COQ5

UniProt ID: Q5HYK3
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

COQ5 is the mitochondrial 2-methoxy-6-polyprenyl-1,4-benzoquinol methylase (EC 2.1.1.201), a Class I S-adenosyl-L-methionine (SAM)-dependent methyltransferase of the MenG/UbiE family. It catalyzes the sole C-methylation step in the biosynthesis of coenzyme Q (ubiquinone; CoQ10 in humans): using SAM as the methyl donor, it transfers a methyl group onto the C2 position of the polyprenylated benzoquinol ring, producing S-adenosyl-L-homocysteine. In humans this converts 2-methoxy-6-(all-trans-decaprenyl)benzene-1,4-diol to the corresponding methylated product en route to CoQ10. The protein is synthesized with an N-terminal mitochondrial transit peptide and localizes as a peripheral membrane protein on the matrix side of the mitochondrial inner membrane, where it is a component of the multi-subunit COQ enzyme complex (the CoQ synthome / COQ metabolon) together with COQ3, COQ4, COQ6, COQ7 and COQ9. Loss-of-function variants cause autosomal recessive primary coenzyme Q10 deficiency (COQ10D9), presenting with cerebellar ataxia and static encephalomyopathy.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0006744 ubiquinone biosynthetic process
IBA
GO_REF:0000033
ACCEPT
Summary: Core biological process. COQ5 performs the only C-methylation of the ubiquinone head group and is a conserved member of the COQ family; the phylogenetic (IBA) inference to ubiquinone biosynthesis is well supported and concordant with direct experimental evidence.
Supporting Evidence:
PMID:25152161
catalyzes the only C-methylation involved in the biosynthesis of coenzyme Q
GO:0008425 2-methoxy-6-polyprenyl-1,4-benzoquinol methyltransferase activity
IBA
GO_REF:0000033
ACCEPT
Summary: Core molecular function; the exact, specific activity of COQ5. The phylogenetic inference matches the enzyme's demonstrated C-methyltransferase activity in the ubiquinone pathway.
Supporting Evidence:
PMID:25152161
catalyzes the only C-methylation involved in the biosynthesis of coenzyme Q
GO:0005743 mitochondrial inner membrane
IEA
GO_REF:0000044
ACCEPT
Summary: Correct localization. COQ5 is a peripheral (extrinsic) inner-membrane protein on the matrix side; the SubCell-based electronic annotation is consistent with experimental IDA/EXP evidence.
Supporting Evidence:
PMID:25152161
associated with the mitochondrial inner membrane on the matrix side
GO:0006744 ubiquinone biosynthetic process
IEA
GO_REF:0000120
ACCEPT
Summary: Correct core BP by electronic pipeline (UniRule/UniPathway UPA00232); redundant with experimental and phylogenetic annotations to the same term.
Supporting Evidence:
PMID:38425362
C2 methylation of 4b by COQ5
GO:0008168 methyltransferase activity
IEA
GO_REF:0000002
MARK AS OVER ANNOTATED
Summary: Correct but generic. GO:0008168 is a broad parent of the specific activity GO:0008425 that is already annotated; the specific term should be preferred, so this general term is an over-annotation.
Reason: Parent (generic methyltransferase activity) of the specific and experimentally supported GO:0008425.
GO:0008425 2-methoxy-6-polyprenyl-1,4-benzoquinol methyltransferase activity
IEA
GO_REF:0000120
ACCEPT
Summary: Core molecular function assigned electronically from RHEA:44764 / EC:2.1.1.201, matching the UniProt catalytic activity; redundant with the experimental IDA annotations to the same term.
Supporting Evidence:
PMID:38425362
C2 methylation of 4b by COQ5
GO:0031314 extrinsic component of mitochondrial inner membrane
IEA
GO_REF:0000104
ACCEPT
Summary: Accurate and informative CC. COQ5 is a peripheral membrane protein bound to the matrix face of the inner membrane, matching "extrinsic component of mitochondrial inner membrane".
