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Molecular basis for the aromatization reaction and exemestane-mediated irreversible inhibition of human aromatase. | LitMetric

Molecular basis for the aromatization reaction and exemestane-mediated irreversible inhibition of human aromatase.

Mol Endocrinol

Department of Surgical Research and Division of Information Sciences, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Duarte, California 91010, USA.

Published: February 2007

AI Article Synopsis

Article Abstract

Aromatase converts androgens to aromatic estrogens. Aromatase inhibitors have been used as first-line drugs in the treatment of hormone-dependent breast cancer. Structural basis of the aromatization reaction and drug recognition by aromatase has remained elusive because of its unknown three-dimensional structure. In this study, recombinant human aromatase was expressed and purified from Escherichia coli. Using this purified and active preparation, the three-dimensional folding of aromatase was revealed by proteomic analysis. Combined with site-directed mutagenesis, several critical residues involved in enzyme catalysis and suicide inhibition by exemestane were evaluated. Based on our results, a new clamping mechanism of substrate/exemestane binding to the active site is proposed. These structure-function studies of aromatase would provide useful information to design more effective aromatase inhibitors for the prevention and the treatment of hormone-dependent breast cancer.

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Source
http://dx.doi.org/10.1210/me.2006-0281DOI Listing

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