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Drug Metabolism by Engineered Toluene o ‐Xylene Monooxygenases of Pseudomonas sp. OX1
Drug Breakdown by Modified Enzymes from Pseudomonas Bacteria
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Abstract
Toluene o-xylene monooxygenase (ToMO) can metabolize chlorzoxazone and resveratrol to form human metabolites at low rates: 6-chlorzoxazone (0.045 ± 0.016 nmol/hr/mg protein) and piceatannol (0.014 ± 0.009 nmol/hr/mg protein).
- ToMO metabolizes acetanilide to produce 2-acetamidophenol (27%), 3-acetamidophenol (42%), and 4-acetamidophenol (31%) at a rate of 3.6 ± 0.3 nmol/hr/mg protein.
- The I100V/E103T variant of ToMO exhibited 2.1- and 49-fold higher activities towards acetanilide and chlorzoxazone, respectively, compared to the native enzyme.
- Variant I100V/E103T changed the regiospecificity of acetanilide metabolism from 31% to 100% 4-acetamidophenol, resembling human liver enzyme behavior.
- Several ToMO variants showed improved selectivity for the formation of 2-, 3-, and 4-acetamidophenol by factors of up to 3.7, 1.6, and 3.2, respectively.
- The I100T/E103L variant demonstrated 34-fold higher activity in metabolizing resveratrol compared to native ToMO.
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