Structures of compounds tested for inhibition of P. mevalonii HMG–CoA reductase and of the substrates, HMG–CoA and mevalonate. (Top left) Positions of the indicated functional groups. (Top right) Structure of Lovastatin.

Inhibition by Lovastatin of P. mevalonii HMG–CoA reductase. (Top) Inhibition of reaction 2, the oxidative acylation of mevalonate to HMG–CoA. Reactions were initiated by adding mevalonate. (Bottom) Inhibition of reaction 1, the reductive deacylation of HMG–CoA to mevalonate. Reactions were initiated by adding HMG–CoA. Activities in the presence of Lovastatin are expressed relative to the maximal observed activity in the absence of Lovastatin, the value at 0.50 mM substrate or coenzyme or at a 1/[S] or 1/[CoE] of 2.0. For both reactions, assays employed 0 (filled circles), 6.5 mM (open circles), 13 mM (filled squares), and 26 mM (open squares) Lovastatin under otherwise standard conditions.

Inhibition of P. mevalonii HMG–CoA reductase by substrate analogs. Assays of reaction 2, the oxidative acylation of mevalonate, were conducted under standard conditions except for the indicated concentrations of compounds tested as inhibitors. All reactions were initiated by adding mevalonate. Activities in the presence of an inhibitor are expressed relative to the maximal observed activity in the absence of inhibitor, the value at 0.50 mM mevalonate or at a 1/[S] of 2.0. (Top left) β-hydroxybutyrate. Assays employed 0 mM (filled circles), 0.65 mM (open circles), 1.25 mM (filled squares), or 2.5 mM (open squares) β-hydroxybutyrate. (Top right) Acetoacetate. Assays employed 0 mM (filled circles), 0.65 mM (open circles), 1.25 mM (filled squares), or 2.5 mM (open squares) acetoacetate. (Bottom left) 3-Hydroxy-3-methylglutarate (HMG). Assays employed 0 mM (filled circles), 12.5 mM (open circles), 25 mM (filled squares), or 50 mM (open squares) 3-hydroxy-3-methylglutarate. (Bottom right) γ-Hydroxybutyrate. Assays employed 0 mM (filled circles), 25 mM (open circles), 50 mM (filled squares), or 100 mM (open squares) γ-hydroxybutyrate.