Frontiers in Bioscience-Landmark (FBL) is published by IMR Press from Volume 26 Issue 5 (2021). Previous articles were published by another publisher on a subscription basis, and they are hosted by IMR Press on imrpress.com as a courtesy and upon agreement with Frontiers in Bioscience.
Academic Editor: Sharron Francis
This review explores the origins, diversity and functions of guanylyl cyclases in cellular organisms. In eukaryotes both cGMP and cAMP are produced by the conserved class III cyclase domains, while prokaryotes use five more unrelated catalysts for cyclic nucleotide synthesis. The class III domain is found embedded in proteins with a large variety of membrane topologies and other functional domains, but the vertebrate guanylyl cyclases take only two forms, the receptor guanylyl cyclases with single transmembrane domain and the soluble enzymes with heme binding domain. The invertebrates additionally show a soluble guanylyl cyclase that cannot bind heme, while the more basal metazoans may lack the heme binding enzymes altogether. Fungi, the closest relatives of the metazoans, completely lack guanylyl cylases, but they appear again in the Dictyostelids, the next relative in line. Remarkably, the two Dictyostelid guanylyl cyclases have little in common with the vertebrate enzymes. There is a soluble guanylyl cyclase, which shows greatest sequence and structural similarity to the vertebrate soluble adenylyl cyclase, and a membrane-bound form with the same configuration as the dodecahelical adenylyl cyclases of vertebrates. There is a difference, the pseudosymmetric C1 and C2 catalytic domains have swapped position in the Dictyostelium enzyme. Unlike the vertebrate guanylyl cyclases, the Dictyostelium enzymes are activated by heterotrimeric G-proteins. Swapped C1 and C2 domains are also found in the structurally similar guanylyl cyclases of ciliates and apicomplexans, but these enzymes additionally harbour an amino-terminal ATPase module with ten transmembrane domains. G-protein regulation could not be demonstrated for these enzymes. Higher plants lack class III cyclase domains, but an unexplored wealth of guanylyl cyclases is present in the green alga Chlamydomonas. Progenitors of all structural variants of the eukaryote guanylyl cyclases are found among the prokaryote adenylyl cyclases. This and the close similarity of many guanylyl cyclases to adenylyl cyclases suggests a paraphyletic origin for the eukaryote enzymes with multiple events of conversion of substrate specificity.