3-(all-trans-decaprenyl)benzoate to 3,4-dihydroxy-5-(all-trans-decaprenyl)benzoate (EC 1.14.15.45) and additionally, acting downstream of the COQ4 decarboxylase, the C1-hydroxylation of 2-methoxy-6-(all-trans-decaprenyl)phenol to 2-methoxy-6-(all-trans-decaprenyl)benzene-1,4-diol (EC 1.14.15.46). Both reactions consume molecular oxygen and require FAD as cofactor, with the reducing electrons delivered from NAD(P)H via the mitochondrial ferredoxin / ferredoxin-reductase couple FDX2/FDXR rather than directly from NAD(P)H. COQ6 is a peripheral membrane protein localized to the matrix face of the mitochondrial inner membrane, where it assembles into the COQ synthome (complex Q) together with COQ3, COQ4, COQ5, COQ7 and COQ9. In humans, biallelic loss-of-function mutations cause primary coenzyme Q10 deficiency-6, presenting as steroid-resistant nephrotic syndrome with sensorineural deafness.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Mitochondrial localization is correct and central to COQ6 function, but this coarse compartment term is subsumed by the more specific mitochondrial inner membrane / matrix-face localization. Retained as non-core. Supporting Evidence: file:human/COQ6/COQ6-uniprot.txt Mitochondrion inner membrane |
| GO:0006744 ubiquinone biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: Ubiquinone biosynthetic process is the core biological process of COQ6. This IBA annotation is correct and agrees with the direct in vitro reconstitution of COQ6's hydroxylation steps (IDA, PMID:38425362). Supporting Evidence: PMID:28927698 The C5-hydroxylation is catalyzed by COQ6 in eukaryotes |
| GO:0016491 oxidoreductase activity | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Correct but very general oxidoreductase parent term. COQ6's specific monooxygenase/hydroxylase activities are captured by GO:0106364 and GO:0120538, so this broad term is retained as non-core. |
| GO:0004497 monooxygenase activity | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: COQ6 is genuinely a monooxygenase, so this ARBA-derived term is not wrong, but it is generic relative to the two specific ferredoxin-dependent hydroxylase terms. Kept as non-core. Supporting Evidence: PMID:38425362 COQ6, a class A flavin-dependent monooxygenase, represents the first protein in the CoQ head group biosynthetic pathway and performs C5 hydroxylation |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Correct localization: COQ6 is a peripheral inner-membrane protein on the matrix side. This IEA agrees with the experimental inner-membrane localization (PMID:27499296). Supporting Evidence: file:human/COQ6/COQ6-uniprot.txt Mitochondrion inner membrane |
| GO:0005794 Golgi apparatus | IEA GO_REF:0000120 | MARK AS OVER ANNOTATED | Summary: Golgi localization is a rule-propagated observation restricted to podocyte cell processes and is not a site of the core ubiquinone biosynthetic function, which occurs in mitochondria. Over-annotated as a general cellular component for this enzyme. Supporting Evidence: file:human/COQ6/COQ6-uniprot.txt Localizes to cell processes and Golgi apparatus in podocytes. |
| GO:0006744 ubiquinone biosynthetic process | IEA GO_REF:0000120 | ACCEPT | Summary: Correct core process; the electronic annotation agrees with the experimental IDA (PMID:38425362) reconstituting COQ6's hydroxylation steps in CoQ head-group synthesis. |
| GO:0016705 oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Accurate parent describing COQ6's oxygenase chemistry, but less informative than the two specific ferredoxin-dependent hydroxylase terms. Kept as non-core. |
| GO:0016712 oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen | IEA GO_REF:0000104 | KEEP AS NON CORE | Summary: Correct grouping term for a flavin-dependent monooxygenase using O2. It accurately reflects COQ6's chemistry but is broader than the specific GO:0106364 / GO:0120538 activities. Kept as non-core. Supporting Evidence: PMID:38425362 COQ6, a class A flavin-dependent monooxygenase, represents the first protein in the CoQ head group biosynthetic pathway and performs C5 hydroxylation |
