Cholesterol side chain, oxidation

Structure and Biosynthesis of Bile Alcohols Disorders of Cholesterol Side-Chain Oxidation in Cerebrotendinous Xanthomatosis... 

In the solid or crystalline phase, cholesterol side chain oxidation occurs at the tertiary carbon-25 position and yields the 25-hydroperoxycholesterol, which is readily degraded thermally into the corresponding 25-hydroxy-cholesterol. Two dihydroperoxides (3j8-hydroxy-207 - and 20iS-cholest-5-ene-20,25-dihydroperoxides) have also been isolated in autoxidized bulk cholesterol. The monohydroperoxides of cholesterol decompose into complex... 

Besides their action on cholesterol biosynthesis, nicotinic acid and chloro-phenoxyisobutyrate (CPIB) could also interfere with cholesterol degradation. In fact, nicotinic acid enhances cholesterol side-chain oxidation by rat-liver mitochondria, an action shared by 3-pyridylacetic acid which has also been reported to have hypocholesterolaemic properties. 

CYP27A1 catalyzes the side chain oxidation (27-hydroxylation) in bile acid biosynthesis. Because bile acid synthesis is the only elimination pathway for cholesterol, mutations in the CYP27A1 gene lead to abnormal deposition of cholesterol and cholestanol in various tissues. This sterol storage disorder is known as cerebrotendinous xanthomatosis. CYP27B1 is the 1-alpha hydroxylase of vitamin D3 that converts it to the active vitamin form. The function of CYP27C1 is not yet known. 

Sib CJ, KC Wang, HH Tai (1968) Mechanisms of steroid oxidation by microorganisms XIII. C22 acid intermediates in the degradation of the cholesterol side chain. Biochemistry 7 796-807. 

In the body, natural steroid hormones are synthesized from cholesterol. The rate-determining step is the oxidation of the cholesterol side chain, which forms pregnenolone and isocaproic aldehyde. 

Defective side-chain oxidation is found in patients affected by cerebrotendinous xanthomatosis (CTX), an autosomal recessive defect characterised by deficit of mitochondrial 27-hydroxylase. The CTX defect leads to an accumulation of cholestanol and cholesterol in most tissues, while serum concentrations of CA, as well as other BAs, are sensibly low. 

The potential role of the RIA technique in the analysis of BAs was investigated some time ago in a study about the development of a method for the detection of 3/I-hy-droxy-5-cholenoic acid [41]. This technique was considered by the authors to be important in the evaluation of oxidation of the cholesterol side chain, a minor pathway of BA biosynthesis. 3/THydroxy-5-cholenoic acid was found in human meconium [42] and in amniotic fluid [43], suggesting an important role in foetal life. In healthy subjects this compound was found in urine [44] but not in serum [45]. The kidney probably excretes it and its serum concentration is too low to be detected. The aim of this report was to provide a new method for the investigation of the role of 3/T hydroxy-5-cholenoic acid in cholestatic disease. 

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.)...

Steroidal Alkaloids.—In the biosynthesis of alkaloids such as solasodine (128), from cholesterol (129), it appears that the cholesterol side-chain is first functionalized at C-26 with the introduction of a hydroxy-group (cf. Vol. 8, p. 28 Vol. 7, p. 32). The 26-amino-compound, (25i )-26-aminocholesterol (130), has been found to act as a significant precursor for solasodine (128) in Solarium laciniatum, whereas (25i )-26-aminocholest-5-ene-3/ ,16/ -diol (131) was poorly utilized.105 This indicates that replacement of the hydroxy-group at C-26 by an amino-group may occur before further oxygenation elsewhere in the steroid nucleus (particularly at C-16). It may also be concluded from this and other evidence (cf. Vol. 9, p. 27) that oxidation at C-22 precedes hydroxylation at C-16. 

NADH dehydrogenase and, 189 ubiquinone reductase and, 178,182,183 Cholesterol, side chain cleavage, 83, 84-85 Choline, oxidation to betaine, 260 Choline dehydrogenase electron transport system and, 261-263 properties, 260-201 Chromatium sulfate reduction by, 281 transhydrogenase of, 54 function of, 80 molecular properties, 58, 69 purification, 55, 56 Chromium... 

