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    • Introduction Adenosine monophosphate cAMP is a general purpo

    2023-12-05

    Introduction Adenosine 3′,5′-monophosphate (cAMP) is a general-purpose signaling molecule present in most branches of life. Intracellular cAMP levels control diverse cellular functions. In bacteria, cAMP regulates metabolism by activation of the catabolite activator protein (CAP), also known as cAMP receptor protein (CRP) [1]. Other cAMP-dependent responses include phototaxis [2], protein secretion, and virulence [3]. In eukaryotes, cAMP acts mainly as a downstream messenger of G protein-coupled receptors, which are involved in many sensory and developmental processes [1,4]. cAMP-producing enzymes were traditionally termed adenylate cyclases (or, from another chemical point of view adenylyl cyclases; abbreviated as ACs; see Dessauer et al. [4] for the history of AC designations), which, despite their common function, do not all originate from a common ancestor. Rather, ACs are currently divided into six unrelated classes, five of which (classes I, II, IV, V, VI) have not been studied in great detail, mostly because they are limited to a narrow range of prokaryotic species [5]. Among them, class II ACs stand out in that they are secreted as toxins by a number of pathogenic bacteria, such as Bacillus anthracis or Bordetella pertussis, perturbing cAMP levels in their hosts [[6], [7], [8]]. Novel evidence for the existence of nucleotide cyclase activity in plants suggest the presence of one or more additional apelin receptor of ACs that await detailed molecular, biochemical and bioinformatic characterization [9]. Class III, finally, is the numerically largest, structurally and functionally most diverse, and pharmacologically most relevant; it is also the only one occurring in animals. The family is defined by its conserved catalytic domains. It is related to the catalytic GGDEF domain of bacterial diguanylate cyclases [10]. Their common ancestor may have evolved from an early nucleotide polymerase (indicated by dotted lines in Fig. 1; [11,12]). Class III also includes the eukaryotic guanylate cyclases (GCs), whose role in regulating cellular processes overlaps little, if at all, with that of ACs. The existence of bacterial GCs is controversial [13]. Two cases of GC activity have been reported from Rhodospirillum [14,15]. However, many ACs show side-activities with other nucleotide triphosphates, such as the mycobacterial Rv1900c, which shows up to 7% GC side activity [16,17]. Class III ACs require dimerization for activity. Bacterial ACs are homodimers, which form two catalytic centers at the subunit interface. Eukaryotic ACs, including all ten human isoforms, are so-called pseudoheterodimers, which consist of two complementary catalytic units joined into a single chain, forming one catalytic center at the subunit interface. The catalytic mechanism has been elucidated and confirmed in biochemical, structural, and computational studies [[18], [19], [20]]. Three pairs of residues are of particular importance: A pair of aspartate residues (Me labels in Fig. 2) coordinates a divalent metal cofactor, Mn2+ or Mg2+, which enables a nucleophilic attack of the ribose 3′-hydroxyl group onto the ATP α-phosphoryl group. The resulting transition state is stabilized by one arginine and one asparagine side chain (Tr labels in Fig. 2). The third pair of residues discriminates between ATP and GTP as substrate (Ad labels in Fig. 2). In ACs, these are typically lysine and aspartate, whereas eukaryotic GCs frequently have glutamate and cysteine, or glutamate and serine in these positions [5].
    Classifications of class III ACs The widespread presence and functional diversity of class III ACs has led to several attempts at subclassification, not least in the interest of a universal ontology that could help to clarify the role of an individual AC within its cellular signaling network. The most widely accepted subclassification of class III ACs is based on sequence similarities between the homologous catalytic domains, resulting in four subclasses, termed IIIa-IIId ([5]; Fig. 1, Fig. 2). The deepest branch-point separates IIIa and IIIb on the one hand from IIIc and IIId on the other. Within the IIIa/b branch, subclasses IIIa and IIIb are each monophyletic, i.e. represent single evolutionary lineages with characteristic features; for example, subclass IIIb ACs show an aspartate-to-threonine substitution in a substrate-determining position, which is possibly linked to bicarbonate sensitivity (Fig. 2; [21]). Subclass IIIa further divides into several subclades, corresponding to a mostly bacterial branch that probably represents the ancestral state, two clades for the catalytic domains in the animal pseudoheterodimers, one that encompasses most eukaryotic GCs, and several minor clades from diverse protozoans [22]. Within the IIIc/d branch, by comparison, several clades separate near the root, of which IIId is one, the others being collected into subclass IIIc (Fig. 1; [23]). Presently, these clades have few members and do not include well-studied proteins, offering little incentive for further subclassification. In the following, we will therefore use IIIc/d as an umbrella term for the various minor lineages forming the outgroup to subclass IIIa and IIIb ACs.