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The Role of Substra...
The Role of Substrate-Coenzyme Crosstalk in Determining Turnover Rates in Rhodococcus ruber Alcohol Dehydrogenase
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- Enugala, Thilak Reddy (author)
- Uppsala universitet,Biokemi,Widersten
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- Corbella Morató, Marina (author)
- Uppsala universitet,Biokemi,Kamerlin
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- Kamerlin, Shina C. L., 1981- (author)
- Uppsala universitet,Biokemi,Kamerlin
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- Widersten, Mikael (author)
- Uppsala universitet,Biokemi,Widersten
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(creator_code:org_t)
- 2020-07-16
- 2020
- English.
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In: ACS Catalysis. - : American Chemical Society (ACS). - 2155-5435. ; 10:16, s. 9115-9128
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Abstract
Subject headings
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- Eight related alcohol dehydrogenases that had been originally isolated by laboratory evolution of ADH-A from Rhodococcus ruber DSM44541 for modified substrate scopes, were together with their parent wild-type, subjected to biochemical characterization of possible activities with a panel of chiral alcohols and pro-chiral ketones. Determinations of rates of catalyzed alcohol oxidations and ketone reductions, and of cofactor release, pointed out to the role of a W295A substitution as being decisive in steering enantioselectivity in the oxidation of arylated 1-methyl substituted alcohols. Molecular dynamics simulations of enzyme-substrate interactions in the Michaelis complexes of wild-type and a Y294F/W295A double mutant could rationalize the experimentally observed shift in enantioselectivity and differences in catalytic activity with 4-phenyl-2-butanol. Finally, we present herein evidence for apparent inter-dependency between substrate/product and the cofactor in the ternary complex, that directly affects the NADH dissociation rates, and thus that this substrate-coenzyme crosstalk plays a direct role in determining the turnover rates.
Subject headings
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
Keyword
- alcohol dehydrogenase
- substrate selectivity
- active-site structure
- stereoselectivity
- molecular dynamics simulations
- Biokemi
- Biochemistry
Publication and Content Type
- ref (subject category)
- art (subject category)
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