Steroids side-chain biosynthesis

EiectrophUic alkylation in steroid side-chain biosynthesis... 

Further exploration125 of the stereochemistry associated with modification of the steroidal side-chain into that of steroidal alkaloids such as solanidine (139) and tomatidine (140) has revealed that on formation of the furan ring in (140) tritium in the 16/8-configuration of cholesterol [as (143)] is retained but appears now in the 16a-configuration. Retention of the tritium excludes a C-16-oxo-intermediate, and the fact that an inversion of configuration is observed excludes hydroxylation with normal retention of configuration. Examination of the fate of the cholesterol 16/S-proton on incorporation into solanidine (139) revealed that during solanidine biosynthesis this proton is lost. 

Similar types of alkylation have been applied in syntheses of other steroidal side-chains, including that of 22-trans-26,27-dinorergosta-5,22-dien-3j8-ol (387), a novel marine sterol. In addition, the Wittig reaction has been used to prepare various possible polyene intermediates in phytosterol biosynthesis. The aldehydes (389) and (390) were prepared (Scheme 26) from stigmasterol acetate (388b) by modification of a known procedure. These aldehydes were then alkylated with a variety of ylides derived from phosphonium salts, leading to a series of polyenes (391) and (392). ... 

The net addition to an olefin moiety of a bridging methylene group derived from the activated methyl fragment of 5-adenosylmethionine commonly occurs in the biosynthesis of cyclopropane-containing steroidal side chains and fatty acids, and has been best studied... 

Results of various in vivo experiments with labelled bile acid precursors in patients with CTX have been published [185,190,195]. All these experiments show that there is a defect in the oxidation of the steroid side chain in the biosynthesis of cholic acid but are not fully conclusive with respect to the site of defect. Bjorkhem et al. administered a mixture of [ H]7a,26-dihydroxy-4-cholesten-3-one and [ " C]7a-hy-droxy-4-cholesten-3-one to a patient with CTX [195]. The ratio between and C in the cholic acid and the chenodeoxycholic acid isolated was 40 and 60 times higher, respectively, than normal. Similar results were obtained after simultaneous administration of H-labelled 5)3-cholestane-3a,7a,26-triol and 4- C-labelled 5j8-cholestane-3a,7a-diol. The results of these experiments are in consonance with the contention that the basic defect in CTX is the lack of the 26-hydroxylase, but do not per se completely exclude other defects in the oxidation of the side chain. 

Pharmacologically active allenic steroids have already been examined intensively for about 30 years [5], Thus, the only naturally occurring allenic steroid 107 had been synthesized 3 years before its isolation from Callyspongia diffusa and it had been identified as an inhibitor of the sterol biosynthesis of the silkworm Bombyx mori (Scheme 18.34) [86d], At this early stage, allenic 3-oxo-5,10-secosteroids of type 108 were also used for the irreversible inhibition of ketosteroid isomerases in bacteria, assuming that their activity is probably caused by Michael addition of a nucleophilic amino acid side chain of the enzyme at the 5-position of the steroid [103, 104]. Since this activity is also observed in the corresponding /3,y-acetylenic ketones, it can be rationalized that the latter are converted in vivo into the allenic steroids 108 by enzymatic isomerization [104, 105],... 

Sterols and Cholesterol. Natural sterols are crystalline C76 C1(1 steroid alcohols containing an aliphatic side chain at C17. Sterols were first isolated as lionsaponifiable fractions of lipids from various plant and animal sources and have been identified in almost all types of living organisms. By far, the most common sterol in vertebrates is cholesterol (8). Cholesterol serves two principal functions in mammals. First, cholesterol plays a role in the structure and function of biological membranes.. Secondly, cholesterol serves as a central intermediate in the biosynthesis of many biologically active steroids, including bile acids, corticosteroids, and sex hormones. 

The initial reaction in steroid hormone biosynthesis is catalyzed by desmolase (side-chain cleavage complex), which is found in the mitochondria of steroid-producing tissues (e.g., adrenals, gonads). The reaction is shown in figure 20.22. The product, pregnenolone, is subsequently transferred to the endoplasmic reticulum, where an oxidation of... 

Steroid hormones bear a remarkable structural similarity to one another (see Fig. 29-1). The precursor for steroid biosynthesis is cholesterol. Consequently, all of the steroid hormones share the same basic chemical configuration as their parent compound. This fact has several important physiologic and pharmacologic implications. First, even relatively minor changes in the side chains of the parent compound create steroids with dramatically different physiologic effects. For instance, the addition of only one hydrogen atom in the sex steroid pathway changes testosterone (the primary male hormone) to estradiol... 

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. 

A symposium213 deals with the methodology of steroid biochemistry and the biosynthesis of trophic hormones. Side-chain cleavage that converts cholesterol into pregnenolone is catalysed, in the rat, by a mitochondrial enzyme complex that... 

The side chain cleavage of cholesterol, producing pregnenolone, is catalyzed by cytochrome P450JCC. This is the initial step in the biosynthesis of several steroid hormones. In this assay, the initial product, pregnenolone, is quantitatively converted to progesterone by treatment with cholesterol oxidase, which increases by about 10-fold the sensitivity of the assay. 

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