Supporting Evidence:
PMID:25152161
associated with the mitochondrial inner membrane on the matrix side
GO:0005515 protein binding
IPI
PMID:27499296
Mitochondrial Protein Interaction Mapping Identifies Regulat...
MARK AS OVER ANNOTATED
Summary: Bona fide binary interaction with COQ9 (O75208), a COQ synthome partner, but "protein binding" is uninformative. The interaction is better captured by the ubiquinone biosynthesis complex (COQ synthome) part_of annotation.
Reason: Uninformative generic GO:0005515; the biology (COQ synthome membership) is captured by GO:0110142.
GO:0006744 ubiquinone biosynthetic process
TAS
Reactome:R-HSA-2142789
ACCEPT
Summary: Correct core BP asserted by Reactome (Ubiquinol biosynthesis); redundant with experimental evidence but accurately captures COQ5's role.
Supporting Evidence:
PMID:38425362
C2 methylation of 4b by COQ5
GO:0008425 2-methoxy-6-polyprenyl-1,4-benzoquinol methyltransferase activity
TAS
Reactome:R-HSA-2162188
ACCEPT
Summary: Correct core MF asserted by Reactome for the COQ5-catalyzed methylation reaction (R-HSA-2162188 "COQ5 methylates MDMQ10H2"); consistent with the experimental IDA annotations.
Supporting Evidence:
PMID:38425362
C2 methylation of 4b by COQ5
GO:0005743 mitochondrial inner membrane
IDA
PMID:27499296
Mitochondrial Protein Interaction Mapping Identifies Regulat...
ACCEPT
Summary: Experimental (ComplexPortal IDA) localization of COQ5 to the mitochondrial inner membrane, consistent with its role as a matrix-side peripheral inner-membrane protein and COQ synthome component.
Supporting Evidence:
PMID:25152161
associated with the mitochondrial inner membrane on the matrix side
GO:0006744 ubiquinone biosynthetic process
NAS
PMID:28927698
Biochemistry of Mitochondrial Coenzyme Q Biosynthesis.
ACCEPT
Summary: Correct core BP asserted (NAS) in a review of mitochondrial coenzyme Q biosynthesis; redundant with experimental evidence but accurate.
Supporting Evidence:
PMID:38425362
C2 methylation of 4b by COQ5
GO:0110142 ubiquinone biosynthesis complex
IPI
PMID:27499296
Mitochondrial Protein Interaction Mapping Identifies Regulat...
ACCEPT
Summary: Core cellular component. COQ5 is a subunit of the multi-subunit COQ enzyme complex (CoQ synthome / COQ metabolon) with COQ3, COQ4, COQ6, COQ7 and COQ9; this part_of annotation precisely captures that membership.
Supporting Evidence:
PMID:25152161
assemble with the multi-subunit complex termed the CoQ-synthome
PMID:38425362
These include COQ3, COQ4, COQ5, COQ6, COQ7 and COQ9
GO:0005739 mitochondrion
IDA
GO_REF:0000052
KEEP AS NON CORE
Summary: Correct but least specific localization (HPA immunofluorescence IDA). The specific matrix / inner-membrane locations are more informative.
Reason: Parent compartment of the specific mitochondrial matrix / inner-membrane annotations.
GO:0005759 mitochondrial matrix
TAS
Reactome:R-HSA-2162186
ACCEPT
Summary: Correct matrix-side localization asserted by Reactome; this Reactome reaction is the COQ3 step but Reactome co-annotates all COQ synthome members to the mitochondrial matrix. Concordant with the experimental IDA matrix annotation.
Supporting Evidence:
PMID:25152161
associated with the mitochondrial inner membrane on the matrix side
GO:0005759 mitochondrial matrix
TAS
Reactome:R-HSA-2162187
ACCEPT
Summary: Correct matrix-side localization asserted by Reactome (COQ6 reaction step, co-annotated to the synthome). Concordant with the experimental IDA matrix annotation.
Supporting Evidence:
PMID:25152161
associated with the mitochondrial inner membrane on the matrix side
