Cholesterol desmolase

Figure 16.4 Biosynthesis of various classes of steroid hormones. Reaction (A) is catalyzed by a cholesterol desmolase, which oxidizes the cholesterol side chain. Reactions (D) are catalyzed by 21-hydroxylases, which are defective in congenital adrenal hyperplasia. (Reproduced by permission from Schwarz V. A Clinical Companion to Biochemical Studies. Reading Freeman, 1978, p. 94.)...

CHOLESTEROL DESMOLASE (CYP11A) I.. 17a-HYDR0XYLASE (CYP17) 17,20-LYASE... 

G-12) Cholesterol desmolase. A partial block at this control step reduces the levels of all the steroid hormones. 

Cholesterol desmolase No information on steroids in urine (cholesterol accumulates in adrenal glands) Low Low... 

This can be due to defects in several enzyme systems required for the formation of cortisol (Fig. 8), but in all cases the inadequate level of cortisol in the blood causes corticotropin to be secreted by the pituitary in increasing amount this in turn causes hyperplasia of the adrenal glands with overproduction of those steroids not affected by the enzyme block. The most common deficiency is in 21-hydroxylase, but deficiencies have also been reported in infants and children of 3j8-HSD, lljff-hydroxy-lase, and cholesterol desmolase, and in older infants of 17a-hydroxylase (N4). 

Morohashi, K.., K. Sogawa, T. Omura, and Y. Fujii-Kuriyama (1987). Gene structure of human cytochrome P-450(SCC), cholesterol desmolase. J Biochem. (Tokyo) 101, 8879-8887. 

F. 34.24. Cellular route for cortisol synthesis. Cholesterol is synthesized from acetyl CoA or derived from low-density lipoprotein (LDL), which is endoc5hosed and digested by lysosomal enzymes. Cholesterol is stored in cells of the adrenal cortex as cholesterol esters. ACTH signals the cell to convert cholesterol to cortisol. 1 = cholesterol desmolase (involved in side chain cleavage) 2 = 3p-hydroxysteroid dehydrogenase 3 = 17a-hydroxylase 4 = 21-hydroxylase 5 = 11 P-hydroxylase. 

Steroid hormones are crucial signal molecules in mammals. (The details of their physiological effects are described in Chapter 34.) Their biosynthesis begins with the desmolase reaction, which converts cholesterol to preg-... 

Aminoglutethimide (Cytadren) is a competitive inhibitor of desmolase, the enzyme that catalyzes the conversion of cholesterol to pregnenolone it also inhibits 11-hydroxylase activity. This drug also reduces estrogen production by inhibiting the aromatase enzyme complex in peripheral (skin, muscle, fat) and steroid target tissues. 

Biosynthesis of progesterone. Desmolase is found in the mitochondria of steroid-producing tissues. Cholesterol is converted to pregnenolone in the mitochondria and then transferred to the endoplasmic reticulum, where it is converted to progesterone. Progesterone is a hormone as well as the precursor of several other hormones. 

Steroid hormones contain 21 or fewer carbon atoms, whereas cholesterol contains 27. Thus, the first stage in the synthesis of steroid hormones is the removal of a six-carbon unit from the side chain of cholesterol to form pregnenolone. The side chain of cholesterol is hydroxylated at C-20 and then at C-22, and the bond between these carbon atoms is subsequently cleaved by desmolase. Three molecules of NADPH and three molecules of O2 are consumed in this remarkable six-electron oxidation. 

Cholesterol side-chain cleavage (SCC, desmolase) 17(X-Hydroxylase/17,20 lyase 2THydroxyIasc p-Hydroxylase... 

Several en2yme defects will cause a deficiency of testosterone production during fetal development. These include 20a-hydroxylase (cholesterol 20,22-desmolase) deficiency, which prevents conversion of cholesterol to pregnenolone and results in congenital lipoid adrenal hyperplasia, so named because the adrenals are large and filled with lipoid... 

The most commonly postulated mechanism for the desmolase reaction has been the suggestion of the enzymatic consecutive reaction sequence cholesterol 20a-hydroxycholesterol — (22R)-20a,22-dihydroxycholesterol pregnenolone (Shimizu et al., 1961, 1962 Constantopoulos and Tchen, 1961). This hypothetical scheme was actually advanced on the basis of three suppositions (1) cholesterol is cleaved between C-20 and C-22, as was discussed in a previous section, (2) 20a-hydroxycholesterol was formed from cholesterol-4- C by a cow adrenocortical homogenate in the presence of 20a-hy-droxycholesterol as a trapping agent (Solomon et al., 1956), and (3) both 20a-hydroxycholesterol and (22R)-20a,22-dihydroxycholesterol are much more efficiently transformed to pregnenolone than is cho-... 

In the isolation of steroids from natural sources one must, of course, consider their stability prior to enzyme inactivation, which usually occurs at the commencement of the isolation procedure, when the tissue is extracted with organic solvents. Kahnt and Neher (1965) could observe in bovine adrenal homogenates only trace amounts of 20a-hydroxycholesterol and (22R)-20,22-dihydroxy-cholesterol, as well as pregnenolone or progesterone (< figlgm). As stated earlier the absence of certain derivatives may be due to either their lack of formation or their rapid disappearance from the system. Until recently, primarily because of the lack of appropriate substrates of high specific activity, quantitative studies on the elucidation of the mechanism of the desmolase reaction could not be performed. The study of Ichii et al. (1967a) appears to entail the assumption of a steady state, for which no proof seems to have been provided. Also,... 

Of incidental interest is a finding by Werbin et al. (1960) who has shown that j8-sitosterol-H (Fig. 8) is transformed to cortisol by guinea pig in vivo. Cholesterol-H was also isolated, and a comparison of its specific activity with that of cortisol-H led to the conclusion that the former could not have been an intermediate in the conversion. Thus it would appear that the additional ethyl group in the side chain does not hinder the action at C-20, 22 of the hydroxylases and desmolase in their preparation and execution of the side chain scission. Pregnenolone-H and possibly a Cg-branched aldehyde or acid moiety are the products at this stage, the steroid being rapidly converted to cortisol-H through the action of adrenal enzymes. The treatment of j8-sitosterol by the liver on the other hand was such that cholesterol-H was resultant. 

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