Monooxygenases cholesterol biosynthesis

Organotellurium compounds such as dimethyltellurium dichloride and dimethyltelluride have been reported as potential inhibitors of squalene monooxygenase, causing a dramatic reduction in the rate of cholesterol biosynthesis and leading to degradation of the myelin sheath. 

During bile acid biosynthesis, modifications to the cyclopentanophen-anthrene (steroid) nucleus are thought to precede the oxidation and cleavage of the cholesterol side chain. The first and rate-controlling step in bile acid synthesis is the 7o-hydroxylation of cholesterol (I) to form 7a-hydroxy-choles-terol (II) (Fig. 3). This step is catalyzed by cholesterol 7a-monooxygenase (cholesterol 7a-hydroxylase) (EC 1.14.13.17), a microsomal enzyme (M37). Further metabolism of 7a-hydroxy-cholesterol involves oxidation of the 3p-hydroxyl group and isomerization of the double bond from C-5,6 to C-4,5,... 

Oxysterols are defined as oxygenated derivatives of cholest-5-en-3(3-ol (cholesterol) (Figure 18.1) or precursors of CHOL that may be formed directly by autoxidation or by the action of a specific monooxygenase, or that may be secondary to enzymatic or nonenzymatic lipid peroxidation (Guardiola et al., 1996 Schroepfer, 2000 Bjorkhem and Diczfalusy, 2002). These OS may be formed in the human body by endogenous free-radical attack on CHOL or by enzymatic processes, mainly in the biosynthesis of bile acids and steroid hormones. In addition, OS may be formed exogenously by autoxidation of CHOL in foods. The nomenclature and abbreviations of OS are presented in Table 18.1. It should be emphasized at this point that the OS that occur in... 

The biosynthesis of glucocorticoids and mineralocorticoids (in the adrenal cortex), and that of sex steroids (in the adrenal cortex and gonads), requires four cytochrome P450 enzymes (see Chapter 24). These monooxygenases are involved in the transfer of electrons from NADPH through electron transfer protein intermediates to molecular oxygen, which then oxidizes a variety of the ring carbons of cholesterol. 

A key intermediate in the biosynthesis of cholesterol and related sterols is squalene, an open-chain isoprenoid hydrocarbon. It is converted to squalene 2,3-epoxide, which in turn is converted to lanosterol. The conversion of squalene to the 2,3-epoxide is catalyzed by a monooxygenase, and molecular oxygen is a required component for this reaction. Under anaerobic conditions, yeast cells cannot synthesize sterols because they lack oxygen, a substrate for the monooxygenase reaction. 

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