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Submitted on February 1, 2005
Accepted on March 10, 2005
-hydroxysteroid dehydrogenase type 1 activity
Division of Medical Sciences, University of Birmingham, Birmingham B15 2TT UK
* To whom correspondence should be addressed. E-mail: p.m.stewart{at}bham.ac.uk.
Hexose 6-phosphate dehydrogenase (H6PDH) is a microsomal enzyme that is able to catalyze the first two reactions of an endoluminal pentose phosphate pathway, thereby generating NADPH within the endoplasmic reticulum (ER). It is distinct from the cytosolic enzyme, glucose-6-phosphate dehydrogenase (G6PDH), using a separate pool of NAD(P)+ and capable of oxidizing several phosphorylated hexoses. It has been proposed to be a NADPH regenerating system for steroid hormone and drug metabolism, specifically in determining the set point of 11
-hydroxysteroid dehydrogenase type 1 (11-HSD1) activity, the enzyme responsible for the activation and inactivation of glucocorticoids. 11-HSD1 is a bidirectional enzyme, but in intact cells displays predominately oxo-reductase activity, a reaction requiring NADPH and leading to activation of glucocorticoids. However, in cellular homogenates or in purified preparations, 11-HSD1 is exclusively a dehydrogenase. As H6PDH and 11-HSD1 are co-expressed in the inner microsomal compartment of cells, we hypothesized that H6PDH may provide 11-HSD1 with NADPH, thus promoting oxo-reductase activity in vivo. Recently, several studies have confirmed this functional cooperation, indicating the importance of intracellular redox mechanisms for the prereceptor control of glucocorticoid availability. With the increased interest in 11-HSD1 oxo-reductase activity in the pathogenesis and treatment of several human diseases including insulin resistance and the metabolic syndrome, H6PDH represents an additional novel candidate for intervention.
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