TY - JOUR
T1 - Minireview
T2 - Cellular redox state regulates hydroxysteroid dehydrogenase activity and intracellular hormone potency
AU - Agarwal, Anil K.
AU - Auchus, Richard J.
PY - 2005/6
Y1 - 2005/6
N2 - 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 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. 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.
AB - 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 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. 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.
UR - http://www.scopus.com/inward/record.url?scp=18844381164&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=18844381164&partnerID=8YFLogxK
U2 - 10.1210/en.2005-0061
DO - 10.1210/en.2005-0061
M3 - Short survey
C2 - 15774561
AN - SCOPUS:18844381164
SN - 0013-7227
VL - 146
SP - 2531
EP - 2538
JO - Endocrinology
JF - Endocrinology
IS - 6
ER -