Reaction Kinetics, Catalytic Mechanisms, Conformational Changes, and Inhibitor Design for Prenyltransferases

Isoprenoids comprise a family of more than 55000 natural products with great structural variety derived from five-carbon isopentenyl diphosphate (IPP) and its isomer dimethylallyl diphosphate (DMAPP). Allylic diphosphates such as farnesyl diphosphate (FPP) synthesized from DMAPP and IPP serve as outlet points for a great variety of products, A group of prenyltransferases catalyzing chain elongation of FPP to designated lengths by consecutive condensation reactions with specific numbers of IPP are classified as cis and trans types according to the stereochemistry of the double bonds formed by I PP condensation. The complete kinetics of the multistep IPP condensation reactions by both types of enzymes has been determined using steady-state and pre-steady-state approaches. Because their crystal structures were determined in conjunction with biochemical studies, a more thorough understanding of their catalytic mechanisms, protein conformational changes, and product chain-length determination mechanisms has been gained recently. Since these prenyltransferases play important roles, potent inhibitors have been identified and their cocrystal structures have been determined for drug development. In this review, the current knowledge of these prenyltransferases that synthesize prenyl oligomers or polymers is summarized.