Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026918 (Mycobacterium)
 52,428 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Rv1625c gene product is an adenylyl cyclase identified in the genome of Mycobacterium tuberculosis strain H37Rv. It shows sequence similarity to the mammalian nucleotide cyclases and functions as a homodimer, with two substrate-binding sites at the dimer interface. A mutant form of the catalytic domain of this enzyme, K296E/F363R/D365C (KFD-->ERC), was overexpressed in Escherichia coli cells in a soluble form. Crystals were obtained using the hanging-drop vapour-diffusion method with PEG 8000 as a precipitant. The protein crystallized in space group P4(1), with unit-cell parameters a = b = 71.25, c = 44.51 A. X-ray diffraction data were collected to a resolution of 3.4 A and the structure has been solved by the molecular-replacement method using a previously built theoretical model of the protein as the search molecule.
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PMID:Purification, crystallization and preliminary X-ray diffraction analysis of the catalytic domain of adenylyl cyclase Rv1625c from Mycobacterium tuberculosis. 1474 29

The NAD kinase gene (nadK) of Sphingomonas sp. A1 was cloned and then overexpressed in Escherichia coli, and the gene product (NadK) was purified from the E. coli cells through five steps with a 25% yield of activity. NadK was a homodimer of 32 kDa subunits, utilized ATP or other nucleoside triphosphates, but not inorganic polyphosphates, as phosphoryl donors for the phosphorylation of NAD, most efficiently at pH 8.0 and 50-55 degrees C, and was designated as ATP-NAD kinase (NadK). NadK showed no NADH kinase activity and was slightly inhibited by NADP(H). Precursors for NAD biosynthesis such as quinolinic acid, nicotinic acid mononucleotide, nicotinic acid adenine dinucleotide, and nicotinic acid had no effect on the NadK activity, as observed in the cases of the NAD kinases of Micrococcus flavus, Mycobacterium tuberculosis, and E. coli. Taken together with the report that the NAD kinase of Bacillus subtilis is activated by quinolinic acid [J. Bacteriol. 185 (2003) 4844], it is indicated that the regulatory patterns of NAD kinases differ even among bacterial NAD kinases.
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PMID:Overexpression, purification, and characterization of ATP-NAD kinase of Sphingomonas sp. A1. 1517 93

Mycobacterium tuberculosis EthR is a repressor of ethA, a gene encoding a mono-oxygenase required for the activation of the prodrug ethionamide. Here we describe the X-ray crystal structure of EthR, a homodimer with an entirely helical structure showing similarities to TetR family members. Each monomer contained a fortuitous ligand identified as hexadecyl octanoate. The crystal structure of EthR purified in M. smegmatis revealed the presence of a comparable ligand. The binding of hexadecyl octanoate to EthR induces a conformational state incompatible with repressor function, which should lead to ethA derepression and consequently to an increased sensitivity to ethionamide and other thioamides. A related, more hydrophilic ketone was found to exhibit synergistic antimycobacterial effects when tested together with ethionamide, indicating that this strategy may help reduce the dosage of potent antibacterial compounds that otherwise are too toxic to be used as first-line drugs.
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PMID:Structure of EthR in a ligand bound conformation reveals therapeutic perspectives against tuberculosis. 1549 16

With the aim of elucidating the biological function of hypothetical proteins unique amongst the Actynomyces sub-group of bacteria, we have solved the crystal structure of the conserved hypothetical protein Rv1155 from Mycobacterium tuberculosis at 1.8 A resolution. Rv1155 is a homodimer both in the crystal structure and in solution and folds into two separate domains consisting of a six-stranded anti-parallel beta-barrel fold flanked by two alpha-helices and a helix-turn-helix domain. Both domains contribute to the formation of two deep clefts at the dimer interface. The overall fold of Rv1155 strikingly resembles that of flavin mononucleotide-binding protein and pyridoxamine 5'-phosphate oxydase, but the architecture of the putative binding pocket is markedly different, consistent with the lack of color of Rv1155 and its inability to bind FMN. Rv1155 thus appears to belong to a group of proteins with stringent conservation of the binding cleft, having evolved towards a new binding function.
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PMID:Crystal structure of the conserved hypothetical protein Rv1155 from Mycobacterium tuberculosis. 1562 Jul 16