In summary, these studies demonstrated that in CTX the impaired synthesis of bile acids is due to a defect in the biosynthetic pathway involving the oxidation of the cholesterol side-chain. As a consequence of the inefficient side-chain oxidation, increased 23, 24 and 25-hydroxylation of bile acid precursors occurs with the consequent marked increase in bile alcohol glucuronides secretions in bile, urine, plasma and feces (free bile alcohols). These compounds were isolated, synthesized and fully characterized by various spectroscopic methods. In addition, their absolute stereochemistiy determined by Lanthanide-Induced Circular Dichroism (CD) and Sharpless Asymmetric Dihydroxylation studies. Further studies demonstrated that (CTX) patients transform cholesterol into bile acids predominantly via the 25-hydroxylation pathway. This pathway involves the 25-hydroxylation of 5P-cholestane-3a,7a, 12a-triol to give 5P-cholestane-5P-cholestane-3a,7a,12a,25- tetrol followed by stereospecific 24S-hydroxylation to yield 5P-cholestane-3a,7a,12a,24S,25-pentol which in turn was converted to cholic acid. 

Setoguchi, T., Salen, G., Tint, G. S. and Mosbach, E. H. (1974). A biochemical abnormality in cerebrotendinous xanthomatosis incomplete oxidation of the cholesterol side chain. J. Clin. Invest. 53 1393-1401. 

The bile acids are 24-carbon steroid derivatives. The two primary bile acids, cholic acid and chenodeoxycholic acid, are synthesized in the hepatocytes from cholesterol by hy-droxylation, reduction, and side chain oxidation. They are conjugated by amide linkage to glycine or taurine before they are secreted into the bile (see cholesterol metabolism. Chapter 19). The mechanism of secretion of bile acids across the canalicular membrane is poorly understood. Bile acids are present as anions at the pH of the bile, and above a certain concentration (critical micellar concentration) they form polyanionic molecular aggregates, or micelles (Chapter 11). The critical micellar concentration for each bile acid and the size of the aggregates are affected by the concentration of Na+ and other electrolytes and of cholesterol and lecithin. Thus, bile consists of mixed micelles of conjugated bile acids, cholesterol, and lecithin. While the excretion of osmotically active bile acids is a primary determinant of water and solute transport across the canalicular membrane, in the canaliculi they contribute relatively little to osmotic activity because their anions aggregate to form micelles. 

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,... 

This rare inherited hpid storage disease is characterized by xanthomas, progressive neurological dysfunction, cataracts and the development of xanthomatous lesions in the brain and lung. In contrast to other diseases with tendon xanthomatosis, plasma cholesterol levels are remarkably low. Large deposits of cholesterol and cholestanol are present in most tissues, and the concentration of cholestanol is 10-100 times higher than normal. Salen and collaborators have made extensive and elegant studies on the various metabolic aspects of this disease [184,185,187-192]. They have conclusively shown that there is a subnormal synthesis of bile acids and that the metabolic defect is an impaired oxidation of the cholesterol side chain. The synthesis of chenodeoxycholic acid is reduced more than that of cholic acid. These patients excrete considerable amounts of bile alcohol in bile and faeces. The bile alcohols have been identified as 5)S-cholestane-3a,7a,12a,25-tetrol, 5 8-cholestane-3a,7a,12a,24,25-pentol and 5/8-cholestane-3 ,7a,12a,23,25-pentol. Two different explanations for the accumulation of these bile alcohols have been presented. 

Androgens, the male sex hormones, proved far more elusive that either the estrogens and progestins since they occur at much lower concentrations in biological fluids. The bioassay used to track the isolation in this case comprised the capon unit . This was the amount of extract that produced a 20% increase in the surface of a rooster s comb. The 15 mg of pure crystalline testosterone isolated in 1931 came from about 15 0001 of urine. The structural investigations of this series relied on the then newly discovered side chain oxidations of cholestanol (13-1) (Scheme 1.13). This method in essence comprised fairly drastic oxidation of reduced cholesterols of known stereochemistry at the A-B junction to afford in fairly low yield products in which the side chain at Cn had been consumed to leave behind a carbonyl group. One of these products proved to be identical with androsterone (13-2). That compound had in turn been obtained from a sequence of reactions starting from dehydroepiandrosterone (13-3) that had been isolated from male urine. 

Kannenberg, F., Ellinghaus, P., Assmann, G., Seedorf, U. 1999. Aberrant oxidation of the cholesterol side chain in bile acid synthesis of sterol carrier protein-2/sterol carrier protein-x knockout mice. J. Biol. Chem. 274 35455-35460. 

Peroxisomes are present in greater number in the liver than in other tissues. Liver peroxisomes contain the enzymes for the oxidation of very-long-chain fatty acids such as C24 0 and phytanic acid, for the cleavage of the cholesterol side chain necessary for the synthesis of bile salts, for a step in the biosynthesis of ether lipids, and for several steps in arachidonic acid metabohsm. Peroxisomes also contain catalase and are capable of detoxifying hydrogen peroxide. 

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