Ubiquinone (coenzyme Q) functions in both mitochondria and plasma membrane electron transport, and a growing body of evidence suggests that the ubiquinol/ubiquinone redox couple also functions as a potent, lipid soluble antioxidant system. In this latter capacity, ubiquinol (coenzyme QH2) may scavenge lipid peroxyl radicals, a class of oxidative products that represents a major cause of damage to cellular membranes, proteins, and DNA. There is a growing body of evidence that oxidative damage in mammalian cells is one of the major causes of cancer and age-related degenerative diseases, and that oxidative modifications of low density lipoprotein lipids may plan an important role in the initiation of coronary artery disease. Ubiquinone/ubiquinol is the only lipid soluble antioxidant that can be synthesized by mammalian cells. Although dietary supplementation with ubiquinone increases ubiquinol levels in the liver and lipoproteins of animals, it has little impact on the levels of ubiquinone in other tissues. Thus, it is de novo synthesis that sets the body level of ubiquinone and ubiquinol. It is surprising that the enzymology of ubiquinone biosynthesis is not understood, and the eukaryotic gene enzyme relationships have not been established. The goals of the proposed research include the elucidation of the gene enzyme relationships of ubiquinone biosynthesis, and the characterization of the polypeptide components responsible for the production of ubiquinone. The experimental system takes advantage of eight complementation groups of ubiquinone deficient (coq) mutants in the yeast Saccharomyces cerevisiae. The availability of the yeast coq mutants provides the basis for the isolation and characterization of the COQ genes and their products in both yeast and mammals. Synthetic analogs of ubiquinone intermediates provide reagents that serve both as standards in the isolation and characterization of ubiquinone intermediates, and as substrates for in vitro assays of enzyme activities. The experimental approach employs the combination of chemistry, genetics, and biochemistry to delineate the eukaryotic biosynthetic steps responsible for the production of ubiquinone, as well as to investigate the function of ubiquinone/ubiquinol as an antioxidant.
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