A prokaryotic non-homologous end-joining (NHEJ) system for the repair of DNA double-strand breaks (DSBs), composed of a Ku homodimer (Mt-Ku) and a multidomain multifunctional ATP-dependent DNA ligase (Mt-Lig), has been described recently in Mycobacterium tuberculosis. Mt-Lig exhibits polymerase and nuclease activity in addition to DNA ligation activity. These functions were ascribed to putative polymerase, nuclease and ligase domains that together constitute a monomeric protein. Here, the separate polymerase, nuclease and ligase domains of Mt-Lig were cloned individually, over-expressed and the soluble proteins purified to homogeneity. The polymerase domain demonstrated DNA-dependent RNA primase activity, catalysing the synthesis of unprimed oligoribonucleotides on single-stranded DNA templates. The polymerase domain can also extend DNA in a template-dependent manner. This activity was eliminated when the catalytic aspartate residues were replaced with alanine. The ligase domain catalysed the sealing of nicked double-stranded DNA designed to mimic a DSB, consistent with the role of Mt-Lig in NHEJ. Deletion of the active-site lysine residue prevented the formation of an adenylated ligase complex and consequently thwarted ligation. The nuclease domain did not function independently as a 3'-5' exonuclease. DNA-binding assays revealed that both the polymerase and ligase domains bind DNA in vitro, the latter with considerably higher affinity. Mt-Ku directly stimulated the polymerase and nuclease activities of Mt-Lig. The polymerase domain bound Mt-Ku in vitro, suggesting it may recruit Mt-Lig to Ku-bound DNA in vivo. Consistent with these data, Mt-Ku stimulated the primer extension activity of the polymerase domain, suggestive of a functional interaction relevant to NHEJ-mediated DSB repair processes.
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PMID:Domain structure of a NHEJ DNA repair ligase from Mycobacterium tuberculosis. 1602 71

Five recombinant antigens (Ags; 85A, 85B, 85C, superoxide dismutase [SOD], and 35-kDa protein) were purified from Mycobacterium avium subsp. paratuberculosis and evaluated for their ability to stimulate peripheral blood mononuclear cells (PMBCs) from fecal-culture-positive cows (low and medium shedders) and culture-negative healthy cows. Recombinant Ags 85A, 85B, and 85C induced significant lymphocyte proliferation as well as the production of gamma interferon (IFN-gamma), interleukin-2 (IL-2), IL-12, and tumor necrosis factor alpha (TNF-alpha), but not IL-4, from low and medium shedders. The 85 antigen complex did not stimulate PMBC proliferation from culture-negative healthy cows. The 35-kDa protein also induced significant lymphocyte proliferation as well as the production of IFN-gamma and IL-4 from low and medium shedders. CD4(+) T cells and CD25(+) (IL-2R) T cells were stimulated the most by 85A and 85B, while the 35-kDa protein primarily stimulated CD21(+) B cells involved in humoral immune responses. Interestingly, SOD was less immunostimulatory than other antigens but strongly induced gammadelta(+) T cells, which are thought to be important in the early stages of infection, such as pathogen entry. These data provide important insight into how improved vaccines against mycobacterial infections might be constructed.
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PMID:In vitro cellular immune responses to recombinant antigens of Mycobacterium avium subsp. paratuberculosis. 1604 Oct 23