GO:0005759 mitochondrial matrix
TAS
Reactome:R-HSA-2162188
ACCEPT
Summary: Correct matrix-side localization asserted by Reactome for the COQ5 methylation reaction step (R-HSA-2162188). Concordant with the experimental IDA matrix annotation.
Supporting Evidence:
PMID:25152161
associated with the mitochondrial inner membrane on the matrix side
GO:0005759 mitochondrial matrix
TAS
Reactome:R-HSA-2162193
ACCEPT
Summary: Correct matrix-side localization asserted by Reactome (COQ3 reaction step, co-annotated to the synthome). Concordant with the experimental IDA matrix annotation.
Supporting Evidence:
PMID:25152161
associated with the mitochondrial inner membrane on the matrix side
GO:0005759 mitochondrial matrix
TAS
Reactome:R-HSA-2162194
ACCEPT
Summary: Correct matrix-side localization asserted by Reactome (COQ7:COQ9 reaction step, co-annotated to the synthome). Concordant with the experimental IDA matrix annotation.
Supporting Evidence:
PMID:25152161
associated with the mitochondrial inner membrane on the matrix side
GO:0005759 mitochondrial matrix
TAS
Reactome:R-HSA-2162195
ACCEPT
Summary: Correct matrix-side localization asserted by Reactome (COQ4 reaction step, co-annotated to the synthome). Concordant with the experimental IDA matrix annotation.
Supporting Evidence:
PMID:25152161
associated with the mitochondrial inner membrane on the matrix side
GO:0005743 mitochondrial inner membrane
EXP
PMID:35614220
Defining mitochondrial protein functions through deep multio...
ACCEPT
Summary: Experimental localization of COQ5 to the mitochondrial inner membrane (deep multiomic profiling study that also defined the direct PYURF-COQ5 interaction). Consistent with the matrix-side peripheral inner-membrane localization.
Supporting Evidence:
file:human/COQ5/COQ5-uniprot.txt
Mitochondrion inner membrane
GO:0006744 ubiquinone biosynthetic process
IDA
PMID:38425362
In vitro construction of the COQ metabolon unveils the molec...
ACCEPT
Summary: Direct experimental support for the core BP. In vitro reconstruction of the COQ metabolon showed COQ5 performs the C2 methylation step of the ubiquinone head-group biosynthetic pathway.
Supporting Evidence:
PMID:38425362
COQ5 was incubated overnight at 30 Β°C with SAM and its substrate, 4b; GC/MS analysis confirmed enzymatic activity and production of 5
GO:0008425 2-methoxy-6-polyprenyl-1,4-benzoquinol methyltransferase activity
IDA
PMID:38425362
In vitro construction of the COQ metabolon unveils the molec...
ACCEPT
Summary: Direct experimental demonstration of the core molecular function. Purified COQ5 catalyzed SAM-dependent C2 methylation of the benzoquinol substrate with Michaelis-Menten kinetics (kcat 2.4 min-1, KM 444 uM).
Supporting Evidence:
PMID:38425362
COQ5 showed typical Michaelisβˆ’Menten kinetics over titration of 4b
GO:0005739 mitochondrion
HTP
PMID:34800366
Quantitative high-confidence human mitochondrial proteome an...
KEEP AS NON CORE
Summary: High-throughput mitochondrial proteome study places COQ5 in the mitochondrion; correct but least specific compartment.
Reason: Parent compartment of the specific matrix / inner-membrane annotations.
GO:0005515 protein binding
IPI
PMID:35614220
Defining mitochondrial protein functions through deep multio...
MARK AS OVER ANNOTATED
Summary: Direct interaction with PYURF (Q96I23), which stabilizes COQ5 and links PYURF to the COQ enzyme complex. A real and biologically important interaction, but the generic "protein binding" term is uninformative.
Reason: Uninformative generic GO:0005515; the PYURF interaction is documented in the description and SUBUNIT notes.
GO:0005515 protein binding
IPI
PMID:25152161
