Hydroxymethylglutaryl-coenzyme A reductase

Chen, G.Z., Foster, L. and Bennett, J.L. (1991) Purification and characterization of 3-hydroxymethylglutaryl-coenzyme A reductase of Schistosoma mansoni regulation of parasite enzyme activity differs from mammalian host. Experimental Parasitology 73, 82-92. 

Garnett WR. Interactions with hydroxymethylglutaryl-coenzyme a reductase inhibitors. Am J Health Syst Pharm 1995 52(15) 1639 15. 

Landesman KA, Stozek M, Freeman NJ. Rhabdomyolysis associated with the combined use of hydroxymethylglutaryl-coenzyme A reductase inhibitors with gemfibrozil and macrolide antibiotics. Conn Med 1999 63(8) 455-7. 

Jamal SM, EisenbergMJ, Christopoulos S. Rhab-domyolysis associated with hydroxymethylglutaryl-coenzyme A reductase inhibitors. Am Heart J. 2004 147 956-965. 

P.-T. Ho and S. Chung, Synthesis of 2,4-dideoxy-D-eryi/tro-hexopyranose. An intermediate for synthesis of the lactone moiety of inhibitors of hydroxymethylglutaryl-coenzyme A reductase, Carbohydr. Res., 125 (1984) 318-322. 

Hakamada-Taguchi R, UeharaY Kuribayashi K, etal. Inhibition of hydroxymethylglutaryl-coenzyme a reductase reduces Th I development and promotes Th2 development, Circ Res 2003 93 948-956. 

Alberts, A.W., Chen, J., Kuron, G., Hunt, V., Huff, J., Hoffman, C., Rothrock, J., Lopez, M., Joshua, H., Harris, E., Patchett, A., Monaghan, R., et al. (1980). Mevinolin a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent. Proc Natl Acad Sci USA 77 3957-3961. 

Einarson TR, Metge CJ, Iskedjian M, Mukherjee J. An examination of the effect of cytochrome P450 drug interactions of hydroxymethylglutaryl-coenzyme A reductase... 

The interruption of enterohepatic recirculation of bile acids by the resins effectively lowers plasma cholesterol levels since cholesterol must now be diverted to de novo synthesis of bile acids. In addition, intestinal absorption of dietary cholesterol, normally facilitated by bile acids, is also reduced due to their excretion. Two significant compensatory mechanisms are called into action increased activity of hydroxymethylglutaryl coenzyme A reductase (HMG CoA reductase), which is the rate-controlling enzyme in the hepatic synthesis of cholesterol (see Fig. 11-4 and discussion to follow), and an increase in the number of LDL receptors. The latter mechanism offered the first meaningful treatment of heterozygous FH. Homozygous FH patients lacking LDL receptors, of course, do not respond. 

Ingebritsen, T.S. Lee, H.-S. Parker, R.A. Gibson, D.M. Reversible modulation of the activities of both liver microsomal hydroxymethylglutaryl coenzyme A reductase and its inactivating enzyme. Evidence for regulation by phosphorylation-dephosphorylation. Biochem. Biophys. Res. Commun., 81, 1268-1277 (1978)... 

Mevinolin and compactin. An example of reversible ring closure is found with mevinolin and compactin, which are both potent inhibitors of hydroxymethylglutaryl-coenzyme A reductase (HMG-CoA reductase), the rate-determining enzyme in the de novo biosynthesis of cholesterol. In vivo these ring-closed derivatives (Fig. 14.8) are hydrolysed to... 

In hypophysectomized rats, the synthesis of cholesterol from acetate (19,20)—but not from mevalonate (21)—is inhibited, indicating that pituitary hormones have an effect on a metabolic step between acetate and mevalonate, probably on hydroxymethylglutaryl-coenzyme A reductase. In terms of tissue cholesterol concentrations, the hypophysectomized rat differs little from the normal. Although bile acid synthesis and excretion are reduced, these animals reach a steady state in which normal cholesterol concentrations in plasma and tissue are maintained (21,22). This is true, however, only when the hypophysectomized rat is maintained on a low-cholesterol diet. When cholesterol intake is increased, both serum and tissue cholesterol reach high levels, presumably because of the decreased ability of the hypophysectomized rat to eliminate that sterol by conversion to bile acids (10, 11,23). 

The discovery of compactin (29a) 63, 64) and mevinolin (29b) (Figure 4) (65) two decades ago as inhibitors of hydroxymethylglutaryl coenzyme A reductase revolutionized research toward the u eatment of hypercholesterolemia. During this period several analogs of mevinolin and compactin, popularly known as statin drugs, have been examined, approved and marketed as cholesterol lowering pharmaceuticals (66). 

Ergot alkaloid biosynthesis and lipid metabolism have some common regulatory points. Hydroxymethylglutaryl-coenzyme-A reductase is the key regulatory enzyme of isoprenyl unit production. The activity pattern of this enzyme in Claviceps (Kfen et al., 1986) reveals that the mevalonate distribution is shared at the beginning of the fermentation by sterol and alkaloid biosynthesis and later it is used solely for alkaloid building. 

Rueckschloss U, Galle I, Holtz J, Zerkowski HR, Morawietz H. Induction of NAD(P)H oxidase hy oxidized low-density lipoprotein in human endothelial cells antioxidative potential of hydroxymethylglutaryl coenzyme A reductase inhibitor therapy. Circulation 2001 104 1767-1772. 

Alberts AW, Chen J, Kuron G, et al. 1980. Mevinolin a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and cholesterol-lowering agent. Proc Natl Acad Sci USA - Biological Sciences 77(7) 3957-3961. 

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