Cofactors, redox state, and directional preferences of hydroxysteroid dehydrogenases

Daniel P. Sherbet, Mahboubeh Papari-Zareei, Naveed Khan, Kamalesh K. Sharma, Andrew Brandmaier, Siayareh Rambally, Arhana Chattopadhyay, Stefan Andersson, Anil K. Agarwal, Richard J. Auchus

Research output: Contribution to journalReview article

23 Scopus citations

Abstract

The hydroxysteroid dehydrogenases (HSDs) interconvert pairs of weak and potent steroids, thus serving as key enzymes in the regulation of intracellular hormone potency. These enzymes may appear to drive unidirectional steroid flux in intact cells but actually catalyze bi-directional metabolism that achieve pseudo-equilibria with strong directional preferences. Even small shifts in the magnitude of these pseudo-equilibria can profoundly change steroid potency and thus contribute to disease. Consequently, we are studying the structural and biochemical principles that govern these directional preferences and the resilience of these pseudo-equilibria in intact cells. HSD directional preferences in intact cells are governed largely by relative affinities for nicotinamide cofactors [NAD(P)(H)] and existing cofactor gradients. We can attenuate the directional preferences for human 17βHSD type 1 and rat AKR1C9 in intact cells by either diminishing the NADPH/NADP+ gradient or by mutating the arginine residues that form salt bridges with the 2′-phosphate of NADP(H) (R38 and R276, respectively).

Original languageEnglish (US)
Pages (from-to)83-88
Number of pages6
JournalMolecular and Cellular Endocrinology
Volume265-266
Issue numberSUPPL.
DOIs
StatePublished - Feb 1 2007

Keywords

  • Androgen
  • Equilibrium
  • Estrogen
  • Glucocorticoid
  • Hydroxysteroid dehydrogenase
  • Nicotinamide cofactor
  • Redox state

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Endocrinology

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    Sherbet, D. P., Papari-Zareei, M., Khan, N., Sharma, K. K., Brandmaier, A., Rambally, S., Chattopadhyay, A., Andersson, S., Agarwal, A. K., & Auchus, R. J. (2007). Cofactors, redox state, and directional preferences of hydroxysteroid dehydrogenases. Molecular and Cellular Endocrinology, 265-266(SUPPL.), 83-88. https://doi.org/10.1016/j.mce.2006.12.021