Molecular characterization of the human COQ5 C-methyltransfe...
MARK AS OVER ANNOTATED
Summary: Bona fide interaction with COQ4 (Q9Y3A0) demonstrated by reciprocal co-immunoprecipitation in human cells, but "protein binding" is uninformative; membership in the COQ synthome is captured by GO:0110142.
Reason: Uninformative generic GO:0005515; the COQ4 interaction reflects COQ synthome membership (GO:0110142).
Supporting Evidence:
PMID:25152161
immune-precipitation of COQ4-V5 captures COQ5-myc and vice versa
GO:0005743 mitochondrial inner membrane
IDA
PMID:25152161
Molecular characterization of the human COQ5 C-methyltransfe...
ACCEPT
Summary: Experimental colocalization of COQ5 with the mitochondrial inner membrane; consistent with its matrix-side peripheral inner-membrane localization. The colocalizes_with qualifier appropriately reflects that it is a peripheral, not integral, membrane protein.
Supporting Evidence:
PMID:25152161
associated with the mitochondrial inner membrane on the matrix side
GO:0005759 mitochondrial matrix
IDA
PMID:25152161
Molecular characterization of the human COQ5 C-methyltransfe...
ACCEPT
Summary: Core cellular component supported by direct experimental evidence. COQ5 is a peripheral inner-membrane protein exposed on the matrix side, consistent with mitochondrial matrix localization.
Supporting Evidence:
PMID:25152161
associated with the mitochondrial inner membrane on the matrix side
GO:0006744 ubiquinone biosynthetic process
IGI
PMID:25152161
Molecular characterization of the human COQ5 C-methyltransfe...
ACCEPT
Summary: Genetic-interaction (yeast complementation) evidence for the core BP. Human COQ5 partially rescued yeast coq5 mutants for respiratory growth and Q6 content, demonstrating a conserved role in ubiquinone biosynthesis.
Supporting Evidence:
PMID:25152161
catalyzes the only C-methylation involved in the biosynthesis of coenzyme Q
GO:0008425 2-methoxy-6-polyprenyl-1,4-benzoquinol methyltransferase activity
IDA
PMID:25152161
Molecular characterization of the human COQ5 C-methyltransfe...
ACCEPT
Summary: Direct experimental support for the core molecular function; COQ5 is the C-methyltransferase catalyzing the sole C-methylation of the coenzyme Q head group.
Supporting Evidence:
PMID:25152161
catalyzes the only C-methylation involved in the biosynthesis of coenzyme Q
GO:0032259 methylation
IDA
PMID:25152161
Molecular characterization of the human COQ5 C-methyltransfe...
MARK AS OVER ANNOTATED
Summary: "Methylation" is a generic BP grouping term. The specific molecular function (GO:0008425) and specific biological process (GO:0006744) already capture the methyltransferase role, making this general term redundant.
Reason: Generic process term subsumed by the specific MF (GO:0008425) and BP (GO:0006744) annotations.
GO:0032991 protein-containing complex
IDA
PMID:25152161
Molecular characterization of the human COQ5 C-methyltransfe...
MARK AS OVER ANNOTATED
Summary: Correct but generic. COQ5 is part of the COQ synthome, but the specific complex term GO:0110142 (ubiquinone biosynthesis complex) is already annotated and is far more informative.
Reason: Parent of the specific GO:0110142 ubiquinone biosynthesis complex.

Core Functions

2-methoxy-6-polyprenyl-1,4-benzoquinol C-methyltransferase: catalyzes the sole C-methylation of the coenzyme Q head group, transferring a methyl group from S-adenosyl-L-methionine to the C2 position of the polyprenylated benzoquinol ring and producing S-adenosyl-L-homocysteine.

Supporting Evidence:

References

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Notes

(COQ5-notes.md)

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