COQ5 (human) — gene review notes

UniProt: Q5HYK3 · HGNC:28722 · Chr 12 · 327 aa precursor (mature chain 43–327 after cleavage of an N-terminal mitochondrial transit peptide, residues 1–42).

Summary of function

COQ5 is the mitochondrial 2-methoxy-6-polyprenyl-1,4-benzoquinol methylase (EC 2.1.1.201), a Class I SAM-dependent methyltransferase of the MenG/UbiE family. It carries out the sole C-methylation step of the coenzyme Q (ubiquinone/CoQ10) head-group biosynthetic pathway, transferring a methyl group from S-adenosyl-L-methionine (SAM) onto the C2 position of the benzoquinol ring, producing S-adenosyl-L-homocysteine (SAH). In humans it converts 2-methoxy-6-(all-trans-decaprenyl)benzene-1,4-diol (DDMQ10H2) to 5-methoxy-2-methyl-3-(all-trans-decaprenyl)benzene-1,4-diol (DMQ10H2).

• UniProt RecName / EC: "2-methoxy-6-polyprenyl-1,4-benzoquinol methylase, mitochondrial ... EC=2.1.1.201" [file:human/COQ5/COQ5-uniprot.txt].
• Catalytic activity (UniProt): "Reaction=2-methoxy-6-(all-trans-decaprenyl)benzene-1,4-diol + S-adenosyl-L-methionine = 5-methoxy-2-methyl-3-(all-trans-decaprenyl)benzene-1,4-diol + S-adenosyl-L-homocysteine + H(+)" [file:human/COQ5/COQ5-uniprot.txt].
• "Coq5 catalyzes the only C-methylation involved in the biosynthesis of coenzyme Q (Q or ubiquinone) in humans and yeast Saccharomyces cerevisiae" PMID:25152161.
• In vitro reconstitution confirmed COQ5 performs the C2 methylation of substrate 4b using SAM (kcat 2.4 min⁻¹, KM 444 µM): "The remaining enzymatic steps include C2 methylation of 4b by COQ5 ... COQ5 was incubated overnight at 30 °C with SAM and its substrate, 4b; GC/MS analysis confirmed enzymatic activity and production of 5" PMID:38425362.

Pathway

Ubiquinone (coenzyme Q10) biosynthesis; UniPathway UPA00232; Reactome R-HSA-2142789 (Ubiquinol biosynthesis).
- UniProt: "PATHWAY: Cofactor biosynthesis; ubiquinone biosynthesis" [file:human/COQ5/COQ5-uniprot.txt].
- The head-group modification pathway is carried out by the COQ metabolon (COQ3, COQ4, COQ5, COQ6, COQ7, COQ9), assembled on the matrix side of the inner mitochondrial membrane PMID:38425362.

Subcellular localization

Mitochondrial inner membrane, peripheral (extrinsic) membrane protein on the matrix side; also annotated as mitochondrial matrix.
- UniProt: "SUBCELLULAR LOCATION: Mitochondrion inner membrane ... Peripheral membrane protein ... Matrix side" [file:human/COQ5/COQ5-uniprot.txt].
- "the COQ5 polypeptide is associated with the mitochondrial inner membrane on the matrix side" PMID:25152161.
- N-terminome / mass-spec studies confirm mitochondrial localization (PMID:25944712 in UniProt; HPA IDA GO:0005739; FlyBase HTP PMID:34800366).

Complex / interactions (COQ synthome / COQ metabolon)

COQ5 is a component of the multi-subunit COQ enzyme complex (CoQ synthome), composed of at least COQ3, COQ4, COQ5, COQ6, COQ7 and COQ9.
- UniProt: "SUBUNIT: Component of a multi-subunit COQ enzyme complex, composed of at least COQ3, COQ4, COQ5, COQ6, COQ7 and COQ9 (PubMed:27499296). Interacts with PYURF; the interaction is direct, stabilizes COQ5 protein and associates PYURF with COQ enzyme complex (PubMed:35614220)" [file:human/COQ5/COQ5-uniprot.txt].
- IntAct binary interactions in UniProt: COQ3 (Q9NZJ6), COQ4 (Q9Y3A0), COQ6 (Q9Y2Z9), COQ7 (Q99807), COQ9 (O75208).
- PYURF is Q96I23 (IPI PMID:35614220 with:from UniProtKB:Q96I23).
- COQ4 co-IP: "immune-precipitation of COQ4-V5 captures COQ5-myc and vice versa, indicating that these COQ proteins physically associate in a complex in human cells" PMID:25152161.

