This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Miller, W. L. Search for Related Content PubMed PubMed Citation Articles by Miller, W. L.

Minireview: Regulation of Steroidogenesis by Electron Transfer

University of California, San Francisco, San Francisco, California 94143-0978

Address all correspondence and requests for reprints to: Professor Walter L. Miller, Department of Pediatrics, Building MR-4, Room 209, University of California, San Francisco, San Francisco, California 94143-0978.

Cytochrome P450 enzymes catalyze the degradation of drugs and xenobiotics, but also catalyze a wide variety of biosynthetic processes, including most steps in steroidogenesis. The catalytic rate of a P450 enzyme is determined in large part by the rate of electron transfer from its redox partners. Type I P450 enzymes, found in mitochondria, receive electrons from reduced nicotinamide adenine dinucleotide (NADPH) via the intermediacy of two proteins—ferredoxin reductase (a flavoprotein) and ferredoxin (an iron/sulfur protein). Type I P450 enzymes include the cholesterol side-chain cleavage enzyme (P450scc), the two isozymes of 11-hydroxylase (P450c11ß and P450c11AS), and several vitamin D-metabolizing enzymes. Disorders of these enzymes, but not of the two redox partners, have been described. Type II P450 enzymes, found in the endoplasmic reticulum, receive electrons from NADPH via P450 oxidoreductase (POR), which contains two flavin moieties. Steroidogenic Type II P450 enzymes include 17-hydroxylase/17,20 lyase (P450c17), 21-hydroxylase (P450c21), and aromatase (P450aro). All P450 enzymes catalyze multiple reactions, but P450c17 appears to be unique in that the ratio of its activities is regulated at a posttranslational level. Three factors can increase the degree of 17,20 lyase activity relative to the 17-hydroxylase activity by increasing electron flow from POR: a high molar ratio of POR to P450c17, serine phosphorylation of P450c17, and the presence of cytochrome b₅, acting as an allosteric factor to promote the interaction of POR with P450c17. POR is required for the activity of all 50 human Type II P450 enzymes, and ablation of the Por gene in mice causes embryonic lethality. Nevertheless, mutation of the human POR gene is compatible with life, causing multiple steroidogenic defects and a skeletal dysplasia called Antley-Bixler syndrome.

This article has been cited by other articles:

				L. G. Gomes, N. Huang, V. Agrawal, B. B. Mendonca, T. A. S. S. Bachega, and W. L. Miller Extraadrenal 21-Hydroxylation by CYP2C19 and CYP3A4: Effect on 21-Hydroxylase Deficiency J. Clin. Endocrinol. Metab., January 1, 2009; 94(1): 89 - 95. [Abstract] [Full Text] [PDF]

				L. G. Gomes, N. Huang, V. Agrawal, B. B. Mendonca, T. A. S. S. Bachega, and W. L. Miller The Common P450 Oxidoreductase Variant A503V Is Not a Modifier Gene for 21-Hydroxylase Deficiency J. Clin. Endocrinol. Metab., July 1, 2008; 93(7): 2913 - 2916. [Abstract] [Full Text] [PDF]

				F. G. Riepe, O. Hiort, J. Grotzinger, W. G. Sippell, N. Krone, and P.-M. Holterhus Functional and Structural Consequences of a Novel Point Mutation in the CYP21A2 Gene Causing Congenital Adrenal Hyperplasia: Potential Relevance of Helix C for P450 Oxidoreductase-21-Hydroxylase Interaction J. Clin. Endocrinol. Metab., July 1, 2008; 93(7): 2891 - 2895. [Abstract] [Full Text] [PDF]

				D. L. Villeneuve, L. S. Blake, J. D. Brodin, J. E. Cavallin, E. J. Durhan, K. M. Jensen, M. D. Kahl, E. A. Makynen, D. Martinovic, N. D. Mueller, et al. Effects of a 3{beta}-Hydroxysteroid Dehydrogenase Inhibitor, Trilostane, on the Fathead Minnow Reproductive Axis Toxicol. Sci., July 1, 2008; 104(1): 113 - 123. [Abstract] [Full Text] [PDF]

				M. K. Tee, Q. Dong, and W. L. Miller Pathways Leading to Phosphorylation of P450c17 and to the Posttranslational Regulation of Androgen Biosynthesis Endocrinology, May 1, 2008; 149(5): 2667 - 2677. [Abstract] [Full Text] [PDF]

				A Stigliano, L Cerquetti, M Borro, G Gentile, B Bucci, S Misiti, P Piergrossi, E Brunetti, M Simmaco, and V Toscano Modulation of proteomic profile in H295R adrenocortical cell line induced by mitotane Endocr. Relat. Cancer, March 1, 2008; 15(1): 1 - 10. [Abstract] [Full Text] [PDF]

				C. J. Kim, L. Lin, N. Huang, C. A. Quigley, T. W. AvRuskin, J. C. Achermann, and W. L. Miller Severe Combined Adrenal and Gonadal Deficiency Caused by Novel Mutations in the Cholesterol Side Chain Cleavage Enzyme, P450scc J. Clin. Endocrinol. Metab., March 1, 2008; 93(3): 696 - 702. [Abstract] [Full Text] [PDF]

