The cyclic nucleotide phosphodiesterase superfamily of enzymes (PDEs) catalyzes the stereospecific hydrolysis of the second messengers adenosine and guanosine 3',5'- cyclic monophosphate (cAMP, cGMP) to produce 5'-AMP and 5'-GMP, respectively. The PDEs are targets of high-throughput screening to determine selective inhibitors for a variety of therapeutic purposes. The catalytic pocket where the hydrolysis takes place is a highly conserved region and has several residues which are absolutely conserved across the PDE families. In this study, we consider a model cyclic substrate in which the adenine/guanine base has been replaced with a hydrogen atom, and we present results of a quantum computational investigation of the hydrolysis reaction as it occurs within the PDE catalytic site using the ONIOM hybrid (B3LYP/6-31g(d):PM3) method. We characterize the bound substrate, the bound hydrolyzed product, and the transition state which connects them for our model cyclic substrate placed in a truncated model of the PDE4D2 catalytic site. We address the role that the conserved histidine proximal to the bimetal system of the catalytic site, along with its conserved glutamine partner, plays in the generation of the hydroxide nucleophile. Our study provides computational evidence for several key features of the cAMP/cGMP hydrolysis mechanism as it occurs within the protein environment across the PDE superfamily.