hexose-6-phosphate dehydrogenase modulates 11β-hydroxysteroid dehydrogenase type 1-dependent metabolism of 7-keto- and 7β-hydroxy-neurosteroidshexose-6-phosphate脱氢酶调节11β-hydroxysteroid脱氢酶7-keto -和7β-hydroxy-neurosteroids 1-dependent代谢类型.pdfVIP

Hexose-6-phosphate Dehydrogenase Modulates 11b-Hydroxysteroid Dehydrogenase Type 1-Dependent Metabolism of 7-keto- and 7b-hydroxy-neurosteroids 1,2 3 1,2 4 2 2 3 Lyubomir G. Nashev , Charlie Chandsawangbhuwana , Zoltan Balazs , Atanas G. Atanasov , Bernhard Dick , Felix J. Frey , Michael E. Baker , Alex Odermatt1,2* 1 Institute of Molecular and Systems Toxicology, University of Basel, Basel, Switzerland, 2 Department of Nephrology and Hypertension, University of Berne, Berne, Switzerland, 3 Department of Medicine, University of California, San Diego, La Jolla, California, United States of America, 4 Division of Immunopathology, Institute of Pathology, University of Berne, Berne, Switzerland Background. The role of 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1) in the regulation of energy metabolism and immune system by locally reactivating glucocorticoids has been extensively studied. Experiments determining initial rates of enzyme activity revealed that 11b-HSD1 can catalyze both the reductase and the dehydrogenase reaction in cell lysates, whereas it predominantly catalyzes the reduction of cortisone to cortisol in intact cells that also express hexose-6-phosphate dehydrogenase (H6PDH), which provides cofactor NADPH. Besides its role in glucocorticoid metabolism, there is evidence that 11b-HSD1 is involved in the metabolism of 7-keto- and 7-hydroxy-steroids; however the impact of H6PDH on this alternative function of 11b-HSD1 has not been assessed. Methodology. We investigated the 11b-HSD1-dependent metabolism of the neurosteroids 7-keto-, 7a-hydroxy- and 7b-hydroxy-dehydroepiandrosterone (DHEA) and 7-keto- and 7b-hydroxy-pregneno- lone, respectively, in the absence or presence of H6PDH in intact cells. 3D-structural modeling