Side-chain cleavage

Side Chain Cleavage.—There are two distinct methods for the degradation of the side chain. In mammalian systems a-glycols are cleaved to give the corresponding ketone. Both androstane and pregnane derivatives may be formed directly. Hydroxylation of cholesterol (91 = H) takes place 

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The rate of side-chain cleavage of sterols is limited by the low solubiUty of substrates and products and thek low transport rates to and from cells. Cyclodextrins have been used to increase the solubiUties of these compounds and to assist in thek cellular transport. Cyclodextrins increase the rate and selectivity of side-chain cleavage of both cholesterol and P-sitosterol with no effect on cell growth. Optimal conditions have resulted in enhancement of molar yields of androsta-l,4-diene-3,17-dione (92) from 35—40% to >80% in the presence of cyclodextrins (120,145,146,155). 

The reduction of isoxazoles is often rather peculiar and its course depends on the nature both of the isoxazole and of the reducing agent. Together with a normal reduction of groupings in the side chain, cleavage of the nitrogen-oxygen bond of the heterocyclic nucleus often occurs. 

Figure 6.14 Enzymatic side chain cleavage of penicillins. 6-Aminopenicillanic acid, a valuable intermediate for the production of various semi-synthetic penicillins, can be obtained through enzyme-mediated hydrolysis of the phenylacety group of penicillin G or the phenoxyacetyl group of penicillin V. The active site of the enzyme recognises the aromatic side chain and the amide linkage, rather than the penidllin nucleus. Chemical entitles other than penicillins are therefore often good substrates, as long as they contain the aromatic acetamide moiety.

B. Cytochrome P450 Side-Chain Cleavage and Cholesterol Monitoring... 

Figure 42-3. Cholesterol side-chain cleavage and basic steroid hormone structures. The basic sterol rings are identified by the letters A-D. The carbon atoms are numbered 1-21 starting with the A ring. Note that the estrane group has 18 carbons (Cl 8), etc.

Testiculat androgens are synthesized in the interstitial tissue by the Leydig cells. The immediate precursor of the gonadal steroids, as for the adrenal steroids, is cholesterol. The rate-limiting step, as in the adrenal, is delivery of cholesterol to the inner membrane of the mitochondria by the transport protein StAR. Once in the proper location, cholesterol is acted upon by the side chain cleavage enzyme P450scc. The conversion of cholesterol to pregnenolone is identical in adrenal, ovary, and testis. In the latter two tissues, however, the reaction is promoted by LH rather than ACTH. 

Akhtar M, DL Corina, SL Miller, AZ Shyadehi (1994) Incorporation of label from into acetate during side-chain cleavage catalyzed by cytochrome P-450j7 (17a-hydroxylase-17,20-lyase). J Chem Soc Perkin Trans T. 263-267. 

Sitosterol is an abundant and low-cost raw material for the production of pharmaceutical steroids. 4-Androstene-3,17-dione, the precursor for the synthesis of corticosteroid hormones, can be derived from the side-chain cleavage of/3-sitosterol. Immobilized cells of Mycobacterium sp. NRRL B-3805 on Celite matrix (80-120 mesh) was found to be effective in cleaving the side chain of /3-sitosterol (5gL ) with a molar conversion yield of 70% in 50 h [30],... 

Dias, A.C.P, Cabral, J.M.S. and Pinheiro, H.M. (1994) Sterol side-chain cleavage with immobilized Mycobacterium cells in water-immiscible organic solvents. Enzyme and Microbial Technology, 16, 708-714. 

Payne AH. Hormonal regulation of cytochrome P450 enzymes, cholesterol side-chain cleavage and 17 alpha-hydroxylase/C 17-20 lyase in Leydig cells. Biol Reprod 1990 42(3) 399-404. 

CYPUAl P450scc Cholesterol side-chain cleavage enzyme— Pregnenolone... 

Takase M, Ukena K, Yamazaki T, Kominami S, Tsutsui K. 1999. Pregnenolone, pregnenolone sulfate, and cytochrome P450 side-chain cleavage enzyme in the amphibian brain and their seasonal changes. Endocrinology 140 1936-1944. 

Ukena K, Usui M, Kohchi C, Tsutsui K. 1998. Cytochrome P450 side-chain cleavage enzyme in the cerebellar Purkinje neuron and its neonatal change in rats. Endocrinology 139 137-147. 

Gamar, Y. and Gannt, J.K. Bacterial metabolism of 4 -chloro-2-methylphenoxyacetate, formation of gl3q>hosate by side-chain cleavage, Blochem. J., 122 527-531, 1971. 

GOG [II]. [X], [VIII], [GOG-Dimer] a, jS-side chain cleavage 5-5 bond formation (polymerization)... 

Figure 10. A proposed depolymerization mechanism of lignin by laccase. (1) Side chain cleavage (2) fi-O-4 ether cleavage.

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