Scharrenbroich, Jessica and Kaever, Volkhard and Dove, Stefan and Seifert, Roland and Schneider, Erich H. (2019) Hydrolysis of the non-canonical cyclic nucleotide cUMP by PDE9A: kinetics and binding mode. NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY, 392 (2). pp. 199-208. ISSN 0028-1298, 1432-1912
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The non-canonical cyclic nucleotide cUMP and the phosphodiesterase PDE9A both occur in neuronal cells. Using HPLC-coupled tandem mass spectrometry, we characterized the kinetics of PDE9A-mediated cUMP hydrolysis. PDE9A is a low-affinity and high-velocity enzyme for cUMP (V-max=6mol/min/mg; K-m=401M). The PDE9 inhibitor BAY 73-6691 inhibited PDE9A-catalyzed cUMP hydrolysis (K-i=590nM). Docking studies indicate two H-bonds between the cUMP uridine moiety and Gln453/Asn405 of PDE9A. By contrast, the guanosine moiety of cGMP forms three H-bonds with Gln453. cCMP is not hydrolyzed at a concentration of 3M, but inhibits the PDE9A-catalyzed cUMP hydrolysis at concentrations of 100M or more. The probable main reason is that the cytosine moiety cannot act as H-bond acceptor for Gln453. A comparison of PDE9A with PDE7A suggests that the preference of the former for cGMP and cUMP and of the latter for cAMP and cCMP is due to stabilized alternative conformations of the side chain amide of Gln453 and Gln413, respectively. This so-called glutamine switch is known to be involved in the regulation of cAMP/cGMP selectivity of some PDEs.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | SOLUBLE ADENYLYL-CYCLASE; SUBSTRATE-SPECIFICITY; CGMP; PHOSPHODIESTERASE; INHIBITOR; CCMP; CAMP; SELECTIVITY; MECHANISM; Cyclic UMP; Cyclic CMP; Phosphodiesterase; PDE9A; Enzyme kinetics; Glutamine switch |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 20 Apr 2020 07:17 |
| Last Modified: | 20 Apr 2020 07:17 |
| URI: | https://pred.uni-regensburg.de/id/eprint/27673 |
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