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14 Mammalian HMG-CoA Reductase and Its Regulation

The Enzymes, ISSN: 1874-6047, Vol: 16, Issue: C, Page: 491-521
1983
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  • Citations
    23
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      23

Article Description

This chapter focuses on the HMG-CoA reductase (mevalonate : NADP + oxidoreductase acetylating CoA) and its regulation. HMG-CoA reductase catalyzes the two-step reduction of D-HMG-CoA to mevalonic acid by NADPH. Several assays for measuring mammalian HMG-CoA reductase activity are available. The most widely used and most sensitive assay is the radiochemical assay, using thin-layer chromatography to separate lactonized mevalonic acid from the substrate. Mammalian liver HMG-CoA reductase is a membrane-bound enzyme localized in the endoplasmic reticulum, which was initially solubilized by treatment with deoxycholate and partially purified several hundredfold. The coadministration of mevinolin, an analog of compactin that is a potent competitive inhibitor of HMG-CoA reductase, causes a very large accumulation of the reductase molecules in liver, but apparently blocks the activation of the enzyme caused by cholestyramine. The mechanism of action of reductase solubilized from rat liver microsome has been investigated using steady-state kinetic analyses. An initial velocity study gave a linear intersecting pattern when HMG-CoA and NADPH were variable substrates, suggesting a sequential mechanism. This result suggests that the formation of a covalently bound acyl-enzyme intermediate, such as HMG-enzyme, does not occur. The dead-end inhibition study, using adenosine 2-monophospho-5-diphosphoribose and compactin as the inhibitors, shows that the two substrates bind to the enzyme in an essentially ordered manner—the enzyme first binds to HMG-CoA, and then binds to one molecule of NADPH to form a ternary complex.

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