Rat liver 3-hydroxy-3-methylglutaryl-CoA reductase. Catalysis of the reverse reaction and two half-reactions.
Rat liver 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase catalyzes, in addition to its normal biosynthetic or forward reaction (HMG-CoA + 2 NADPH + 2H+----mevalonate + 2 NAD+ + CoASH), the reverse reaction (mevalonate + CoASH + 2 NADP+----HMG-CoA + 2 NADPH + 2H+) and two "half-reactions" that involve the presumed intermediate mevaldate (mevaldate + CoASH + NADP+----HMG-CoA + NADPH + H+ and mevaldate + NADPH + H+----mevalonate + NADP+). These reactions were studied using both enzyme solubilized by the traditional freeze-thaw method and enzyme solubilized with a nonionic detergent in the presence of inhibitors of proteolysis. All four reactions were inhibited by mevinolin, a known inhibitor of the forward (biosynthetic) reaction catalyzed by HMG-CoA reductase. When the enzyme was inactivated by ATP and a cytosolic, ADP-dependent HMG-CoA reductase kinase, the rates of both the forward reaction and the half-reactions decreased to comparable extents. Although coenzyme A is not a stoichiometric participant in the second half-reaction (mevaldate + NADPH + H+----mevalonate + NADP+), it was required as an activator of this reaction. This observation implies that coenzyme A may remain bound to the enzyme throughout the normal catalytic cycle of HMG-CoA reductase.
Sherban
D G
DG
Kennelly
P J
PJ
Brandt
K G
KG
Rodwell
V W
VW
D000818:Animals; D002384:Catalysis; D003065:Coenzyme A / Q000378:metabolism / Q000494:pharmacology; D003600:Cytosol / Q000201:enzymology; D005976:Glutaral / Q000031:analogs & derivatives / Q000378:metabolism; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008148:Lovastatin; D015093:Meglutol / Q000378:metabolism; D008798:Mevalonic Acid / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology; D051381:Rats; D013053:Spectrophotometry
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009281:Naphthalenes; D009243:NAD; D009249:NADP; D008148:Lovastatin; D015093:Meglutol; D006903:Hydroxymethylglutaryl CoA Reductases; D008798:Mevalonic Acid; D003065:Coenzyme A; D005976:Glutaral; C005261:mevaldic acid