Fellowship for Fredrick Onono: Physiological role of isoprenols in sterol synthesis and protein isoprenylation

The isoprenoid diphosphates farnesyl diphosphate (FPP) and geranylgeranyl diphosphate (GGPP) are precursors for the addition of isoprenoid anchors to a wide variety of proteins which is a critical post translational modification that regulates protein function and localization. FPP is also an intermediate in the de novo synthesis of cholesterol and related sterols. Inhibition of de novo cholesterol synthesis by the class of drugs termed statins is currently the most effective pharmacological strategy for treatment of hypercholsterolemia and protection from cardiovascular disease. A detailed knowledge of isoprenoid diphosphate metabolism is therefore necessary for both understanding the actions of these drugs and for the design of potentially more effective therapies. The mevalonate pathway synthesizes FPP and GGPP without producing their corresponding isoprenols yet isoprenols including farnesol and geranylgeraniol are readily detected in cells and tissues and, like cholesterol, are a constituent of many foods. It has been known for many years that exogenously provided farnesol and geranylgeraniol can be incorporated into proteins and sterols by cultured cells. Our laboratory has developed a chemical biology/mass spectrometry based strategy for monitoring isoprenoid phosphate metabolism in live cells. We recently used this approach to identify and characterize an integral membrane phosphatase (type 1 polyisoprenoid diphosphate phosphatase, PDP1) that dephosphorylates FPP and GGPP to form farnesol and geranylgeraniol respectively