Commonality of Mechanism in Glycoside Hydrolases, Nucleoside Hydrolases, and Phosphorylases: Importance of Side-Chain Conformation Preorganization

A survey of the Protein Data Bank reveals that the arabinofuranosidase class of enzymes broadly restrict their substrate side chains to the <i>gauche,gauche</i> (<i>gg</i>) 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 <i>gg</i> conformation is sterically hindered, restrict their substrate side chains to the next most positive charge-stabilizing <i>gauche,trans</i> (<i>gt</i>) 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.