Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:2.7.7.7 (DNA polymerase)
17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The in vivo induced antigen technology (IVIAT)(1) has been used for the identification of open reading frames (ORFs) which could be possible therapeutic targets. A recombinant lambdagt11:: Mycobacterium tuberculosis H37Rv expression library was screened with pooled TB patient sera preabsorbed with in vitro grown M. tuberculosis H37Rv. Preabsorption of pooled TB patient sera allowed identification of antigens specifically expressed or upregulated during infection and growth in vivo. Six ORFs were identified, of which four (rv0287, rv2402, rv3878 and rv1045) were of hypothetical functions. Rv0287 is a probable regulatory protein. Rv3878 is present uniquely in M. tuberculosis H37Rv and is a part of RDI deletion region of M. bovis BCG, which includes esat 6 region. This could be exploited as a tool for diagnosis. Two ORFs were assigned function solely on the basis of homology, dnaQ (rv3711c) and lpdA (rv3303c). dnaQ codes for the epsilon subunit of DNA polymerase III, which is responsible for the proofreading activity of the complex. lpdA codes for dihydrolipoamide dehydrogenase, which is a part of many multienzyme complexes such as pyruvate dehydrogenase, keto-acid dehydrogenase and alpha-ketoglutarate dehydrogenase. These two enzymes appear to be potential targets for drug development.
...
PMID:Selective identification of new therapeutic targets of Mycobacterium tuberculosis by IVIAT approach. 1246 89

Benzalkonium chloride (BC) continues to be used as an antiseptic and contributes to serious outbreaks of disease. In July 1999, 6 postinjection joint infections caused by Mycobacterium abscessus were reported to the Texas Department of Health (Austin). We investigated this outbreak and identified 12 case patients who had been seen by the same physician and who had received an intra-articular or periarticular steroid injection during the period of 1 April through 31 July 1999. M. abscessus was cultured from either joint fluid or periarticular soft-tissue specimens obtained from 10 patients. We cultured environmental samples, and we compared isolates recovered from case patients with environmental isolates by pulsed-field gel electrophoresis and randomly amplified polymorphic DNA polymerase chain reaction (RAPD-PCR). Four environmental samples containing diluted BC yielded M. abscessus. Clinical and environmental strains of M. abscessus were indistinguishable by RAPD-PCR. The case patients' strain was resistant to BC. The use of BC as an antiseptic should be discontinued.
...
PMID:Forty years of disinfectant failure: outbreak of postinjection Mycobacterium abscessus infection caused by contamination of benzalkonium chloride. 1268 6

In this issue of Cell, a study by Valerie Mizrahi and her colleagues suggests that a putative error-prone DNA polymerase encoded by the dnaE2 gene of Mycobacterium tuberculosis may bypass certain types of DNA base damage, generating mutations. This may be an important mechanism for generating drug-resistant strains of M. tuberculosis.
...
PMID:TB or Not TB: how Mycobacterium tuberculosis may evade drug treatment. 127 May 86

The presence of multiple copies of the major replicative DNA polymerase (DnaE) in some organisms, including important pathogens and symbionts, has remained an unresolved enigma. We postulated that one copy might participate in error-prone DNA repair synthesis. We found that UV irradiation of Mycobacterium tuberculosis results in increased mutation frequency in the surviving fraction. We identified dnaE2 as a gene that is upregulated in vitro by several DNA damaging agents, as well as during infection of mice. Loss of this protein reduces both survival of the bacillus after UV irradiation and the virulence of the organism in mice. Our data suggest that DnaE2, and not a member of the Y family of error-prone DNA polymerases, is the primary mediator of survival through inducible mutagenesis and can contribute directly to the emergence of drug resistance in vivo. These results may indicate a potential new target for therapeutic intervention.
...
PMID:DnaE2 polymerase contributes to in vivo survival and the emergence of drug resistance in Mycobacterium tuberculosis. 1270 67

Gammadelta T lymphocytes have a heterodimeric complex formed by the association of gamma and delta chains as receptor. Proliferation of this lymphocyte population has been observed, when infection by several pathogens such as Mycobacterium tuberculosis and Plasmodium spp. occurs. The New World Monkey Aotus nancymaae has become a very good experimental model for the immunological and physiopathological study of these infectious agents. The A. nancymaae gamma-variable region was characterized from peripheral blood samples by using cDNA and genomic DNA polymerase chain reaction amplification, DNA sequencing, and dot-blot hybridization techniques. Seventeen different T-cell receptor gamma-variable (TCRGV) sequences were obtained. These sequences were distributed among TCRGV subsets 1, 2, or 3, according to human subset classification. Although no subset 4 amplification was obtained, this subset was detected by dot-blot hybridization. The presence of these 4 subsets resembles the behavior displayed by 'gammadelta-low species' (humans and mice), where high diversity among these lymphocytes can be observed. Homologies greater than 70% were found with respect to humans. Sequence convergence between human and A. nancymaae subsets 1 and 3 highlights Aotus as a promising model for studying these lymphocyte functions.
...
PMID:Characterizing T-cell receptor gamma-variable gene in Aotus nancymaae owl monkey peripheral blood. 1461 30

