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Thesis

French

ID: <

10670/1.zea9tt

>

Where these data come from
Study of The Biosynthetic Pathway of Coenzyne Q in Saccharomyces cerevisiae.

Abstract

Coenzyme Q (ubiquinone or Q) is a lipophilic organic molecule composed of a substituted benzoquinone and a polyisoprenyl chain containing 6 units in Saccharomyces cerevisiae (Q6), 8 in Escherichia coli (Q8) and 10 in humans (Q10). Q has a well known role as an electron carrier in the mitochondrial respiratory chain and also functions as a membrane soluble antioxidant. Primary Q10 deficiency has now been linked to mutations in six genes of Q biosynthesis and results in severe pathologies. The biosynthesis of Q is mitochondrial and requires at least nine proteins in yeast (Coq1-Coq9). 4-hydroxybenzoate (4-HB) and para-aminobenzoic acid (pABA) are the long-known aromatic precursors of the benzoquinone ring of Q. Despite intensive research efforts and the biological importance of Q, some biosynthetic steps are still uncharacterized. Herein we report that Coq6, a predicted flavin-dependent monooxygenase, is involved exclusively in the C5-hydroxylation reaction. We also demonstrate that the overexpression of the protein Coq8, which is proposed to be a kinase, in Δcoq strains restores steady state levels of the unstable Coq proteins. Moreover, we provide evidence that the kinase activity is essential for the stabilizing effect of Coq8 in the Δcoq strains. The overexpression of Coq8 helped us clarify the role of some proteins (Coq4, Coq9). We also show that using synthetic analogues of 4-HB and pABA allows bypassing deficient biosynthetic steps in some mutants. This result opens new perspectives to address the deficiencies in coenzyme Q which until now are processed by Q supplementation. Finally, the deamination reaction, which is essential for Q6 biosynthesis from pABA remains misunderstood but our results strongly suggest the involvement of Coq6 in this step.

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