Functional classification of cNMP-binding proteins and nucleotide cyclaseswith implications for novel regulatory pathways in Mycobacterium tuberculosis

We have analyzed the cyclic nucleotide (cNMP)-binding protein and nucleotid e cyclase superfamilies using Bayesian computational methods of protein fam ily identification and classification. In addition to the known cNMP-bindin g proteins (cNMP-dependent kinases, cNMP-gated channels, cAMP-guanine nucle otide exchange factors, and bacterial cAMP-dependent transcription factors) , new functional groups of cNMP-binding proteins were identified, including putative ABC-transporter subunits, translocases, and esterases. Classifica tion of the nucleotide cyclases revealed subtle differences in sequence con servation of the active site that distinguish the five classes of cyclases: the multicellular eukaryotic adenylyl cyclases, the eukaryotic receptor-ty pe guanylyl cyclases, the eukaryotic soluble guanylyl cyclases, the unicell ular eukaryotic and prokaryotic adenylyl cyclases, and the putative prokary otic guanylyl cyclases. Phylogenetic distribution of the cNMP-binding prote ins and cyclases was analyzed, with particular attention to the 22 complete archaeal and eubacterial genome sequences. Mycobacterium tuberculosis H37R v and Synechocystis PCC6803 were each found to encode several more putative cNMP-binding proteins than other prokaryotes; many of these proteins are o f unknown function. M. tuberculosis also encodes several more putative nucl eotide cyclases than other prokaryotic species.