Evidence for two catalytic centers and Mn2+ as physiological cofactor of soluble guanylyl cyclase

Background Soluble guanylyl cyclase (sGC) constitutes a family of enzymes that catalyses the cyclization of guanosine 5’-triphosphate (GTP) to guanosine 3’,5’-cyclic monophosphate (cGMP). The heterodimeric hemoprotein is activated by nitric oxide and mediates a wide range of physiological effects like regulation of blood pressure and neuronal cell development. sGC is an important target for the treatment of cardiovascular diseases. In addition to the biosynthesis of cGMP, we recently showed that invitro and in presence of Mn ions sGC also generates the cyclic purine nucleotides adenosine 3’,5’-cyclic monophosphate (cAMP), inosine 3’,5’-cyclic monophosphate (cIMP), and xanthosine 3’,5’-cyclic monophosphate (cXMP)[1]. For all purine nucleotides, a second low-affinity site was described[1]. Moreover, sGC shows a pyrimidinylyl cyclase activity for uridine 3’,5’-cyclic monophosphate (cUMP) and cytosine 3’,5’cyclic monophosphate (cCMP). In this case, no second binding site could be identified[1]. Lastly, no formation of the cyclic desoxyribonucleotide thymidine 3’,5’-cyclic monophosphate (cTMP) was detected[1].