ATP stimulates human placental 11beta-hydroxysteroid dehydrogenase type 2 activity by a novel mechanism independent of phosphorylation.
The human placental 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) is believed to play a key role in fetal development since this enzyme protects the fetus from exposure to high levels of maternal cortisol by virtue of converting maternal cortisol to its inert metabolite cortisone. The present study was undertaken to examine the effect of ATP on 11beta-HSD2 activity in human placental microsomes. Enzyme activity, reflected by the rate of conversion of cortisol to cortisone, was stimulated more than six-fold by 0.5 mM ATP (EC(50) = 0.2 mM). Such stimulation appears to be mediated through a novel mechanism independent of ATP-induced phosphorylation of the reaction components since AMP-PNP, a non-hydrolyzable analogue of ATP, was equally effective. The ATP-induced stimulation of 11beta-HSD2 activity is adenine nucleotide specific in that a similar stimulation was observed with ADP and AMP but not with CTP, GTP, or UTP. Furthermore, ATP increased the maximal velocity (V(max)) of the 11beta-HSD2 catalyzed conversion of cortisol to cortisone without altering the apparent K(m) of 11beta-HSD2 for cortisol, suggesting that ATP may stimulate enzyme activity by interacting with the enzyme at a site other than that involved in substrate binding. In conclusion, the present study has identified ATP as a novel regulator of human placental 11beta-HSD2 in vitro. It is conceivable that intracellular ATP may have a profound effect on 11beta-HSD2 function in vivo.
Yang
K
K
CIHR Group in Fetal and Neonatal Health and Development, Child Health Research Institute & Lawson Health Research Institute, St. Joseph's Health Care London, Ontario, Canada. kyang@uwo.ca
Hardy
D B
DB
Doumouras
M A
MA
van Beek
J P
JP
Rocha
E
E
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000266:Adenylyl Imidodiphosphate / Q000494:pharmacology; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000378:metabolism*; D007700:Kinetics; D010766:Phosphorylation; D010920:Placenta / Q000187:drug effects* / Q000201:enzymology
D000266:Adenylyl Imidodiphosphate; D000255:Adenosine Triphosphate; D006913:Hydroxysteroid Dehydrogenases; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; C468387:HSD11B2 protein, human