2014
DOI: 10.1002/ange.201402653
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A Smart Library of Epoxide Hydrolase Variants and the Top Hits for Synthesis of (S)‐β‐Blocker Precursors

Abstract: Microtuning of the enzyme active pocket has led to a smart library of epoxide hydrolase variants with an expanded substrate spectrum covering a series of typical β‐blocker precursors. Improved activities of 6‐ to 430‐fold were achieved by redesigning the active site at two predicted hot spots. This study represents a breakthrough in protein engineering of epoxide hydrolases and resulted in enhanced activity toward bulky substrates.

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Cited by 12 publications
(7 citation statements)
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“…Interestingly, it contains a "U" shape substrate binding pocket (SBP) with the active site residues placed in the center, giving rise to two narrow tunnels (tunnel 1 and tunnel 2), whose spatial properties have an effect on the substrate preference. 28,39 Tunnel 1 was constituted of W 102 , I 105 , V 126 , P 127 , L 129 , T 137 , A 143 , M 144 , I 151 , V 264 , S 267 , L 268 , and M 270 , whereas tunnel 2 was constituted of F 33 , P 34 , I 176 , T 179 , K 181 , G 183 , P 185 , N 197 , M 263 , and F 298 (Figure S3). Both tunnels of VrEH3 SBP are interlinked with each other and also lead eventually to the exterior of the protein, which dramatically differs with those SBPs of other α/β hydrolase fold EHs, such as StEH (PDB: 2CJP), 27 AnEH LCP (PDB: 3G0I), 40 BmEH (PDB: 4G02), 41 and MtEHB (PDB: 2ZJF), 42 whose tunnels closed at the internal region.…”
Section: Journal Of Agricultural and Food Chemistrymentioning
confidence: 99%
“…Interestingly, it contains a "U" shape substrate binding pocket (SBP) with the active site residues placed in the center, giving rise to two narrow tunnels (tunnel 1 and tunnel 2), whose spatial properties have an effect on the substrate preference. 28,39 Tunnel 1 was constituted of W 102 , I 105 , V 126 , P 127 , L 129 , T 137 , A 143 , M 144 , I 151 , V 264 , S 267 , L 268 , and M 270 , whereas tunnel 2 was constituted of F 33 , P 34 , I 176 , T 179 , K 181 , G 183 , P 185 , N 197 , M 263 , and F 298 (Figure S3). Both tunnels of VrEH3 SBP are interlinked with each other and also lead eventually to the exterior of the protein, which dramatically differs with those SBPs of other α/β hydrolase fold EHs, such as StEH (PDB: 2CJP), 27 AnEH LCP (PDB: 3G0I), 40 BmEH (PDB: 4G02), 41 and MtEHB (PDB: 2ZJF), 42 whose tunnels closed at the internal region.…”
Section: Journal Of Agricultural and Food Chemistrymentioning
confidence: 99%
“…Recently, protein engineering has emerged as a powerful tool in tuning enzyme properties, 21 including catalytic activity, 22 substrate spectrum, 23 selectivity, 24,25 thermostability, 26 and new reaction types. 27 The same strategy has also been applied in the engineering of IDOs aiming to improve their catalytic activities.…”
Section: ■ Introductionmentioning
confidence: 99%
“…Epoxides are known versatile intermediates giving rise to drugs such as pioglitazone, metoprolol and levofloxacin; or chemical probes such as wiskostatin [ 23 , 31 , 37 , 38 ]. Epoxide installation is typically by direct coupling of an epihalohydrin [ 37 40 ] or through m -chloroperoxybenzoic acid, hydrogen peroxide or tert -butyl hydroperoxide olefin epoxidation [ 41 43 ].…”
Section: Introductionmentioning
confidence: 99%