Cholesterol monooxygenase

Cholesterol monooxygenase (side-chain-cleaving) [heme]... 

Cholesterol monooxygenase (side-chain-cleaving) (EC 1.14.15.6). Deficient conversion of cholesterol to pregnenolone therefore impaired synthesis of miner-alocorticoids, glucocorticoids and sex hormones. Adrenal hyperplasia //, or Nonvlrllizing congenital adrenal hyperplasia. 

Cholesterol monooxygenase (side-chain-ctearit ) EC LI .15l6... 

In the skin, cholesterol is converted to 7-dehydrocholes-terol by desaturation of the 9,10-carbon bond and ultraviolet light breaks this bond to produce cholecalciferol (Figure 15.12). The cholecalciferol is transported via the bloodstream to the liver where the first step in the activation of the hormone occurs, namely hydroxylation by a monooxygenase to produce 25-hydroxy cholecalciferol, which is transported to the kidney where a further hydroxylation takes place at the 1-position to produce la,25-dihydroxycholecalciferol, which is the active form of the hormone (Figure 15.13). 

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. 

The endoplasmic reticulum is composed of a convoluted network of channels and so has a large surface area. Apart from cytochromes P-450, the endoplasmic reticulum has many enzymes and functions, besides the metabolism of foreign compounds. These include the synthesis of proteins and triglycerides and other aspects of lipid metabolism and fatty acid metabolism. Specific enzymes present on the endoplasmic reticulum include cholesterol esterase, azo reductase, glucuronosyl transferase, NADPH cytochromes P-450 reductase and NADH cytochrome b5 reductase and cytochrome b5. A FAD-containing monooxygenase is also found in the endoplasmic reticulum, and this is discussed later in this chapter. 

FIGURE 21-37 Ring closure converts linear squalene to the condensed steroid nucleus. The first step in this sequence is catalyzed by a mixed-function oxidase (a monooxygenase), for which the cosubstrate is NADPH. The product is an epoxide, which in the next step is cyclized to the steroid nucleus. The final product of these reactions in animal cells is cholesterol in other organisms, slightly different sterols are produced, as shown. 

Mitochondrial system The function of the mitochondrial cyto chrome P450 monooxygenase system is to participate in the hydroxylation of steroids, a process that makes these hydropho bic compounds more water soluble. For example, in the steroid hormone-producing tissues, such as the placenta, ovaries, testes, and adrenal cortex, it is used to hydroxylate intermediates in the conversion of cholesterol to steroid hormones. The liver uses this system in bile acid synthesis (see p. 222), and the kidney uses it to hydroxylate vitamin 25-hydroxycholecalciferol (vitamin D, see p. 384) to its biologically active 1,25-hydroxylated form. 

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 metabolism of cholesterol involves modifications to the alkyl side chain and the introduction of substituents onto the phenanthrene ring. A group of enzymes, monooxygenases, plays an important role in catalyzing the formation of bile salts in the liver and steroid hormones in the adrenal gland... 

The synthesis of all steroid hormones begins with the conversion of cholesterol to pregnenolone. The pathway of this conversion is shown in Fig. 13-25. The side chain of cholesterol is cleaved by three successive monooxygenase reactions, which introduce a keto group at the site of cleavage of the side chain. 

The available knowledge about the structural and mechanistic properties of flavoenzymes is extremely valuable for the discovery and characterization of new flavoenzymes and for the development of practical applications. Several fiavoenzyme-inspired applications already exist but many more can be foreseen. Glucose oxidase (EC 1.1.3.4) (27) and cholesterol oxidase (EC 1.1.3.6) (28) are widely applied in diagnostics. Many fiavopro-tein oxidases and monooxygenases serve as biocatalysts for the... 

In addition to bile salts, which facilitate the digestion of lipids, five major classes of steroid hormones are derived from cholesterol progestagens, glucocorticoids, mineralocorticoids, androgens, and estrogens. Hydroxylations by P450 monooxygenases that use NADPH and O2 play an important role in the synthesis of steroid hormones and bile salts from... 

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,... 

Higher cholesterol levels (correlated with exposure levels), higher blood creatinine levels, marked disturbances of the hepatic cytochrome P-450 content and of the associated microsomal monooxygenase system, as well as the inhibition of succinic-oxidase enzyme activity, may also be considered as nonspecific biomarkers of carbon disulfide exposure. More research, however, needs to be done in order to determine whether a direct correlation exists between these parameters and carbon disulfide exposure. 

The existence of an alternate pathway for the synthesis of bile acids was suspected because it was possible for oxysterols to be converted into bile acids (N. Wachtel, 1968). It is now recognized that a variety of oxysterols produced by an assortment of cell types can be converted into bile acids. The production of these oxysterols is catalyzed by several sterol hydroxylases sterol 27-hydroxylase (CYP27A1) (J.J. Cali, 1991), cholesterol 25-hydroxylase (CH25H) (E.G. Lund, 1998), and cholesterol 24-hydroxylase (CYP46A1) (E.G. Lund, 1999). Cholesterol 25-hydroxylase is not a cytochrome P-450 monooxygenase, unlike the two other enzymes. Almost all of the 24-hydroxycholesterol that ends up in the liver originates from the brain, and it has been suggested that the production of... 

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