Molecular basis for the aromatization reaction and exemestane-mediated irreversible inhibition of human aromatase.
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.[1]References
- Molecular basis for the aromatization reaction and exemestane-mediated irreversible inhibition of human aromatase. Hong, Y., Yu, B., Sherman, M., Yuan, Y.C., Zhou, D., Chen, S. Mol. Endocrinol. (2007) [Pubmed]
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