Mycobacterium tuberculosis utilizes many mechanisms to establish itself within the macrophage, and bacterially derived cAMP is important in modulating the host cellular response. Although the genome of M. tuberculosis is endowed with a number of mammalian-like adenylyl cyclases, only a single cAMP phosphodiesterase has been identified that can decrease levels of cAMP produced by the bacterium. We present the crystal structure of the full-length and sole cAMP phosphodiesterase, Rv0805, found in M. tuberculosis, whose orthologs are present only in the genomes of slow growing and pathogenic mycobacteria. The dimeric core catalytic domain of Rv0805 adopts a metallophosphoesterase-fold, and the C-terminal region builds the active site and contributes to multiple substrate utilization. Localization of Rv0805 to the cell wall is dependent on its C terminus, and expression of either wild type or mutationally inactivated Rv0805 in M. smegmatis alters cell permeability to hydrophobic cytotoxic compounds. Rv0805 may therefore play a key role in the pathogenicity of mycobacteria, not only by hydrolyzing bacterial cAMP, but also by moonlighting as a protein that can alter cell wall functioning.Mycobacterium tuberculosis is probably one of the most successful human pathogens known so far, being singly responsible for the largest number of deaths worldwide due to an infectious disease. M. tuberculosis is phagocytosed by the macrophage and is able to subvert the defenses of the host by a number of mechanisms. These include the presence of a complex cell wall that prevents free passage of potentially toxic material, the ability of the bacteria to withstand the acidic environment of the phagolysosome, and to neutralize reactive oxygen and nitrogen species produced by the activated macrophage (1). An increased understanding of mechanisms utilized by this pathogen to evade the host immune system and continue to reside in the hostile environment of the macrophage, would no doubt provide avenues for the development of drugs to novel targets in the bacterium.Cross-communication between the pathogen and host could involve the utilization of signaling molecules that are conserved evolutionarily. Cyclic AMP is found in all kingdoms of life, and proteins that synthesize and degrade the cyclic nucleotide have been well characterized. The genome of M. tuberculosis H37Rv encodes 16 mammalian-like nucleotide cyclase-like genes (2), and intracellular and extracellular levels of cAMP are very high in both pathogenic and non-pathogenic (e.g. Mycobacterium smegmatis) mycobacteria (2, 3). Recent evidence has highlighted the importance of cAMP in modulating the host macrophage response to M. tuberculosis infection (4). A single adenylyl cyclase was shown to be responsible for the burst of cAMP that is seen in the macrophage following phagocytosis of M. tuberculosis, and this bacterially derived increase in cAMP was essential to attenuate the response of the macrophage to the pathogen.The regulated degradation of cAMP is as important as its synthesi...

No abstract

No abstract

No abstract