A survey of nucleotide cyclases in Actinobacteria: unique domain organization and expansion of the class III cyclase family in Mycobacterium tuberculosis

Abstract

Cyclic nucleotides are well-known second messengers involved in the regulation of important metabolic pathways or virulence factors. There are six different classes of nucleotide cyclases that can accomplish the task of generating cAMP, and four of these are restricted to the prokaryotes. The role of cAMP has been implicated in the virulence and regulation of secondary metabolites in the phylum Actinobacteria, which contains important pathogens, such as Mycobacterium tuberculosis, M. leprae, M. bovis and Corynebacterium, and industrial organisms from the genus Streptomyces. We have analysed the actinobacterial genome sequences found in current databases for the presence of different classes of nucleotide cyclases, and find that only class III cyclases are present in these organisms. Importantly, prominent members such as M. tuberculosis and M. leprae have 17 and 4 class III cyclases, respectively, encoded in their genomes, some of which display interesting domain fusions seen for the first time. In addition, a pseudogene corresponding to a cyclase from M. avium has been identified as the only cyclase pseudogene in M. tuberculosis and M. bovis. The Corynebacterium and Streptomyces genomes encode only a single adenylyl cyclase each, both of which have corresponding orthologues in M. tuberculosis. A clustering of the cyclase domains in Actinobacteria reveals the presence of typical eukaryote-like, fungi-like and other bacteria-like class III cyclase sequences within this phylum, suggesting that these proteins may have significant roles to play in this important group of organisms.

Cyclic AMP-dependent Protein Lysine Acylation in Mycobacteria Regulates Fatty Acid and Propionate Metabolism

“…The availability of the genome sequence of M. tuberculosis served as an important molecular tool in dissecting the roles of individual genes in pathogenesis (1). We found some years ago that a number of genes involved in cAMP (3Ј,5Ј-cAMP) synthesis (adenylyl cyclases) were encoded in many mycobacterial genomes (2,3). Cyclic AMP, a universal second messenger, provides a means by which the pathogen can communicate with and hijack host signaling within macrophages during early infection (4,5).…”

Genome-Wide Identification of In Vivo Binding Sites of GlxR, a Cyclic AMP Receptor Protein-Type Regulator in Corynebacterium glutamicum

“…On the other hand, almost all the remaining genes in the putative Rv3676 regulon encode proteins specific to M. tuberculosis, suggesting that GlxR-and Rv3676-dependent regulatory systems have diversified to adapt to the habitat of each organism over the evolutionary history. This may also be represented by the low response of Rv3676 to cAMP and high intracellular cAMP levels in M. tuberculosis, possessing 17 adenylate cyclase genes in the genome (70).…”

Cyclic AMP in Mycobacteria: Characterization and Functional Role of the Rv1647 Ortholog in Mycobacterium smegmatis

“…The genomes of Mycobacterium tuberculosis strains H37Rv and CDC1551 encode 16 and 17 class III cyclases, respectively (24,33). The presence of multiple cyclases within a genome is in striking contrast to the well-studied paradigm of the single-copy class I cyclase gene in Escherichia coli.…”