Carboxylic acid reductases in metabolic engineering

Carboxylic acid reductases (CARs) catalyze the conversion of carboxylic acids to aldehydes, which are a valuable class of chemicals for many consumer and industrial applications. CARs generally exhibit broad substrate specificity that encompasses aromatic, aliphatic, and di/tri-carboxylic acids, enabling the development of biosynthetic pathways to a wide array of potential aldehyde products. De novo synthetic pathways implementing CARs have enabled the production of sustainable aldehyde products or utilized highly reactive aldehydes as intermediates in the production of chemicals including amines, alcohols, and alkanes. Recent determination of crystal structures of the domains of three CARs has provided insight into the substrate binding and domain dynamics of CARs, which could enable future engineering efforts to both alter the specificity of CAR and expand its potential in future synthetic pathways. In this review, we summarize the current structural and mechanistic understanding of CARs including substrate and catalytic scope, their potential for future engineering, and the advantages and challenges of their application in de novo synthesis.