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Characterizing the stabilizing effect of the putative kinase Coq8 and the function of the Coq9 polypeptide in yeast coenzyme Q biosynthesis


Coenzyme Q (Q) is an essential lipid in cellular energy metabolism, but its biosynthesis is not fully understood. Q functions as an electron carrier in the mitochondrial respiratory chain and as a lipid-soluble antioxidant. Q biosynthesis in yeast Saccharomyces cerevisiae requires a multi-subunit Coq polypeptide complex composed of the Coq3−Coq9 polypeptides, but the function of several Coq polypeptides is unknown, including Coq9. Deletion of any of the COQ3−COQ9 genes leads to the decreased steady state of other Coq polypeptides. The over-expression of the putative kinase, Coq8, in some of the yeast coq null mutants, restored steady state levels of Coq polypeptides to near wild-type levels and led to the production of late-stage Q intermediates. In this dissertation, the following chapters summarize four projects on Q biosynthesis: Chapter 2 investigates whether Coenzyme Q6 supplementation or over-expression of Coq8 stabilizes high molecular mass Coq polypeptide complexes. Based on our findings, we proposed a new model for the complex, which we called the CoQ-synthome. In Chapter 3, the characterization of Coq9 function is described. We conclude that Coq9 is required for the function of Coq6 and Coq7 and for the removal of the nitrogen substituent from Q-intermediates derived from para-aminobenzoic acid. The functional role of human Coq9 in Q10 biosynthesis is not understood. In Chapter 4 we found that human COQ9 rescues the growth of a temperature-sensitive yeast coq9 mutant, TS19, on non-fermentable carbon source and increases the content of Q6, possibly by increasing the Q biosynthesis from 4-hydroxybenzoic acid (4HB). Chapter 5 demonstrates that para-coumarate is a ring precursor for Q biosynthesis in E. coli, S. cerevisiae, and human cells. This work aids our understanding of Q biosynthesis and suggests new approaches that may enhance Q biosynthesis and function in human disease.

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