Family / domain

Class I-like SAM-binding methyltransferase superfamily; MenG/UbiE family. Pfam PF01209 (Ubie_methyltran); PROSITE PS51608 (SAM_MT_UBIE); InterPro IPR004033 (UbiE/COQ5_MeTrFase). SAM-binding residues (BINDING) at 117, 171, 199–200.
- UniProt: "SIMILARITY: Belongs to the class I-like SAM-binding methyltransferase superfamily. MenG/UbiE family" [file:human/COQ5/COQ5-uniprot.txt].

Disease

Primary coenzyme Q10 deficiency, type 9 (COQ10D9; MIM:619028), autosomal recessive; cerebellar ataxia and static encephalomyopathy due to COQ5 C-methyltransferase deficiency [PMID:29044765 — Malicdan et al. 2018 Hum Mutat; not cached locally, cited from UniProt DISEASE section].
- UniProt: "DISEASE: Coenzyme Q10 deficiency, primary, 9 (COQ10D9) [MIM:619028]" [file:human/COQ5/COQ5-uniprot.txt].

Tissue expression

Widely expressed; highest in liver, lung, placenta and skeletal muscle (UniProt TISSUE SPECIFICITY, PMID:25152161).

Curation reasoning (for the review)

Core molecular function

• GO:0008425 2-methoxy-6-polyprenyl-1,4-benzoquinol methyltransferase activity — the exact, specific MF. go.db definition matches the UniProt catalytic activity (SAM → SAH, C-methylation of benzoquinol). Supported experimentally (IDA PMID:25152161, IDA PMID:38425362) and by IBA/IEA/TAS. This is THE core function → ACCEPT the experimental IDA annotations; IBA/IEA/TAS to same term ACCEPT (redundant but correct).
• GO:0008168 methyltransferase activity (IEA, InterPro) — correct but a generic parent of GO:0008425 → MARK_AS_OVER_ANNOTATED (less informative than the specific term already present).

Core biological process

• GO:0006744 ubiquinone biosynthetic process — core BP. Multiple experimental/phylogenetic supports (IGI PMID:25152161, IDA PMID:38425362, IBA). ACCEPT the strongest; keep others.
• GO:0032259 methylation (IDA PMID:25152161) — this is a generic BP grouping term; the specific ubiquinone-biosynthesis BP + the specific MF already capture the methylation. Keep but MARK_AS_OVER_ANNOTATED (redundant generic term). Note UniProt DR also carries GO:0032259 as P:methylation IDA.

Cellular component

• GO:0005759 mitochondrial matrix (IDA PMID:25152161) — core location (matrix-side peripheral IM protein). ACCEPT experimental; Reactome TAS duplicates KEEP_AS_NON_CORE.
• GO:0005743 mitochondrial inner membrane — peripheral, matrix side. IDA (ComplexPortal PMID:27499296), EXP (PMID:35614220), colocalizes_with IDA (PMID:25152161) → ACCEPT/KEEP. IEA SubCell also correct.
• GO:0031314 extrinsic component of mitochondrial inner membrane (IEA UniRule) — precise and consistent with "peripheral membrane protein, matrix side"; ACCEPT (informative CC).
• GO:0005739 mitochondrion — correct but least specific CC; HPA IDA and FlyBase HTP → KEEP_AS_NON_CORE (parent of matrix/IM).
• GO:0110142 ubiquinone biosynthesis complex (IPI PMID:27499296, ComplexPortal) — the COQ synthome; part_of. ACCEPT (core, matches SUBUNIT).
• GO:0032991 protein-containing complex (IDA PMID:25152161) — generic parent of GO:0110142 → MARK_AS_OVER_ANNOTATED.

Protein binding (GO:0005515) IPI

Five IntAct IPIs (PMID:27499296: COQ9 O75208, COQ7 Q99807, COQ3 Q9NZJ6, COQ6 Q9Y2Z9, COQ4 Q9Y3A0) + PMID:35614220 (PYURF Q96I23) + PMID:25152161 (COQ4 Q9Y3A0). All are bona fide COQ synthome / PYURF interactions but "protein binding" is uninformative → MARK_AS_OVER_ANNOTATED each (per policy, never REMOVE an IPI protein binding). The interactions are better captured by GO:0110142 part_of and by core MF.

Reactome TAS (matrix + reaction terms)

Multiple Reactome TAS to GO:0005759 (matrix) and to GO:0008425 / GO:0006744. The reaction-specific ones (R-HSA-2162188 "COQ5 methylates MDMQ10H2") are correctly COQ5's step; others (R-HSA-2162186 COQ3, -2162187 COQ6, -2162193 COQ3, -2162194 COQ7:COQ9, -2162195 COQ4) are other pathway steps but Reactome co-annotates all synthome members to the matrix location. TAS location annotations: KEEP_AS_NON_CORE (correct location, non-experimental, redundant with IDA matrix). The R-HSA-2162188 GO:0008425 TAS is directly COQ5 → ACCEPT.