Back to Search Start Over

Studies on the catalytic function of aromatase: aromatization of 6-alkoxy-substituted androgens

Authors :
Mitsuteru Numazawa
Momoko Ando
Rika Zennyoji
Source :
The Journal of Steroid Biochemistry and Molecular Biology. 82:65-73
Publication Year :
2002
Publisher :
Elsevier BV, 2002.

Abstract

To gain insight into the catalytic function of aromatase, we studied aromatization of a series of 6α- and 6β-ether-substituted (methoxy, ethoxy, and n -butoxy) androst-4-ene-3,17-dione (AD) steroids ( 1 and 2 ) and their androsta-1,4-diene-3,17-dione (ADD) derivatives ( 3 and 4 ) with human placental aromatase by gas chromatography–mass spectrometry (GC–MS). Among the steroids examined, 6β-methoxy and 6β-ethoxyADDs ( 4a and 4b ) are suicide substrates of aromatase. All of the steroids were found to be converted into the corresponding 6-alkoxy estrogens. Introduction of the alkoxy groups at C-6 of AD or ADD decreased the ability of these to serve as a substrate of aromatase. In 6α-alkoxy steroid series, compounds 1 and 3 , the aromatization rate increased by elongating the 6-methoxy group up to the n -butoxy group whereas, in the 6β-isomers series, 2 and 4 , the rate decreased due to this structural modification. 6β-Alkoxy steroids, 2 and 4 , including the suicide substrates, were extremely poor substrates for the aromatization reaction. Apparent K m values obtained for 6α-alkoxy compounds 1 and 3 were similar to each other, ranging from 92 to 111 nM, as shown by their previously-obtained K i values. The findings indicate that the stereochemistry as well as the bulkiness of the 6-ether-substituent play an important role in the ability to serve as a substrate. It is also predicted that the aromatization reaction and the mechanism-based inactivation reaction would be related and have a definite partition number which is characteristic to the compound in a series of suicide substrates.

Details

ISSN :
09600760
Volume :
82
Database :
OpenAIRE
Journal :
The Journal of Steroid Biochemistry and Molecular Biology
Accession number :
edsair.doi.dedup.....76828ff78520575fed918951715c186f
Full Text :
https://doi.org/10.1016/s0960-0760(02)00148-6