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 M and V max 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.
Keywords
Very recently, the first detailed analysis of enzyme kinetics was reported for cUMP hydrolysis by a class I phosphodiesterase, PDE3A (Berrisch et al. 2016). The hydrolysis of cUMP occurs with a K M value of 143 μM, which is about 200-fold higher than the K M value for cAMP (0.7 μM, determined under the same conditions). Moreover, the V max for cUMP hydrolysis is 42 μmol/min/mg, which is more than 30-fold faster than the V max reached by the cAMP-saturated enzyme (1.2 μmol/min/mg, determined under the same conditions) (Berrisch et al. 2016). Thus, PDE3A is a low affinity and high capacity PDE for cUMP. The PDE3 inhibitor milrinone reduced PDE3A-mediated cUMP hydrolysis with a K i value of 57 nM (Berrisch et al. 2016), which is in good agreement with the K i value reported in the literature for milrinone inhibition of cAMP hydrolysis (150 nM) (Ito et al. 1988). Thus, cUMP may bind to the same site as cAMP. Nevertheless, first experiments with HL-1 cardiomyogenic cells suggest that PDE-independent mechanisms are more important than PDE3 for the disposal of low intracellular cUMP concentrations (Berrisch et al. 2016). PDE3 may, however, prevent the toxic effects of cUMP under pathophysiological conditions (e.g. presence of cUMP-synthesizing bacterial nucleotidyl cyclases like ExoY).
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Schneider, E.H., Seifert, R. (2016). Inactivation of Non-canonical Cyclic Nucleotides: Hydrolysis and Transport. In: Seifert, R. (eds) Non-canonical Cyclic Nucleotides. Handbook of Experimental Pharmacology, vol 238. Springer, Cham. https://doi.org/10.1007/164_2016_5004
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