Structural highlights
Publication Abstract from PubMedOptically pure epoxides are essential chiral precursors for the production of (S)-propranolol, (S)-alprenolol, and other beta-adrenergic receptor blocking drugs. Although the enzymatic production of these bulky epoxides has proven difficult, here we report a method to effectively improve the activity of BmEH, an epoxide hydrolase from Bacillus megaterium ECU1001 toward alpha-naphthyl glycidyl ether, the precursor of (S)-propranolol, by eliminating the steric hindrance near the potential product-release site. Using X-ray crystallography, mass spectrum, and molecular dynamics calculations, we have identified an active tunnel for substrate access and product release of this enzyme. The crystal structures revealed that there is an independent product-release site in BmEH that was not included in other reported epoxide hydrolase structures. By alanine scanning, two mutants, F128A and M145A, targeted to expand the potential product-release site displayed 42 and 25 times higher activities toward alpha-naphthyl glycidyl ether than the wild-type enzyme, respectively. These results show great promise for structure-based rational design in improving the catalytic efficiency of industrial enzymes for bulky substrates. Engineering of an epoxide hydrolase for efficient bioresolution of bulky pharmaco substrates.,Kong XD, Yuan S, Li L, Chen S, Xu JH, Zhou J Proc Natl Acad Sci U S A. 2014 Nov 4;111(44):15717-22. doi:, 10.1073/pnas.1404915111. Epub 2014 Oct 20. PMID:25331869[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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