At least 11 families of PDE including PDE1–7 and PDE8–11 are known to exist based upon a variety of criteria including substrate specificity, inhibitor potency, enzyme kinetics and amino acid sequence. These enzymes are distributed widely throughout the body, differentially expressed in cells and localized to different compartments within cells. The functional significance of the subcellular localization of PDEs is not completely understood, although there is a considerable body of evidence to suggest that the expression of PDE in cellular domains can tightly regulate the levels of cyclic nucleotides in the vicinity of effector proteins and is therefore implicated in the regulation of cell function.
Classification of phosphodiesterase enzymes
PDE enzymes function by hydrolysing the phosphodiester bond of the second messenger molecules cyclic 3′, 5′-adenosine monophosphate (cAMP) and cyclic 3′, 5′-guanosine monophosphate (cGMP). This converts cAMP and cGMP to their inactive 5′- mononucleotides; adenosine monophosphate (AMP) and guanosine monophosphate (GMP). These products are incapable of activating specific cyclic nucleotide-dependent protein kinase cascades.
The PDE enzyme family consists of a growing number of genetically heterologous isoenzymes (Table 7.1).
Regarding substrate affinities, PDE4 and PDE7 are highly selective for cAMP. Although PDE3 hydrolyses cAMP and cGMP with equal affinity (Km: 0.1–0.5 μM), its Vmax (‘Velocity’ of action) for cAMP is five-fold greater than for cGMP. Functionally, then, PDE3 favours cAMP. Conversely, cGMP is the preferred substrate for PDE5 and PDE6, whereas PDE1 and PDE2 hydrolyse either cyclic nucleotide.