Coenzyme Q10 (ubiquinone) biosynthesis (PDSS1/2, COQ2-COQ9)

Coenzyme Q10 (ubiquinone-10) is the lipophilic electron/proton carrier of the mitochondrial inner membrane that shuttles electrons from respiratory Complexes I and II (and from electron-transfer flavoprotein, dihydroorotate dehydrogenase and others) to Complex III, and is a membrane antioxidant. Its biosynthesis has two arms that meet at the matrix face of the inner membrane. First, the C50 polyisoprenoid tail is built: the all-trans-decaprenyl-diphosphate synthase, a heterotetramer of PDSS1 and PDSS2, condenses (2E,6E)-farnesyl diphosphate with isopentenyl diphosphate units to all-trans- decaprenyl diphosphate. The polytopic inner-membrane prenyltransferase COQ2 then attaches this tail to the ring precursor 4-hydroxybenzoate, committing it to the pathway. A series of ring modifications, carried out by a membrane-associated multienzyme assembly (the "COQ synthome"/complex Q), converts the polyprenyl-hydroxybenzoate to ubiquinol: FAD-dependent hydroxylation by COQ6, C-methylation by the SAM-dependent methyltransferase COQ5, Zn-dependent C1 decarboxylation by COQ4, di-iron C6 hydroxylation by COQ7 (whose lipophilic substrate is bound and presented by the lipid-binding protein COQ9), and the two O-methylation steps performed by COQ3 (not covered here). Assembly and activity of the synthome require the atypical UbiB-family kinase/ATPases COQ8A and COQ8B. The exact order of the head-group modifications in humans is not fully resolved, and the enzymes act within the synthome complex rather than as free-standing steps. Defects in any of these genes cause primary coenzyme Q10 deficiency, a clinically heterogeneous mitochondrial disease (encephalomyopathy, cerebellar ataxia, steroid-resistant nephrotic syndrome, Leigh syndrome), some forms of which are partially responsive to oral CoQ10.