| GO:0031314 extrinsic component of mitochondrial inner membrane | IEA GO_REF:0000104 | ACCEPT | Summary: Accurately captures the peripheral, matrix-side association of COQ6 with the inner membrane, consistent with UniProt (peripheral membrane protein, matrix side) and the COQ synthome being peripherally attached to the matrix face of the inner membrane. Supporting Evidence: PMID:28927698 peripherally associated with the matrix face of the inner membrane |
| GO:0050660 flavin adenine dinucleotide binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: COQ6 binds FAD as its cofactor; this term is correct. It is near-synonymous with the FAD binding term (GO:0071949) also annotated from InterPro, so it is kept as non-core to avoid redundancy. Supporting Evidence: PMID:38425362 Full-length COQ6 was purified as a flavin adenine dinucleotide (FAD)-bound protein |
| GO:0071949 FAD binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: COQ6 was purified as an FAD-bound flavoprotein and requires FAD for catalysis; FAD binding is a genuine, well-supported cofactor-binding molecular function, kept as non-core (the catalytic hydroxylase activities are the core functions), consistent with GO:0050660. Supporting Evidence: PMID:38425362 Full-length COQ6 was purified as a flavin adenine dinucleotide (FAD)-bound protein |
| GO:0106364 4-hydroxy-3-all-trans-polyprenylbenzoate oxygenase activity | IEA GO_REF:0000120 | ACCEPT | Summary: This is the canonical C5-ring hydroxylase activity of COQ6 (EC 1.14.15.45). The IEA agrees with the direct biochemical demonstration of this activity (IDA, PMID:38425362). Supporting Evidence: PMID:38425362 COQ6, a class A flavin-dependent monooxygenase, represents the first protein in the CoQ head group biosynthetic pathway and performs C5 hydroxylation |
| GO:0120538 2-methoxy-6-polyprenolphenol 4-hydroxylase activity | IEA GO_REF:0000120 | ACCEPT | Summary: This is the C1-hydroxylase activity of COQ6 (EC 1.14.15.46). The IEA agrees with the direct biochemical demonstration of this activity (IDA, PMID:38425362). Supporting Evidence: PMID:38425362 corroborating its dual functionality as both a C5 and C1 hydroxylase |
| GO:0005515 protein binding | IPI PMID:27499296 Mitochondrial Protein Interaction Mapping Identifies Regulat... | REMOVE | Summary: Bare protein binding (IPI) recording binary interactions of COQ6 with other COQ synthome subunits (COQ3, COQ4, COQ5, COQ7). The interactions are real but uninformative as a stand-alone molecular function; the biology is captured by the ubiquinone biosynthesis complex (GO:0110142) membership term, so this row is removed (removal does not mean the interactions are false). Supporting Evidence: PMID:27499296 identify a dynamic human coenzyme Q biosynthetic complex that includes multiple MXPs |
| GO:0005743 mitochondrial inner membrane | IDA PMID:27499296 Mitochondrial Protein Interaction Mapping Identifies Regulat... | ACCEPT | Summary: Direct assay localizing COQ6 to the mitochondrial inner membrane as part of the CoQ biosynthetic complex. This is the core cellular-component localization for COQ6. Supporting Evidence: file:human/COQ6/COQ6-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0006744 ubiquinone biosynthetic process | NAS PMID:28927698 Biochemistry of Mitochondrial Coenzyme Q Biosynthesis. | ACCEPT | Summary: Correct core process, asserted in a review (NAS). Duplicates the experimental IDA (PMID:38425362) also accepted. Supporting Evidence: PMID:28927698 The C5-hydroxylation is catalyzed by COQ6 in eukaryotes |
| GO:0110142 ubiquinone biosynthesis complex | IPI PMID:27499296 Mitochondrial Protein Interaction Mapping Identifies Regulat... | ACCEPT | Summary: COQ6 is a component of the CoQ synthome (complex Q) on the matrix face of the inner mitochondrial membrane, together with COQ3, COQ4, COQ5, COQ7 and COQ9. This is a core cellular-component assignment. Supporting Evidence: PMID:27499296 identify a dynamic human coenzyme Q biosynthetic complex that includes multiple MXPs |
