Two‐Enzyme Hydrogen‐Borrowing Amination of Alcohols Enabled by a Cofactor‐Switched Alcohol Dehydrogenase

The NADPH‐dependent secondary alcohol dehydrogenase from Thermoanaerobacter ethanolicus (TeSADH), displaying broad substrate specificity and low enantioselectivity, was engineered to accept NADH as a cofactor. The engineered TeSADH showed a >10 000‐fold switch from NADPH towards NADH compared to the wildtype enzyme. This TeSADH variant was applied to a biocatalytic hydrogen‐borrowing system that employed catalytic amounts of NAD+, ammonia, and an amine dehydrogenase, which thereby enabled the conversion a range of alcohols into chiral amines. Designed to share: Rational engineering of the cofactor dependence in a nonselective alcohol dehydrogenase opens the door to a second generation of hydrogen‐borrowing enzyme cascades for the amination of alcohols.