COQ7 (Q99807) — gene review notes

Human COQ7 / CLK-1 (Timing protein clk-1 homolog). HGNC:2244. Chromosome 16. 217 aa precursor
(mitochondrial transit peptide 1-35; mature chain 36-217). Two isoforms (Q99807-1 canonical;
Q99807-2 lacks residues 1-38). EC 1.14.13.253.

Core biology

COQ7 is the mitochondrial carboxylate-bridged di-iron hydroxylase that catalyzes the
penultimate step of coenzyme Q (ubiquinone / CoQ10) biosynthesis: hydroxylation of
5-demethoxyubiquinol/5-methoxy-2-methyl-3-(all-trans-polyprenyl)benzoquinone (DMQ) at the C6
position, yielding demethyl-ubiquinol, which is then O-methylated by COQ3 to give CoQ.

• UniProt names it "NADPH-dependent 3-demethoxyubiquinone 3-hydroxylase, mitochondrial"
  [file:human/COQ7/COQ7-uniprot.txt "RecName: Full=NADPH-dependent 3-demethoxyubiquinone 3-hydroxylase, mitochondrial"].
• The di-iron center is a ferritin-like fold (InterPro Ferritin-like_SF; SUPFAM Ferritin-like).
  UniProt cofactor: "Binds 2 iron ions per subunit"
  [file:human/COQ7/COQ7-uniprot.txt "Note=Binds 2 iron ions per subunit."]. Fe-binding residues:
  E60, E90, H93, E142, E178, E181 (BINDING lines).
• Mechanism (Lippard, PMID:23445365): the enzyme is a 5-demethoxyubiquinone hydroxylase using
  a carboxylate-bridged diiron center; DMQ binding mediates reduction of the diiron center by
  NADH and initiates O2 activation for subsequent DMQ hydroxylation. This is a di-iron, NOT a
  flavin, enzyme. [PMID:23445365 "GB1-hCLK-1 functions as a 5-demethoxyubiquinone-hydroxylase,
  utilizing its carboxylate-bridged diiron center"; "The binding of DMQn (n = 0 or 2) to
  GB1-hCLK-1 mediates reduction of the diiron center by nicotinamide adenine dinucleotide (NADH)
  and initiates O2 activation for subsequent DMQ hydroxylation."]

COQ synthome / partners

• Part of the eukaryotic CoQ biosynthetic (COQ) metabolon / synthome on the matrix face of the
  inner mitochondrial membrane, comprising COQ3, COQ4, COQ5, COQ6, COQ7, COQ9
  PMID:38425362. GO:0110142 (ubiquinone biosynthesis complex) definition explicitly lists
  COQ3-7,9.
• COQ9 is a lipid-binding protein that binds and presents the lipophilic DMQ substrate to COQ7
  [PMID:25339443 "COQ9 specifically interacts with COQ7 through a series of conserved residues";
  "suggesting that COQ9 might serve to present its bound lipid to COQ7"]. COQ9 boosts COQ7
  catalytic efficiency in vitro PMID:38425362.
• In vitro reconstitution confirms COQ7 as the NADH-dependent hydroxylase with a
  carboxylate-bridged diiron centre converting substrate 5 to 6 (C6 step)
  PMID:38425362.
• UniProt SUBUNIT: interacts with COQ8B and COQ6 (PMID:24270420), COQ9 (PMID:25339443); IntAct
  binary partners COQ3, COQ4, COQ5, COQ6, COQ9. The cryo-EM structure is a multimeric
  COQ7:COQ9 octamer (PDB 7SSP/7SSS; PMID:36306796).
• Floyd et al. mito-interaction map identified the dynamic human CoQ biosynthetic complex
  PMID:27499296.

Localization

• Canonical: mitochondrion inner membrane, peripheral membrane protein, matrix side
  [file:human/COQ7/COQ7-uniprot.txt "Mitochondrion inner membrane"]. Confirmed by ComplexPortal
  IDA (GO:0005743), Reactome TAS, and mito-proteome HTP (PMID:34800366, MitoCoP).
• A distinct nuclear pool of uncleaved COQ7/CLK-1 exists and has a moonlighting retrograde-
  signaling role independent of ubiquinone biosynthesis [PMID:25961505 "we have uncovered a
  distinct nuclear form of CLK-1 that independently regulates lifespan"; "COQ7 has a biologically
  relevant nuclear role that is independent of its characterised mitochondrial function in
  ubiquinone biosynthesis"]. This pool associates with chromatin
  PMID:25961505 and modulates
  ROS metabolism and the UPRmt via gene expression. This is a genuine but non-core secondary
  function; the primary, disease-relevant function is the mitochondrial CoQ hydroxylase step.