| GO:0006744 ubiquinone biosynthetic process | IDA PMID:38425362 In vitro construction of the COQ metabolon unveils the molec... | ACCEPT | Summary: Direct in vitro reconstitution showing COQ6 initiates and performs hydroxylation steps of the CoQ biosynthetic pathway. This is the core biological process for COQ6. Supporting Evidence: PMID:38425362 COQ6, a class A flavin-dependent monooxygenase, represents the first protein in the CoQ head group biosynthetic pathway and performs C5 hydroxylation |
| GO:0106364 4-hydroxy-3-all-trans-polyprenylbenzoate oxygenase activity | IDA PMID:38425362 In vitro construction of the COQ metabolon unveils the molec... | ACCEPT | Summary: Directly demonstrated C5-ring hydroxylase activity (EC 1.14.15.45): COQ6 converts 4-hydroxy-3-(all-trans-decaprenyl)benzoate to the 3,4-dihydroxy product, dependent on the FDXR/FDX2 electron-donor couple. This is a core molecular function of COQ6. Supporting Evidence: PMID:38425362 COQ6 activity, and the first reaction step in CoQ biosynthesis, is triggered by a coupled ferredoxin pair |
| GO:0120538 2-methoxy-6-polyprenolphenol 4-hydroxylase activity | IDA PMID:38425362 In vitro construction of the COQ metabolon unveils the molec... | ACCEPT | Summary: Directly demonstrated C1-hydroxylase activity (EC 1.14.15.46): downstream of COQ4, COQ6 hydroxylates 2-methoxy-6-(all-trans-decaprenyl)phenol, establishing its dual C5/C1 hydroxylase role. This is a core molecular function of COQ6. Supporting Evidence: PMID:38425362 corroborating its dual functionality as both a C5 and C1 hydroxylase |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | KEEP AS NON CORE | Summary: High-throughput proteomic evidence of mitochondrial localization; correct but subsumed by the specific inner-membrane/matrix-face localization. Kept as non-core. |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-2162186 | ACCEPT | Summary: Reactome TAS localization to the inner membrane, correct and consistent with the experimental localization (UniProt records the inner-membrane location from PMID:27499296). |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-2162187 | ACCEPT | Summary: Reactome TAS localization (COQ6 hydroxylates DHB reaction), correct and consistent with the experimental inner-membrane localization (UniProt, from PMID:27499296). |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-2162188 | ACCEPT | Summary: Reactome TAS localization to the inner membrane, correct and consistent with the experimental localization (UniProt records the inner-membrane location from PMID:27499296). |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-2162193 | ACCEPT | Summary: Reactome TAS localization to the inner membrane, correct and consistent with the experimental localization (UniProt records the inner-membrane location from PMID:27499296). |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-2162194 | ACCEPT | Summary: Reactome TAS localization to the inner membrane, correct and consistent with the experimental localization (UniProt records the inner-membrane location from PMID:27499296). |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-2162195 | ACCEPT | Summary: Reactome TAS localization to the inner membrane, correct and consistent with the experimental localization (UniProt records the inner-membrane location from PMID:27499296). |
| GO:0005739 mitochondrion | IDA GO_REF:0000054 | KEEP AS NON CORE | Summary: Localization of an expressed fusion protein to mitochondria; correct core compartment but coarser than the specific inner-membrane/matrix-face localization retained as core. Kept as non-core. |
Loading supporting content…
Download this section (compressed HTML)Q: In human mitochondria, does COQ6 C5-hydroxylation precede or follow COQ4 C1-decarboxylation, and does the order differ between tissues such as podocytes and neurons?
Experiment: Assay recombinant COQ6 variants found in COQ10D6 patients for C5 versus C1 hydroxylase activity with FDX2/FDXR as electron donor, to test whether nephrotic-syndrome alleles selectively impair one of the two reactions.
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)