A survey of the Protein Data Bank reveals that the arabinofuranosidase class of enzymes broadly restrict their substrate side chains to the gauche,gauche (gg) conformation that provides maximum electrostatic stabilization to oxocarbenium ion-like transition states and so employ the strategy reported previously for the majority of glycoside hydrolases, transglycosidases, and glycosyltransferases acting on pyranosyl substrates. The fructofuranosidases, ribonucleosidases, ribonucleoside phosphorylases, and nucleoside 2′-deoxyribosyltransferases, whose gg conformation is sterically hindered, restrict their substrate side chains to the next most positive charge-stabilizing gauche,trans (gt) conformation. These conclusions are supported by extensive literature studies on the mechanisms of C–N bond cleavage by members of the nucleosidase and nucleoside phosphorylase families and are discussed in terms of Warshel’s concept of the electrostatic origin of the catalytic power of enzymes and the role of preorganized active sites.

Necessity is the mother of invention. Most synthetic chemistry innovations are driven by our desire to make molecules. In the first half of the 20th century, much of this work was inspired by natural ...