High serum cholesterol is a major cause of coronary heart disease in the United STATes. Although diet is an important factor, a significant portion of the population suffers from a genetic disorder, familial hypercholesterolemia, which impairs the ability of cells to recognize or utilize blood cholesterol. These individuals, who comprise approximately 0.2% of the world-wide population, account for 5% of heart attack victims under the age of 60. Major therapeutic breakthroughs are being achieved with highly specific inhibitors of HMGCoA reductase. This proposal seeks to study other likely therapeutic targets among enzyme in the cholesterol pathway at the genetic, structural, and mechanistic levels. The three enzymes addressed in this proposal are IPP isomerase, FPP synthetase, and squalene synthetase. Specific goals to be achieved include: (1) cloning the structural genes for IPP isomerase and squalene synthetase form Saccharomyces cerevisiae, (2) developing expression systems for overproduction of the enzymes, (3) kinetic characterization of the enzymes, (4) determining catalytically important residues in the enzyme, and (5) defining the topology of the catalytic sites.
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