Disease

• Primary CoQ10 deficiency-8 (COQ10D8, MIM:616733), autosomal recessive: decreased CoQ10 from
  loss of COQ7 hydroxylase activity; multisystem (renal, cardiac, neuropathy). Variants V141E,
  L111P, R107W, R54Q, Y149C etc. Pathogenic variants lower CoQ and enzyme activity
  PMID:28409910. DHB (2,4-dihydroxybenzoate) bypass can rescue.
• Distal hereditary motor neuronopathy AR-9 (HMNR9, MIM:620402) (PMID:36758993, 37392700).

Annotation review orientation (GOA has 37 rows)

• Core MF: GO:0160224 3-demethoxyubiquinone 3-hydroxylase (NADH) activity — EXP (PMID:23445365),
  IDA (PMID:38425362), plus IBA/IEA. The GO term's reaction definition exactly matches the UniProt
  Rhea reaction. ACCEPT.
• Iron ion binding: GOA has only generic GO:0046872 metal ion binding (IEA-KW). The di-iron
  center is well documented; GO:0005506 iron ion binding is the accurate specific MF — propose in
  core_functions and MODIFY the metal-ion-binding IEA toward it. (No existing GO:0005506 row.)
• Core BP: GO:0006744 ubiquinone biosynthetic process — IDA (PMID:38425362), IMP (PMID:28409910),
  plus IBA/IEA/NAS. ACCEPT.
• GO:0004497 monooxygenase activity (IEA InterPro) and GO:0016709 (IEA UniRule) are correct
  parent MF terms but less informative than GO:0160224 → MARK_AS_OVER_ANNOTATED (redundant generic
  parents; not wrong — COQ7 IS a monooxygenase; note it is di-iron, not flavin/heme).
• GO:0005743 mitochondrial inner membrane (many rows: IDA ComplexPortal, IBA, IEA, 6x Reactome
  TAS): correct core location. Accept the experimental/curated ones; the 6 Reactome TAS rows are
  redundant duplicates → KEEP_AS_NON_CORE (accurate but low added value). GO:0031314 extrinsic
  component of mitochondrial inner membrane (IEA) is a more precise topology consistent with
  "peripheral membrane protein; matrix side" → ACCEPT/KEEP.
• GO:0005739 mitochondrion (IEA, IDA PMID:25961505, HTP PMID:34800366): correct but less
  specific than inner membrane → KEEP_AS_NON_CORE.
• GO:0005634 nucleus (IBA, IEA-SubCell, EXP PMID:25961505, IDA LIFEdb) and GO:0005694
  chromosome (IEA-SubCell, EXP PMID:25961505): real moonlighting location (PMID:25961505) →
  KEEP_AS_NON_CORE. The IBA "is_active_in nucleus" is over-propagated to a mitochondrial enzyme
  family → MARK_AS_OVER_ANNOTATED.
• GO:0110142 ubiquinone biosynthesis complex (IPI, ComplexPortal PMID:27499296): correct
  complex membership → ACCEPT (in_complex in core_functions).
• GO:0005515 protein binding (5x IPI): all to COQ synthome partners (COQ9=O75208, COQ5=Q5HYK3,
  COQ3=Q9NZJ6, COQ6=Q9Y2Z9, COQ4=Q9Y3A0). Real but uninformative bare "protein binding" →
  MARK_AS_OVER_ANNOTATED (do NOT remove IPI; policy). The biology (COQ9 presenting substrate) is
  captured better as complex membership + substrate presentation.
• GO:0008340 determination of adult lifespan (IBA): CLK-1/clk-1 longevity is genuine in worm/
  mouse but is largely a consequence of altered CoQ/ROS, and a nuclear moonlighting effect
  (PMID:25961505) → KEEP_AS_NON_CORE.
• GO:2000377 regulation of ROS metabolic process (IBA): supported for the nuclear pool
  (PMID:25961505) → KEEP_AS_NON_CORE.
• GO:0009410 response to xenobiotic stimulus (IEA, Ensembl ortholog from rat Q63619): weak
  electronic ortholog transfer, not supported for human COQ7 core function →
  MARK_AS_OVER_ANNOTATED (electronic, do not REMOVE recklessly; keep as caution).

2026-10-11 completion pass (claude-code)

GO:0160224 is defined on the quinone: "a 5-methoxy-2-methyl-3-(all-trans-polyprenyl)benzoquinone + NADH + O2 = a 3-demethylubiquinone" (RHEA:81211). The description and core function now say DMQ (quinone) -> 3-demethylubiquinone, where they previously said demethoxyubiquinol. UniProt's recommended name says NADPH, but its catalytic-activity line says NADH PMID:23445365. Iron ion binding was removed from core_functions because it is cofactor binding. Status COMPLETE.