title: Inactivation of Non-canonical Cyclic Nucleotides: Hydrolysis and Transport.
abstract: This chapter addresses cNMP hydrolysis by phosphodiesterases (PDEs) and export by multidrug resistance associated proteins (MRPs). Both mechanisms are well-established for the canonical cNMPs, cAMP, and cGMP. Increasing evidence shows that non-canonical cNMPs (specifically cCMP, cUMP) are also PDE and MRP substrates. Hydrolysis of cUMP is achieved by PDE 3A, 3B, and 9A, which possibly explains the cUMP-degrading activities previously reported for heart, adipose tissue, and brain. Regarding cCMP, the only known "conventional" (class I) PDE that hydrolyzes cCMP is PDE7A. Older reports describe cCMP-degrading PDE-like activities in mammalian tissues, bacteria, and plants, but the molecular identity of these enzymes is not clear. High KMand Vmaxvalues, insensitivity to common inhibitors, and unusually broad substrate specificities indicate that these activities probably do not represent class I PDEs. Moreover, the older results have to be interpreted with caution, since the historical analytical methods were not as reliable as modern highly sensitive and specific techniques like HPLC-MS/MS. Besides PDEs, the transporters MRP4 and 5 are of major importance for cAMP and cGMP disposal. Additionally, both MRPs also export cUMP, while cCMP is only exported by MRP5. Much less data are available for the non-canonical cNMPs, cIMP, cXMP, and cTMP. None of these cNMPs has been examined as MRP substrate. It was shown, however, that they are hydrolyzed by several conventional class I PDEs. Finally, this chapter reveals that there are still large gaps in our knowledge about PDE and MRP activities for canonical and non-canonical cNMPs. Future research should perform a comprehensive characterization of the known PDEs and MRPs with the physiologically most important cNMP substrates.
authors.affiliation: Institute of Pharmacology, Medical School of Hannover, Carl-Neuberg-Str. 1, 30625, Hannover, Germany. schneider.erich@mh-hannover.de.
authors.forename: Erich H
authors.initials: EH
authors.lastname: Schneider
authors.affiliation: Institute of Pharmacology, Medical School of Hannover, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Seifert
mesh_terms: D000818:Animals; D001665:Binding Sites; D001692:Biological Transport; D020134:Catalytic Domain; D006801:Humans; D006868:Hydrolysis; D007700:Kinetics; D015394:Molecular Structure; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D009712:Nucleotides, Cyclic / Q000737:chemistry / Q000378:metabolism*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D011485:Protein Binding; D013379:Substrate Specificity
chemical_list: D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009712:Nucleotides, Cyclic; D010727:Phosphoric Diester Hydrolases
keywords: Multifunctional PDE; Non-canonical cyclic nucleotides; Phosphodiesterases; cCMP; cUMP