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 K and V values, 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.

Therapeutic targeting of 3′,5′-cyclic nucleotide phosphodiesterases: inhibition and beyond

“…Cyclic cytidine monophosphate (cCMP) and cyclic uridine monophosphate (cUMP) are synthesized by soluble guanylate and soluble adenylate cyclases in mammalian systems, although an as-yetto-be identified generator likely accounts for the majority of production given the dissociation between sGC/sAC and cCMP/cUMP expression patterns (9). ExoY, a bacterial nucleotidyl cyclase, is known to generate cUMP in non-mammalian systems (7). Hydrolysis of cCMP is catalyzed by PDE7A whereas cUMP is broken down by PDE3A, PDE3B and PDE9A (7).…”

“…ExoY, a bacterial nucleotidyl cyclase, is known to generate cUMP in non-mammalian systems (7). Hydrolysis of cCMP is catalyzed by PDE7A whereas cUMP is broken down by PDE3A, PDE3B and PDE9A (7). Functionally both nucleotides have been shown to activate PKA/PKG (287), cyclic nucleotide gated channels (288), and cCMP is described as a partial agonist of EPAC (289).…”

“…Signaling through either the cAMP or cGMP pathways ultimately leads to phosphorylation of a myriad of downstream targets, including the transcription factor cAMP response element binding protein (CREB). In addition to cAMP and cGMP, several PDEs also hydrolyze the non-canonical cyclic nucleotides (not included) cUMP (PDE3A, PDE3B, PDE9A), cCMP (PDE7A), and c-di-GMPa (bacterial PDEs), albeit with much lower affinity(7,8).…”

Alteration of the soluble guanylate cyclase system in coronary arteries of high cholesterol diet‐fed rabbits

“…Intracellular cGMP is reduced through the degradation by phosphodiesterases or through extracellular export via multidrug resistanceassociated proteins (MRPs). 28 Phosphodiesterase 1 expression has been found to be increased in neointimal lesions in human coronary arteries. 4 In addition, an upregulated MRP4 and MRP5 expression has also been shown in human atherosclerotic coronary arteries.…”

cGMP: a unique 2nd messenger molecule – recent developments in cGMP research and development

“…In addition, PDE2 and PDE3, whose activity may be modulated by cGMP, are also involved in NO and NP signaling. More recently, it was also demonstrated that PDEs are able to cleave non-canonical cNMPs (in particular, cCMP and cUMP) in addition to hydrolyzing the canonical cNMPs, cAMP, and cGMP (Schneider and Seifert 2017) which may broaden the therapeutic impact of PDE inhibitors in the future. In recent years, it turned out that PDE inhibition provides effective treatment approaches in various diseases (Baillie et al 2019).…”