Abstract
Dehydroepiandrosterone sulfate (DHEAS) is the most abundant circulating steroid in human, with the highest concentrations between age 20 and 30, but displaying a significant decrease with age. Many beneficial functions are ascribed to DHEAS. Nevertheless, long-term studies are very scarce concerning the intake of DHEAS over several years, and molecular investigations on DHEAS action are missing so far. In this study, the role of DHEAS on the first and rate-limiting step of steroid hormone biosynthesis was analyzed in a reconstituted in vitro system, consisting of purified CYP11A1, adrenodoxin and adrenodoxin reductase. DHEAS enhances the conversion of cholesterol by 26%. Detailed analyses of the mechanism of DHEAS action revealed increased binding affinity of cholesterol to CYP11A1 and enforced interaction with the electron transfer partner, adrenodoxin. Difference spectroscopy showed K d-values of 40±2.7 µM and 24.8±0.5 µM for CYP11A1 and cholesterol without and with addition of DHEAS, respectively. To determine the K d-value for CYP11A1 and adrenodoxin, surface plasmon resonance measurements were performed, demonstrating a K d-value of 3.0±0.35 nM (with cholesterol) and of 2.4±0.05 nM when cholesterol and DHEAS were added. Kinetic experiments showed a lower Km and a higher kcat value for CYP11A1 in the presence of DHEAS leading to an increase of the catalytic efficiency by 75%. These findings indicate that DHEAS affects steroid hormone biosynthesis on a molecular level resulting in an increased formation of pregnenolone.
Highlights
IntroductionSteroid hormones are indispensable for a normal development
In mammalian organisms, steroid hormones are indispensable for a normal development
These characteristics are unique for DHEA or Dehydroepiandrosterone sulfate (DHEAS) and in contrast to other steroid hormones like aldosterone or cortisol, whose serum concentrations stay constant during life
Summary
Steroid hormones are indispensable for a normal development. Considering their action, these steroids are classified into three main groups. Biosynthesis of all steroid hormones (Fig. 1) is initiated by CYP11A1 with the side chain cleavage of cholesterol yielding pregnenolone [1,2]. This ratelimiting step of the steroid hormone biosynthesis is carried out in the inner mitochondrial membrane and displays three hydroxylation reactions. The cleavage of the side chain of cholesterol is initiated by a third hydroxylation. The product pregnenolone serves as precursor for mineralocorticoids, glucocorticoids, as well as DHEA and its derived sexual hormones
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