Insight into enzymatic nitrile reduction: QM/MM study of the catalytic mechanism of QueF nitrile reductase

The NADPH-dependent QueF nitrile reductases catalyze the unprecedented four-electron reduction of nitrile to amine. QueF nitrile reductases can be found in the tRNA biosynthetic pathway of many bacteria and are potential antimicrobial drug targets. QueF enzymes have also attracted great attention as potential industrial biocatalysts for replacing the nitrile-reducing metal hydride catalysts used commonly in the chemical and pharmaceutical industries. Because of their narrow substrate specificity, engineering of the QueF enzymes to generate variants with altered or broadened substrate specificity is crucial for producing practically useful biocatalysts. A better understanding of the catalytic mechanism of the QueF enzymes would expedite rational inhibitor design and enzyme engineering. In this work, we probed the catalytic mechanism of the Vibrio cholerae QueF nitrile reductase by state of the art QM/MM calculations at the ONIOM(B3LYP/6-311+G(2d,2p):AMBER) level. The QM/MM computational results suggest tha...

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