Figure 1.

Schematic representation of the biosynthesis of farnesyl and geranyl pyrophosphates. HMG-CoA is synthesized from acetyl-CoA and acetoacetyl-CoA; this step is catalyzed by HMG-CoA-synthetase. HMG-CoA-reductase catalyzes the conversion of HMG-CoA to MVA, which is the precursor for cholesterol biosynthesis. MVA also serves as the precursor molecule for the biosynthesis of farnesyl pyrophosphate (farnesyl-pp) and geranylgeranyl pyrophosphates (geranylgeranyl-pp). These MVA derivatives, in turn, are incorporated into candidate substrate proteins via the prenylation reaction catalyzed by FTase and GGTase. Due to the paucity of specific inhibitors for FTase/GGTase, initial studies used LOVA to decipher the roles for protein prenylation in insulin secretion. Follow-up studies using more specific inhibitors of these enzymes further confirmed the novel roles of these lipid modification steps in insulin secretion (25,47).