				N. Huang, V. Agrawal, K. M. Giacomini, and W. L. Miller Genetics of P450 oxidoreductase: Sequence variation in 842 individuals of four ethnicities and activities of 15 missense mutations PNAS, February 5, 2008; 105(5): 1733 - 1738. [Abstract] [Full Text] [PDF]

				H. Dassen, C. Punyadeera, R. Kamps, B. Delvoux, A. Van Langendonckt, J. Donnez, B. Husen, H. Thole, G. Dunselman, and P. Groothuis Estrogen metabolizing enzymes in endometrium and endometriosis Hum. Reprod., December 1, 2007; 22(12): 3148 - 3158. [Abstract] [Full Text] [PDF]

				L. M. Podust, J. P. von Kries, A. N. Eddine, Y. Kim, L. V. Yermalitskaya, R. Kuehne, H. Ouellet, T. Warrier, M. Altekoster, J.-S. Lee, et al. Small-Molecule Scaffolds for CYP51 Inhibitors Identified by High-Throughput Screening and Defined by X-Ray Crystallography Antimicrob. Agents Chemother., November 1, 2007; 51(11): 3915 - 3923. [Abstract] [Full Text] [PDF]

				A. V. Pandey, P. Kempna, G. Hofer, P. E. Mullis, and C. E. Fluck Modulation of Human CYP19A1 Activity by Mutant NADPH P450 Oxidoreductase Mol. Endocrinol., October 1, 2007; 21(10): 2579 - 2595. [Abstract] [Full Text] [PDF]

				L.-Y. Zhou, D.-S. Wang, T. Kobayashi, A. Yano, B. Paul-Prasanth, A. Suzuki, F. Sakai, and Y. Nagahama A Novel Type of P450c17 Lacking the Lyase Activity Is Responsible for C21-Steroid Biosynthesis in the Fish Ovary and Head Kidney Endocrinology, September 1, 2007; 148(9): 4282 - 4291. [Abstract] [Full Text] [PDF]

				C. J. Kim, L. E. Kaplan, F. Perwad, N. Huang, A. Sharma, Y. Choi, W. L. Miller, and A. A. Portale Vitamin D 1{alpha}-Hydroxylase Gene Mutations in Patients with 1{alpha}-Hydroxylase Deficiency J. Clin. Endocrinol. Metab., August 1, 2007; 92(8): 3177 - 3182. [Abstract] [Full Text] [PDF]

				D. L. Villeneuve, L. S. Blake, J. D. Brodin, K. J. Greene, I. Knoebl, A. L. Miracle, D. Martinovic, and G. T. Ankley Transcription of Key Genes Regulating Gonadal Steroidogenesis in Control and Ketoconazole- or Vinclozolin-Exposed Fathead Minnows Toxicol. Sci., August 1, 2007; 98(2): 395 - 407. [Abstract] [Full Text] [PDF]

				R. R. Scott, L. G. Gomes, N. Huang, G. Van Vliet, and W. L. Miller Apparent Manifesting Heterozygosity in P450 Oxidoreductase Deficiency and Its Effect on Coexisting 21-Hydroxylase Deficiency J. Clin. Endocrinol. Metab., June 1, 2007; 92(6): 2318 - 2322. [Abstract] [Full Text] [PDF]

				C. A. Haiman, V. W. Setiawan, L. Y. Xia, L. Le Marchand, S. A. Ingles, G. Ursin, M. F. Press, L. Bernstein, E. M. John, and B. E. Henderson A Variant in the Cytochrome P450 Oxidoreductase Gene Is Associated with Breast Cancer Risk in African Americans Cancer Res., April 15, 2007; 67(8): 3565 - 3568. [Abstract] [Full Text] [PDF]

				I.-C. Guo, C.-Y. Huang, C.-K. L. Wang, and B.-c. Chung Activating Protein-1 Cooperates with Steroidogenic Factor-1 to Regulate 3',5'-Cyclic Adenosine 5'-Monophosphate-Dependent Human CYP11A1 Transcription in Vitro and in Vivo Endocrinology, April 1, 2007; 148(4): 1804 - 1812. [Abstract] [Full Text] [PDF]

				P Browne, N J Place, J D Vidal, I T Moore, G R Cunha, S E Glickman, and A J Conley Endocrine differentiation of fetal ovaries and testes of the spotted hyena (Crocuta crocuta): timing of androgen-independent versus androgen-driven genital development. Reproduction, October 1, 2006; 132(4): 649 - 659. [Abstract] [Full Text] [PDF]

				C. Agca, J. E Ries, S. J Kolath, J.-H. Kim, L. J Forrester, E. Antoniou, K. M Whitworth, N. Mathialagan, G. K Springer, R. S Prather, et al. Luteinization of porcine preovulatory follicles leads to systematic changes in follicular gene expression Reproduction, July 1, 2006; 132(1): 133 - 145. [Abstract] [Full Text] [PDF]

				B. P. Schimmer, M. Cordova, H. Cheng, A. Tsao, A. B. Goryachev, A. D. Schimmer, and Q. Morris Global Profiles of Gene Expression Induced by Adrenocorticotropin in Y1 Mouse Adrenal Cells Endocrinology, May 1, 2006; 147(5): 2357 - 2367. [Abstract] [Full Text] [PDF]