Carboxylic acid reductase enzymes (CARs) meet the demand in synthetic chemistry for a green and regiospecific route to aldehydes from their respective carboxylic acids. However, relatively few of these enzymes have been characterized. A sequence alignment with members of the ANL (Acyl‐CoA synthetase/ NRPS adenylation domain/Luciferase) superfamily of enzymes shed light on CAR functional dynamics. Four unstudied enzymes were selected by using a phylogenetic analysis of known and hypothetical CARs, and for the first time, a thorough biochemical characterization was performed. Kinetic analysis of these enzymes with various substrates shows that they have a broad but similar substrate specificity. Electron‐rich acids are favored, which suggests that the first step in the proposed reaction mechanism, attack by the carboxylate on the α‐phosphate of adenosine triphosphate (ATP), is the step that determines the substrate specificity and reaction kinetics. The effects of pH and temperature provide a clear operational window for the use of these CARs, whereas an investigation of product inhibition by NADP+, adenosine monophosphate, and pyrophosphate indicates that the binding of substrates at the adenylation domain is ordered with ATP binding first. This study consolidates CARs as important and exciting enzymes in the toolbox for sustainable chemistry and provides specifications for their use as a biocatalyst.

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Reagent guides ranking commonly used reagents for 15 transformations have been developed to reduce the environmental impact of drug discovery and development. Reagents have been scored by a combination of health, safety and environmental risk phrases, life cycle analysis (where possible) and an assessment of the chemistry including considerations of atom efficiency, stoichiometry, work-up and other issues. Guides covering alkene reduction, amide formation, C-H bromination, C-H chlorination, deoxychlorination, epoxidation, ester formation, ether formation, fluorination, iodination, ketone reduction, nitro reduction, oxidation of alcohols to aldehydes and ketones, reductive amination and sulfur oxidation are shared, with an explanation of the methodology behind their generation. † Electronic supplementary information (ESI) available. See

Biocatalysis over the past few years has matured into an essential tool for modern, cost effective and sustainable pharmaceutical manufacturing. While some reaction classes are well established, and may even be the option of first intent, other more recently discovered enzyme classes are being rapidly developed both in academia and industry. Notwithstanding this, there are further promising enzymes that require further investment and investigation to allow their future industrial use. We here outline GSK's perspective on the current status of biocatalysis for pharmaceutical manufacturing and provide our views on areas of significant potential.

Triple mutant K66Q/S149G/N262C (TM_pheDH) of Rhodococcus phenylalanine dehydrogenase (pheDH) was engineered by directed evolution as the first enzyme for the highly enantioselective reductive amination of phenylacetone 1 and 4-phenyl-2-butanone 3, giving (R)amphetamine 2 and (R)-1-methyl-3-phenylpropylamine 4 in >98% ee, respectively. The new amine dehydrogenase TM_pheDH with special substrate specificity is a valuable addition to the amine dehydrogenase family with very limited number, for asymmetric reductive amination of ketone, an important reaction in sustainable pharmaceutical manufacturing. Molecular docking provided insight into the role of key mutations of pheDH, being useful for engineering new amine dehydrogenases with higher activity and unique substrate scope.