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    • In eukaryotes class III ACs including GCs are almost

    2023-02-06

    In eukaryotes, class III ACs (including GCs) are almost universally present, with the noteworthy exception of higher plants. Our dataset comprises 9690 sequences of class III nucleotide cyclases from 710 eukaryotic species. Approximately 80% thereof belong to subclass IIIa and 10% to subclasses IIIb and IIIc/d, respectively. Most sequences in subclasses IIIa and IIIb originate from animals (7153 protein sequences from 243 species), including vertebrates (3131 sequences from 101 species). Other clades in this group include Alveolates (270 sequences from 32 species), green algae (169 sequences from 10 species), fungi (79 sequences from 5 species), and a small number of daunorubicin and basal plants. Approximately one third of the eukaryotic subclass IIIa nucleotide cyclases can be predicted to have GTP substrate-specificity (3422 sequences from 259 species). Interestingly, the GCs from animals, green algae (Chlorophyta), diatoms, and two clades of fungi (Blastocladiomycota and Chytridiomycota) are encompassed in one homologous group, but not the ones from Amoebae and deeply branching protozoans, such as Plasmodium, which could have evolved their substrate-specificity independently [38,39]. Subclass IIIc/d, on the other hand, is absent from animals and found entirely in fungi, diatoms, and green algae. As in prokaryotes, the number of ACs and GCs can vary greatly between eukaryotic species, such as in Chlamydomonas reinhardtii and Naegleria gruberi, which encode more than one hundred class III ACs each. Contrary to the situation in bacteria, however, eukaryotic ACs show comparatively low structural diversity and their domain architectures are frequently conserved throughout major clades; for example, in all animals we observe only two architectural types of ACs and three types of GCs (one of which is restricted to arthropods). Some of these have undergone an extensive lineage-specific expansion, leading to multiple genomic copies of the same type, such as the nine membrane-bound isoforms of humans (mAC; AC1-9; see Table 1). We note that these nine isoforms were numbered in the order of their cloning, without regards for potential similarities which were unrecognizable at the time. Later it was recognized that the membrane domains of ACs 1, 3 and 8 share similarities, as do those from isoforms 2, 4 and 7, and of 5 and 6. The membrane anchor domains of AC9 differ from all others. We further note that AC isoforms cloned from insects and worms have been named without considerations of potential mammalian next of kin. Table 1 gives an overview of AC descriptors commonly used in differing animals and their relationship among each other. Evidently, it would be preferable to harmonize the class IIIa nomenclature in the future.
    Domain architectures of class III ACs For assigning the domains of these proteins, we used HMMer3 profiles [35] of the SMART (version 6.0, [40]) and PFAM (version 31.0, [41]) databases, annotated to a significance threshold of E = 1E-5 and followed by interactive manual refinement. This identified a great variety of domain architectures, although not as many as reported earlier (e.g. [26]), arguably due to improved genome assemblies and domain definitions. In bacteria, most domain architectures appear to be conserved only between closely related species and only few architectures are substantially widespread (Fig. 3, Fig. 4).
    Implications for mammalian ACs The observation that class III ACs are widely represented in bacteria, often in multiple copies per genome, whereas they are largely absent from archaea, suggests that this protein family originated in bacteria and spread into eukaryotes via the mitochondrial endosymbiont. This conjecture is further supported by the large architectural and domain diversity of bacterial ACs (Fig. 3, Fig. 4), as contrasted with the very limited number of architectures and constituent domains found in eukaryotes (Fig. 5). In fact, the membrane-bound ACs of animals and fungi all have a single architecture, consisting of just two domain types (6TM membrane domain and AC catalytic domain) arranged in a pseudoheterodimer as TM6-AC-TM6-AC. This architecture mirrors the most widely represented form of class IIIa ACs in bacteria, which is 6TM-AC and must dimerize for activity.