Abstract
To gain insight into the catalytic function of aromatase and its substrate specificity, we studied reversible inhibition of 16α-hydroxyandrostenedione (16α-OHAD) aromatization in human placental microsomes by several suicide substrates of androstenedione (AD) aromatization, including 4-hydroxyAD (1), 6-oxoAD (2) and its 19-hydroxy analogue 3, androst-5-ene-4,7,17-trione (4), and 10β-acetoxyandrost-5-en-7,17-dione (5) that, in contrast, do not cause a suicide inactivation of 16α-OHAD aromatization. All inhibitors examined blocked 16α-OHAD aromatization in a competitive manner with apparent Ki values ranging from 0.50 to 980 nM. The relative Ki values between inhibitors 1—5 obtained in the 16α-OHAD aromatization experiments were markedly different from those obtained in the AD aromatization experiments. The results predict that all inhibitors examined bind to the 16α-OHAD binding site in a manner that does not cause suicide inactivation of 16α-OHAD aromatization. These findings would be useful for understanding the active (binding) site structure as well as the catalytic function of aromatase.
