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Submitted on January 14, 2005
Accepted on February 2, 2005
Donald W. Reynolds Cardiovascular Clinical Research Center (R.J.A), the Divisions of Endocrinology & Metabolism (R.J.A.) and Nutrition & Metabolic Diseases (A.K.A.), Department of Internal Medicine, and the Center for Human Nutrition (A.K.A.), University of Texas Southwestern Medical Center, Dallas, TX
* To whom correspondence should be addressed. E-mail: richard.auchus{at}UTSouthwestern.edu.
Hydroxysteroid dehydrogenases (HSDs) interconvert potent and relatively inactive forms of individual steroid hormones using nicotinamide cofactors NADPH/NADP+ and NADH/NAD+. Although reactions with purified enzymes in vitro may be driven in either direction depending on the assay conditions, HSD enzymes appear to function in one direction or the other in intact cells. At least for some of these enzymes, however, the apparent uni-directional metabolism actually reflects bi-directional catalysis that reaches a pseudo-equilibrium state with a strong directional preference. This directional preference, in turn, derives from intracellular concentration gradients for the nicotinamide cofactors and the relative affinities of each HSD for these cofactors. Since the concentrations of free cofactor exceed those of steroids by many orders of magnitude, the activities of these enzymes are predominantly driven by cofactor abundance, which is linked to intermediary metabolism. Consequently, the amount of active steroids in cells containing HSDs may be modulated by cofactor abundance and hence intracellular redox state. We will review the evidence linking cofactor handling and HSD activity, speculate on additional ways that intracellular metabolism can alter HSD activity and thus hormone potency, and discuss fruitful avenues of further investigation.
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