The adenylyl cyclase Rv1625c from Mycobacterium tuberculosis codes for a protein with six transmembrane spans and a catalytic domain, i.e. it corresponds to one half of the pseudoheterodimeric mammalian adenylyl cyclases (ACs). Rv1625c is active as a homodimer. We investigated the role of the Rv1625c membrane domain and demonstrate that it efficiently dimerizes the protein resulting in a 7.5-fold drop in K(m) for ATP. Next, we generated a duplicated Rv1625c AC dimer by a head-to-tail concatenation. This produced an AC with a domain order exactly as the mammalian pseudoheterodimers. It displayed positive cooperativity and a 60% increase of v(max) compared with the Rv1625c monomer. Further, we probed the compatibility of mycobacterial and mammalian membrane domains. The second membrane anchor in the Rv1625c concatamer was replaced with membrane domain I or II of rabbit type V AC. The mycobacterial and either mammalian membrane domains are compatible with each other and both recombinant proteins are active. A M. tuberculosis Rv1625c knockout strain was assayed in a mouse infection model. In vitro growth characteristics and in vivo organ infection and mortality were unaltered in the knockout strain indicating that AC Rv1625c alone is not a virulence factor.
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PMID:Interaction of Rv1625c, a mycobacterial class IIIa adenylyl cyclase, with a mammalian congener. 1604 12

Mycobacterium leprae, the causative agent of leprosy, invades peripheral nerve Schwann cells, resulting in deformities associated with this disease. NF-kappaB is an important transcription factor involved in the regulation of host immune antimicrobial responses. We aimed in this work to investigate NF-kappaB signaling pathways in the human ST88-14 Schwannoma cell line infected with M. leprae. Gel shift and supershift assays indicate that two NF-kappaB dimers, p65/p50 and p50/p50, translocate to the nucleus in Schwann cells treated with lethally irradiated M. leprae. Consistent with p65/p50 and p50/p50 activation, we observed IkappaB-alpha degradation and reduction of p105 levels. The nuclear translocation of p50/p50 complex due to M. leprae treatment correlated with repression of NF-kappaB-driven transcription induced by TNF-alpha. Moreover, thalidomide inhibited p50 homodimer nuclear translocation induced by M. leprae and consequently rescues Schwann cells from NF-kappaB-dependent transcriptional repression. Here, we report for the first time that M. leprae induces NF-kappaB activation in Schwann cells and thalidomide is able to modulate this activation.
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PMID:Mycobacterium leprae induces NF-kappaB-dependent transcription repression in human Schwann cells. 1605 86

Produced by macrophages and dendritic cells, interleukin (IL)-12 is composed of a p35 and a p40 subunit and promotes protection against intracellular pathogens through the development of interferon-gamma (IFNgamma) -producing T cells. The p40 subunit is also shared by the dimeric cytokines IL-12p40 homodimer and IL-23. In man, genetic defects in IL-12p40-mediated mechanisms are responsible for the familial occurrence of nontuberculous mycobacterial infections, the most common of which is infection with Mycobacterium avium. To experimentally differentiate the contribution of IL-12p40-containing cytokines in the outcome of M. avium infection, we studied wild-type, p35- and p35/p40 doubly deficient mice in an intravenous infection model which reflects many parameters of the disseminated infection in humans. Our study shows that in contrast to p35/p40 doubly deficient mice, p35-deficient mice mount a transient antibacterially protective response against M. avium although such animals were unable to produce detectable levels of IFNgamma or generate efficient granulomas. In conclusion, our results identify an antibacterial effector mechanism preserved in p35-deficient mice that is absent in mice devoid of p35 and p40. This phenotype probably reflects an IL-12p40-dependent effect on macrophage activation at the level of innate immunity.
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PMID:Interleukin-12p40 mediates transient protection against Mycobacterium avium infection in the absence of interleukin-12. 1616 29

Mycobacterium tuberculosis PknB is an essential receptor-like protein kinase involved in cell growth control. Here, we demonstrate that mitoxantrone, an anthraquinone derivative used in cancer therapy, is a PknB inhibitor capable of preventing mycobacterial growth. The structure of the complex reveals that mitoxantrone partially occupies the adenine-binding pocket in PknB, providing a framework for the design of compounds with potential therapeutic applications. PknB crystallizes as a 'back-to-back' homodimer identical to those observed in other structures of PknB in complex with ATP analogs. This organization resembles that of the RNA-dependent protein kinase PKR, suggesting a mechanism for kinase activation in mycobacteria.
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PMID:The structure of PknB in complex with mitoxantrone, an ATP-competitive inhibitor, suggests a mode of protein kinase regulation in mycobacteria. 1667 48


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