New assumptions about oxidative processes involved in steroid hormone biosynthesis: Is the role of cytochrome P-450-activated dioxygen limited to hydroxylation reactions or are dioxygen insertion reactions also possible?

• Published in: The Journal of steroid biochemistry and molecular biology Vol. 94; no. 5; pp. 405 - 420
• Main Authors: Lieberman, Seymour, Ma, Shuren, He, Yan
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.04.2005; Elsevier Science
• Subjects: Aldosterone; Animals; Biological and medical sciences; Cortisol; Cyclic peroxides; Cytochrome P-450 Enzyme System - metabolism; Cytochrome P-450-activated dioxygen; Estradiol; Fundamental and applied biological sciences. Psychology; Hormones - biosynthesis; Hormones - chemistry; Hydroxylation; Molecular Structure; Oxidation-Reduction; Oxygen - chemistry; Oxygen - metabolism; Peroxides; Steroidogenesis; Steroids - biosynthesis; Steroids - chemistry; Vertebrates: endocrinology; Cytochrome P-450-activated dioxygen; Hydroxylation; Cyclic peroxides; Steroidogenesis; Peroxides; Cortisol; Aldosterone; Estradiol; Cytochrome; Corticosteroid; Mineralocorticoid; Steroid hormone; Estrogen; 17β-Estradiol; Biosynthesis; Hydrocortisone; Glucocorticoid; Ovarian hormone; Adrenal hormone; Sex steroid hormone
• ISSN: 0960-0760; 1879-1220
• DOI: 10.1016/j.jsbmb.2004.12.040

The traditional conception of the chemical pathways leading to the formation of the steroid hormones is derived by piecing together the results of several independent in vitro incubation experiments. The results of these experiments have led to the assumption that some relevant cytochrome P-450's (P-450 scc, P-450 arom, P-450 aldo, etc.) are “polyfunctional” and catalyze several successive hydroxylation reactions, which lead to the formation of the hormonal products. This essay offers an alternative view. It advances the suggestion that the oxygenated intermediates in the relevant biosynthetic conversions are reactive species that are formed by addition of both atoms of dioxygen onto two neighboring carbon atoms of steroidal precursors. Space-filled Stuart molecular models, generated by a computer program, suggest that the oxidized intermediates resemble hydroperoxides or cyclic peroxides (1,2-dioxanes). For the aromatization process required for estrogen biosynthesis, the atoms of dioxygen are bonded to C-2 and C-19 of the C 19-precursor. For aldosterone formation, dioxygen is bonded to C-11 and C-18 of an appropriate precursor. Moreover, the results obtained from a computer program that provides information about “molecular mechanics” (bond angles and bond distances as well as total potential energies for each conformation of a molecule) suggest that consideration be given to the possibility that cortisol also can be biosynthesized by P-450-activated dioxygen addition to C-11 and C-17 of an appropriate precursor. Neither the traditional view of steroidogenic pathways nor the suggestions advanced here have been established by compelling experimental findings. Both hypotheses are saddled with untested assumptions, which are necessary because the dynamic processes can only be discerned by indirect means. The origins of some naturally occurring steroids hydroxylated at C-17, C-18 and C-19 are examined in the light of the suggestions made in this essay.