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Studies on the catalytic function of aromatase: aromatization of 6-alkoxy-substituted androgens
- 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.
- Subjects :
- medicine.drug_class
Stereochemistry
Placenta
Endocrinology, Diabetes and Metabolism
medicine.medical_treatment
Clinical Biochemistry
Biochemistry
Catalysis
Gas Chromatography-Mass Spectrometry
Steroid
Structure-Activity Relationship
Aromatase
Endocrinology
Pregnancy
Microsomes
medicine
Humans
Organic chemistry
Enzyme Inhibitors
Molecular Biology
Aromatase inhibitor
Molecular Structure
biology
Chemistry
Catalytic function
Androstenedione
Aromatization
Substrate (chemistry)
Cell Biology
Kinetics
Alkoxy group
biology.protein
Molecular Medicine
Female
Gas chromatography–mass spectrometry
Subjects
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