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 journalArticle

23 Citations (Scopus)

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 2007

Fingerprint

Hydroxysteroid Dehydrogenases
NADP
Oxidation-Reduction
Steroids
Niacinamide
Enzymes
Metabolism
NAD
Arginine
Rats
Salts
Phosphates
Hormones
Fluxes

Keywords

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

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Sherbet, D. P., Papari-Zareei, M., Khan, N., Sharma, K. K., Brandmaier, A., Rambally, S., ... 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

Cofactors, redox state, and directional preferences of hydroxysteroid dehydrogenases. / Sherbet, Daniel P.; Papari-Zareei, Mahboubeh; Khan, Naveed; Sharma, Kamalesh K.; Brandmaier, Andrew; Rambally, Siayareh; Chattopadhyay, Arhana; Andersson, Stefan; Agarwal, Anil K.; Auchus, Richard J.

In: Molecular and Cellular Endocrinology, Vol. 265-266, No. SUPPL., 02.2007, p. 83-88.

Research output: Contribution to journalArticle

Sherbet, DP, Papari-Zareei, M, Khan, N, Sharma, KK, Brandmaier, A, Rambally, S, Chattopadhyay, A, Andersson, S, Agarwal, AK & Auchus, RJ 2007, 'Cofactors, redox state, and directional preferences of hydroxysteroid dehydrogenases', Molecular and Cellular Endocrinology, vol. 265-266, no. SUPPL., pp. 83-88. https://doi.org/10.1016/j.mce.2006.12.021
Sherbet, Daniel P. ; Papari-Zareei, Mahboubeh ; Khan, Naveed ; Sharma, Kamalesh K. ; Brandmaier, Andrew ; Rambally, Siayareh ; Chattopadhyay, Arhana ; Andersson, Stefan ; Agarwal, Anil K. ; Auchus, Richard J. / Cofactors, redox state, and directional preferences of hydroxysteroid dehydrogenases. In: Molecular and Cellular Endocrinology. 2007 ; Vol. 265-266, No. SUPPL. pp. 83-88.
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