Coenzyme Q Biosynthesis: Evidence for a Substrate Access Channel in the FAD-Dependent Monooxygenase Coq6

PLoS Computational Biology
Alexandre IsmailMarc Fontecave

Abstract

Coq6 is an enzyme involved in the biosynthesis of coenzyme Q, a polyisoprenylated benzoquinone lipid essential to the function of the mitochondrial respiratory chain. In the yeast Saccharomyces cerevisiae, this putative flavin-dependent monooxygenase is proposed to hydroxylate the benzene ring of coenzyme Q (ubiquinone) precursor at position C5. We show here through biochemical studies that Coq6 is a flavoprotein using FAD as a cofactor. Homology models of the Coq6-FAD complex are constructed and studied through molecular dynamics and substrate docking calculations of 3-hexaprenyl-4-hydroxyphenol (4-HP6), a bulky hydrophobic model substrate. We identify a putative access channel for Coq6 in a wild type model and propose in silico mutations positioned at its entrance capable of partially (G248R and L382E single mutations) or completely (a G248R-L382E double-mutation) blocking access to the channel for the substrate. Further in vivo assays support the computational predictions, thus explaining the decreased activities or inactivation of the mutated enzymes. This work provides the first detailed structural information of an important and highly conserved enzyme of ubiquinone biosynthesis.

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Citations

Jan 4, 2019·International Journal of Environmental Research and Public Health·Shan LiuWenjun Ding
Jul 8, 2018·Essays in Biochemistry·Agape M AwadCatherine F Clarke
Dec 18, 2020·International Journal of Molecular Sciences·Abigail L BarkerFranck E Dayan

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Methods Mentioned

BETA
gene knockouts
PCR
gel filtration

Software Mentioned

ClustalX
ConSurf
ROBETTA
MODELLER
Vina
DALI
Phyre2 DataBank
DiscoveryStudio
AutoDock Tools
GROMACS

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