The low-barrier hydrogen bond in enzymic catalysis

This chapter describes the various aspects of the low-barrier hydrogen bond in enzymic catalysis. Hydrogen bonds come in a continuum of bond lengths and strengths. The first examples of enzymatic reactions where low-barrier hydrogen bonds played a role involved enolization of the substrate to change the pK of a key group in the reaction. Mandelate racemase enolizes R or S mandelate to convert the carboxyl group into an aci-carboxylate, which can be protonated on opposite sides to give the R or S forms. A low-barrier hydrogen bond forms between Asp102 and His57 in the tetrahedral intermediate of the reaction catalyzed by chymotrypsin and similar serine proteases. Phospholipase A2 catalyzes the hydrolysis of phospholipids at the sn-2 bond, using a water molecule coordinated to Ca2+. Enzymes from bovine pancreas and bee venom are similar in many respects and both contain anaspartate and histidine as catalytic groups. In the presence of phosphonate inhibitors that mimic a tetrahedral intermediate, a low-barrier hydrogen bond exists between the histidine and phosphonate oxygen, whereas the hydrogen bond between the histidine and aspartate is a normal one. A general acid–base catalysis provides a five orders of magnitude rate of acceleration in enzymatic reactions, which is consistent with the energy provided by forming a low-barrier hydrogen bond in the transition state. © 2010 Elsevier Ltd