Abstract
Human estrogenic 17β-hydroxysteroid dehydrogenase (17β-HSD1) plays a crucial role in the last step of the synthesis of estrogens. A detailed kinetic study demonstrated that the enzyme shows about 240 fold higher specificity towards estrone reduction than estradiol oxidation at physiological pH using tri-phosphate cofactors. The kcat/Km values are 96 ± 10 and 0.4 ± 0.1 s−1 (μM)−1 respectively for the above two reactions. However, it has been shown that this difference is closely linked to the use of NADPH and NADP cofactors. A binding study using equilibrium dialysis indicated similar KD (equilibrium dissociation constant) of 11 ± 1 and 4.7 ± 0.9 μM for estrone and estradiol, respectively. The binding affinity of 17β-HSD1 to estrone was significantly increased with a KD of 1.6 ± 0.2 μM in the presence of NADP, the latter used as an analogue of the NADPH. The results of binding studies agree with the steady-state kinetics, which showed that the Km of estrone is 12-fold lower when using NADPH as a cofactor than when using NADH. These results strongly suggest that the cofactor plays a crucial role in the stimulation of the specificity for estrogen reduction.
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