Minireview: cellular redox state regulates hydroxysteroid dehydrogenase activity and intracellular hormone potency.
Hydroxysteroid dehydrogenases (HSDs) interconvert potent and relatively inactive forms of individual steroid hormones using nicotinamide cofactors NADPH/NADP(+) and NADH/NAD(+) [nicotinamide adenine dinucleotide (phosphate), reduced/oxidized forms]. 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 unidirectional metabolism actually reflects bidirectional catalysis that reaches a pseudoequilibrium 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. Because 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.
Agarwal
Anil K
AK
Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-8857, USA.
Auchus
Richard J
RJ
D000818:Animals; D004734:Energy Metabolism / Q000502:physiology*; D006728:Hormones / Q000378:metabolism*; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000737:chemistry / Q000378:metabolism*; D010084:Oxidation-Reduction; D013256:Steroids / Q000378:metabolism*
D006728:Hormones; D013256:Steroids; D006913:Hydroxysteroid Dehydrogenases