Disease relevance of PDE2A

• The design of more potent and selective inhibitors of PDE2A for the treatment of heart disease would be greatly aided by the identification of active site residues in PDE2A that determine substrate and inhibitor selectivity [1].

High impact information on PDE2A

• Phosphate and ribose group contacts are similar to those in PDE2A [2].
• However, the purine-binding pockets appear very different from that in PDE2A GAF-B [2].
• The 2.9-A crystal structure of the mouse PDE2A regulatory segment reported in this paper reveals that the GAF A domain functions as a dimerization locus [3].
• Studies of cGMP binding to both the native cyclic GMP-stimulated phosphodiesterase and to two unique isolated chymotryptic fragments lacking the catalytic domain suggest that the enzyme contains two noncatalytic cGMP-binding sites/homodimer [4].
• Erythro-9-(2-hydroxy-3-nonyl)adenine inhibits cyclic GMP-stimulated phosphodiesterase in isolated cardiac myocytes [5].

Biological context of PDE2A

• However, other GAF-PDEs, PDE2A and PDE10A, displayed different exon organization from PDE11A although these three PDEs are similar in their amino-acid sequences to each other [6].
• Here we report an alternative approach to rapidly produce active site mutants of human PDE2A and identify their enzymatic properties using a wheat germ in vitro translation (IVT, also known as cell-free translation) system [1].
• We also present the crystal structure of the catalytic domain of human PDE2A determined at 1.7 A resolution, which provided a framework for the rational design of active site mutants [1].
• PDE2A is involved in the regulation of blood pressure and fluid homeostasis by the atrial natriuretic peptide (ANP), making PDE2-type enzymes important targets for drug discovery [1].
• An inhibitor of platelet PDE2A increases cAMP more than inhibitors of PDE3A but has much less effect on platelet activation, suggesting that these enzymes are present in different compartments of the cell [7].

Anatomical context of PDE2A

• In a genome-wide DNA microarray analysis, PDE3A and PDE2A were found to be significantly increased in HeLa cells compared to the other cell lines [8].
• Human PDE2A is expressed in brain and to a lesser extent in heart, placenta, lung, skeletal muscle, kidney and pancreas [9].
• Based on PDE expression, we identified THP-1 and U937 cell lines as possible models for studying the roles of PDE1B and PDE2A in macrophage function [10].
• We find that PDE1B and PDE2A are expressed at low levels in monocytes, but are the major cGMP PDEs expressed in macrophages [10].
• PDE2A immunostaining was detected in the endothelial cells of a variety of microvessels, including those in renal and cardiac interstitial spaces, renal glomerulus, skin, brain, and liver [11].

Associations of PDE2A with chemical compounds

• PDE2A immunostaining was also absent from luminal endothelial cells of large vessels, such as aorta, pulmonary, and renal arteries, but was present in the endothelial cells of the vasa vasorum [11].
• In PDE2A, cGMP binds to a well-defined pocket in one of the two GAF domains that is analogous to the ligand-binding pocket of the distantly related PAS domains of photoactive yellow protein and FixL [12].
• These results indicate that large increases in cGMP may regulate cAMP via cGMP-PDE whereas the small increase induced by bradykinin is insufficient and that cGMP is not involved in the inhibitory action of bradykinin on cAMP levels in D384 cells [13].
• The present studies were performed in order to examine the possible role of cyclic GMP-stimulated phosphodiesterase (cGMP-PDE) activity in the inhibitory action of the inflammatory peptide bradykinin on cyclic AMP (cAMP) accumulation in D384 cells [13].
• Similar results were obtained when using IBMX, trequinsin and dipyridamole, which inhibit PDE2A nonselectively with lower potency [14].

Other interactions of PDE2A

• Platelets contain two cAMP phosphodiesterases (PDEs) which regulate intracellular cAMP levels, cGMP-inhibited cAMP PDE (PDE3A) and cGMP-stimulated PDE (PDE2A) [15].
• Therefore, the GAFa domain of PDE5A adopts a structure similar to the GAFb domain of PDE2A, and provides the sole site for cGMP binding in PDE5A [16].

Analytical, diagnostic and therapeutic context of PDE2A

• Although PDE2A was not readily detected in arterial endothelial cells by immunocytochemistry of intact tissue, it was detected at low levels in cultured arterial endothelial cells [11].

References