Cytochrome P450 enzymes steroid biosynthesis

The biosynthesis of glucocorticoids and mineralocorticoids (in the adrenal cortex), and that of sex steroids (in the adrenal cortex and gonads), requires four cytochrome P450 enzymes (see Chapter 24). These monooxygenases are involved in the transfer of electrons from NADPH through electron transfer protein intermediates to molecular oxygen, which then oxidizes a variety of the ring carbons of cholesterol. 

Cytochromes P450 form a very large group of heme enzymes that catalyze the hydroxylation of a variety of substrates. They are important in drug metabolism, in cholesterol and steroid hormone biosynthesis, and in numerous other pathways. They have been found to participate in reactions other than hydroxyla-tions. 

Cytochromes P450 are monooxygenases whose cosubstrates, often NADH or NADPH, deliver electrons to the active center heme via a separate flavoprotein and often via an iron-sulfur protein as well 476a b A typical reaction (Eq. 18-55) is the 11 (3-hydroxylation of a steroid, an essential step in the biosynthesis of steroid hormones (Fig. 22-11). The hydroxyl group is introduced without inversion of configuration. The same enzyme converts unsaturated derivatives to epoxides (Eq. 18-56), while other cytochromes P450... 

Jarman M, Smith HJ, Nicholls PJ and Simons C (1998) Inhibitors of enzymes of androgen biosynthesis cytochrome P450 7l, and 5a-steroid reductase. Nat Prod Rep 15, 495-512. 

Cytochrome P450 22A1 (the trivial name of which is cytochrome P450scc) was identified in human and bovine adrenal mitochondria. This enzyme mediates the cleavage of the cholesterol side chain to pregnenolone, which is the first stage in the biosynthesis of several steroidal hormones. 

A flavoprotein monooxygenase (MtmOIV) involved in the biosynthesis of mithra-mycin, and a heme-containing BVMO belonging to the cytochrome P450 superfamily have recently been reported ]64]. Both enzymes were shown to catalyze BV oxidations [65]. In addition, a plant enzyme turned out to be capable of modifying steroids via BV oxidation [66]. Further studies will reveal more mechanistic details concerning these newly identified BVMOs that may be useful for the development of new biocatalytic applications in the future. 

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