Basic: Our lab explores the fundamental chemical principles that govern the biosynthesis of steroid hormones in human beings and how these principles relate to human disease. We study the cytochrome P450 enzymes P450c17 (CYP17A1, 17-hydroxylase/17,20-lyase) and P450c21 (CYP21A2, 21-hydroxylase). For both enzymes, we are probing the structural and chemical features that regulate the regiochemistry and substrate preferences of these related enzymes. For CYP17A1, we are exploring the mechanism of how cytochrome b5 selectively stimulates the 17,20-lyase reaction. For CYP21A2, we have developed mutations that alter its regiochemistry and are developing models that explain these phenomena. In addition, we are characterizing the molecular genetics and clinical manifestations of CYP17A1 deficiencies and alternative pathways to dihydrotestosterone in model systems.
Another focus is the origin of the strong directional preferences exhibited by the hydroxysteroid dehydrogenase (HSD) enzymes in intact cells. We have shown that the directional preference is driven by the abundance and utilization of nicotinamide cofactors NAD(P)(H) and can alter the magnitude of this preference using mutagenesis or alterations in fuel supply. We are expanding our studies to other HSD enzymes with important physiologic functions or interesting chemical properties to characterize their structure and function.
Translational: We participate in several translational research projects that are collaborations with other investigators, laboratories, and clinical research centers. These include-- Molecular and genetic mechanisms of human hypertension; Improved diagnostic studies and management in primary aldosteronism and Cushing syndromes; Modifier genes in 21-hydroxylase deficiency; Cardiovascular disease in polycystic ovary syndrome; The endocrinology of traumatic brain injury.
RESEARCH INTERESTS
Steroid Biosynthesis
Enzymology
Protein Engineering
Endocrine Tumors
RECENT PUBLICATIONS
J.N. Naffin-Olivos and R.J. Auchus, "Human cytochrome b5 requires residues E48 and E49 to stimulate the 17, 20-lyase activity of cytochrome P450c17" Biochemistry, 45:755-762, 2006
M. Papari-Zareei, A. Brandmaier, and R.J. Auchus, "Arginine 276 Controls the Directional Preference of AKR1C9 (Rat Liver 3alpha-Hydroxysteroid Dehydrogenase) in HEK-293 Cells" Endocrinology, 147:1591-1597, 2006
D.L. Motola, C.L. Cummins, V. Rottiers, K.K. Sharma, T. Li, Y. Li, K. Suino-Powell, H.E. Xu, R.J. Auchus, A. Antebi, and D.J. Mangelsdorf, "Identification of hormonal ligands for the orphan nuclear receptor DAF-12 that govern dauer formation and reproduction in C. elegans" Cell, 124:1209-1223, 2006
R.J. Auchus, D.W. Chandler, S. Singeetham, N. Chokshi, F.E. Nwariaku, B.L. Dolmatch, S.A. Holt, F.H. Wians, Jr, S.C. Josephs, C.K. Trimmer, J. Lopera, W. Vongpatanasin, S.D. Nesbitt, D. Leonard, and R.G. Victor, "Measurement of 18-hydroxycorticosterone during adrenal vein sampling for primary aldosteronism" J Clin Endocrinol Metab, 92:2648-2651, 2007
Mitchell IC, Auchus RJ, Juneja K, Chang AY, Snyder III WH, Nwariaku FE, "Subclinical Cushing Syndrome is not subclinical: improvement after adrenalectomy in 9 patients." 2007, Surgery/142:900-905
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