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- W4241349043 endingPage "12654" @default.
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- W4241349043 abstract "Diaryl ketones are important building blocks for synthesizing pharmaceuticals and are generally regarded as difficult-to-reduce ketones due to the large steric hindrance of their two bulky aromatic side chains. Alcohol dehydrogenase from Kluyveromyces polyspora ( KpADH) has been identified as a robust biocatalyst due to its high conversion of diaryl ketone substrate (4-chlorophenyl)(pyridine-2-yl)ketone (CPMK) with a moderate R-selectivity of 82% ee. To modulate the stereoselectivity of KpADH, a polarity scanning strategy was proposed, in which six key residues inside and at the entrance of the substrate binding pocket were identified. After iterative combinatorial mutagenesis, variants Mu-R2 and Mu-S5 with enhanced (99.2% ee, R) and inverted (97.8% ee, S) stereoselectivity were obtained. The crystal structures of KpADH and two mutants in complex with NADPH were resolved to elucidate the evolution of enantioselective inversion. Based on MD simulation, Mu-R2-CPMKProR and Mu-S5-CPMKProS were more favorable in the formation of prereaction states. Interestingly, a quadrilateral plane formed by α-carbons of four residues (N136, V161, C237, and G214) was identified at the entrance of the substrate binding pocket of Mu-S5; this plane acts as a polar gate for substrates. Due to the discrepancy in charge characteristics between chlorophenyl and pyridine substituents, the pro- S orientation of CPMK is defined when it passes through the polar gate in Mu-S5, whereas the similar plane in wild-type is blocked by several aromatic residues. Our result paves the way for engineering stereocomplementary ADH toward bulky diaryl ketones and provides structural insight into the mechanism of stereoselective inversion." @default.
- W4241349043 created "2022-05-12" @default.
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- W4241349043 date "2018-09-24" @default.
- W4241349043 modified "2023-10-16" @default.
- W4241349043 title "Structural Insight into Enantioselective Inversion of an Alcohol Dehydrogenase Reveals a “Polar Gate” in Stereorecognition of Diaryl Ketones" @default.
- W4241349043 cites W1539796472 @default.
- W4241349043 cites W1770208509 @default.
- W4241349043 cites W1849836964 @default.
- W4241349043 cites W1975304761 @default.
- W4241349043 cites W1976236461 @default.
- W4241349043 cites W1984444568 @default.
- W4241349043 cites W1985502939 @default.
- W4241349043 cites W1992218202 @default.
- W4241349043 cites W1999771835 @default.
- W4241349043 cites W2000346188 @default.
- W4241349043 cites W2005470370 @default.
- W4241349043 cites W2010361927 @default.
- W4241349043 cites W2013754949 @default.
- W4241349043 cites W2019051049 @default.
- W4241349043 cites W2023588906 @default.
- W4241349043 cites W2026024113 @default.
- W4241349043 cites W2026114850 @default.
- W4241349043 cites W2026694261 @default.
- W4241349043 cites W2027915877 @default.
- W4241349043 cites W2032422364 @default.
- W4241349043 cites W2032556604 @default.
- W4241349043 cites W2038555855 @default.
- W4241349043 cites W2039373781 @default.
- W4241349043 cites W2040955773 @default.
- W4241349043 cites W2053914556 @default.
- W4241349043 cites W2060002622 @default.
- W4241349043 cites W2062275861 @default.
- W4241349043 cites W2064027022 @default.
- W4241349043 cites W2069439613 @default.
- W4241349043 cites W2071268710 @default.
- W4241349043 cites W2073277085 @default.
- W4241349043 cites W2074711797 @default.
- W4241349043 cites W2077253206 @default.
- W4241349043 cites W2094966898 @default.
- W4241349043 cites W2095851453 @default.
- W4241349043 cites W2103559641 @default.
- W4241349043 cites W2109184569 @default.
- W4241349043 cites W2109209239 @default.
- W4241349043 cites W2122199548 @default.
- W4241349043 cites W2135486490 @default.
- W4241349043 cites W2138310781 @default.
- W4241349043 cites W2141469073 @default.
- W4241349043 cites W2143183478 @default.
- W4241349043 cites W2144081223 @default.
- W4241349043 cites W2156499913 @default.
- W4241349043 cites W2160622786 @default.
- W4241349043 cites W2176182974 @default.
- W4241349043 cites W2178379440 @default.
- W4241349043 cites W2253084053 @default.
- W4241349043 cites W2287014099 @default.
- W4241349043 cites W2300539438 @default.
- W4241349043 cites W2315052340 @default.
- W4241349043 cites W2318997946 @default.
- W4241349043 cites W2324638794 @default.
- W4241349043 cites W2339574018 @default.
- W4241349043 cites W2396584208 @default.
- W4241349043 cites W2404201931 @default.
- W4241349043 cites W2471309061 @default.
- W4241349043 cites W2472269420 @default.
- W4241349043 cites W2502787567 @default.
- W4241349043 cites W2509806303 @default.
- W4241349043 cites W2587291347 @default.
- W4241349043 cites W2589531002 @default.
- W4241349043 cites W2600336435 @default.
- W4241349043 cites W2605081065 @default.
- W4241349043 cites W2606937441 @default.
- W4241349043 cites W2613121502 @default.
- W4241349043 cites W2765921351 @default.
- W4241349043 cites W2771004266 @default.
- W4241349043 cites W2786318551 @default.
- W4241349043 cites W2788902425 @default.
- W4241349043 cites W2791092339 @default.
- W4241349043 cites W2796863654 @default.
- W4241349043 cites W2949061022 @default.
- W4241349043 cites W3004862859 @default.
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- W4241349043 doi "https://doi.org/10.1021/jacs.8b08640" @default.
- W4241349043 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/30247889" @default.
- W4241349043 hasPublicationYear "2018" @default.
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