title: Mechanism of inhibition of yeast squalene synthase by substrate analog inhibitors.
abstract: Squalene synthase catalyzes the reductive condensation of two identical substrate molecules, farnesyl diphosphate, to the hydrocarbon squalene via an obligatory intermediate, presqualene pyrophosphate. Since the kinetic mechanism of the transformation is sequential, two substrate binding pockets that recognize the same molecule must exist in the enzyme active site. This raises the possibility of a choice of binding pockets for inhibitors that are designed as substrate or reaction intermediate analogs and thus may provide some information on the mechanism of differentiation of the two identical molecules. In this report, we have investigated the mechanism of inhibition of a series of farnesyl diphosphate analog inhibitors. The inhibitors fall into two categories. One class of compounds binds to free enzyme as well as the enzyme substrate complex, and the binding is refractory to the concentration of the substrate. The second class binds only to the free enzyme, and its binding is significantly modulated by the substrate concentration. Very modest structural changes in the compounds appear to dictate which class of inhibitor any compound may fall into. The significance of these observations with respect to the mechanism of the enzyme are discussed.
authors.affiliation: Department of Metabolic Diseases, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey, 08543-4000, USA.
authors.forename: S S
authors.initials: SS
authors.lastname: Kalinowski
authors.forename: K A
authors.initials: KA
authors.lastname: Mookhtiar
mesh_terms: D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000201:enzymology*; D013185:Squalene / Q000737:chemistry / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D013185:Squalene; D013186:Farnesyl-Diphosphate Farnesyltransferase