GE 23077 factors A1, A2, B1 and B2 are novel antibiotics isolated from fermentation broths of an Actinomadura sp. strain. GE23077 antibiotics are cyclic peptides, which inhibit Escherichia coli RNA polymerase at nM concentrations. Both rifampicin-sensitive and rifampicin-resistant polymerases are inhibited, whereas E. coli DNA polymerase and wheat germ RNA polymerase are substantially not affected. In spite of the potent activity on the enzyme, the antibiotics generally show poor activity against whole cell bacteria. The spectrum of activity is restricted to Moraxella catarrhalis, including clinical isolates, with partial activity against Neisseria gonorrhoeae and Mycobacterium smegmatis.
...
PMID:Antibiotics GE23077, novel inhibitors of bacterial RNA polymerase. I. Taxonomy, isolation and characterization. 1515 7

The structure of Mycobacterium tuberculosis dUTP nucleotidohydrolase (dUTPase) has been determined at 1.3 Angstrom resolution in complex with magnesium ion and the non-hydrolyzable substrate analog, alpha,beta-imido dUTP. dUTPase is an enzyme essential for depleting potentially toxic concentrations of dUTP in the cell. Given the importance of its biological role, it has been proposed that inhibiting M.tuberculosis dUTPase might be an effective means to treat tuberculosis infection in humans. The crystal structure presented here offers some insight into the potential for designing a specific inhibitor of the M.tuberculosis dUTPase enzyme. The structure also offers new insights into the mechanism of dUTP hydrolysis by providing an accurate representation of the enzyme-substrate complex in which both the metal ion and dUTP analog are included. The structure suggests that inclusion of a magnesium ion is important for stabilizing the position of the alpha-phosphorus for an in-line nucleophilic attack. In the absence of magnesium, the alpha-phosphate of dUTP can have either of the two positions which differ by 4.5 Angstrom. A transiently ordered C-terminal loop further assists catalysis by shielding the general base, Asp83, from solvent thus elevating its pK(a) so that it might in turn activate a tightly bound water molecule for nucleophilic attack. The metal ion coordinates alpha, beta, and gamma phosphate groups with tridentate geometry identical with that observed in the crystal structure of DNA polymerase beta complexed with magnesium and dNTP analog, revealing some common features in catalytic mechanism.
...
PMID:Crystal structure of the Mycobacterium tuberculosis dUTPase: insights into the catalytic mechanism. 1527 40

Reactive oxygen species produced as a part of cellular metabolism or environmental agent cause a multitude of damages in cell. Oxidative damages to DNA or the free nucleotide pool result in occurrence of 7,8-dihydro-8-oxoguanine (8-oxoG) in DNA, and failure to replace it with the correct base results in a variety of mutations in the genome. Formamidopyrimidine DNA glycosylase (Fpg/MutM), a functionally conserved repair enzyme initiates the 8-oxoG repair pathway in all eubacteria. DNA in mycobacteria with G+C rich genomes is particularly vulnerable to the oxidative damage. In this study, we disrupted fpg gene in Mycobacterium smegmatis to generate an Fpg deficient strain. The strain showed an enhanced mutator phenotype and susceptibility to hydrogen peroxide. Analyses of rifampicin resistance determining region (RRDR) revealed that, in contrast to Fpg deficient Escherichia coli where C to A mutations predominate, Fpg deficient M. smegmatis shows a remarkable increase in accumulation of A to G (or T to C) mutations. Interestingly, exposure of the mutant to sub-lethal level of hydrogen peroxide results in a major shift towards C to G (or G to C) mutations. Biochemical analysis showed that mycobacterial Fpg; and MutY (which excises misincorporated A against 8-oxoG) possess substrate specificities similar to their counterparts in E. coli. However, the DNA polymerase assays with cell-free extracts showed preferential incorporation of G in M. smegmatis as opposed to an A in E. coli. Our studies highlight the importance and the distinctive features of Fpg mediated DNA repair in mycobacteria.
...
PMID:A distinct role of formamidopyrimidine DNA glycosylase (MutM) in down-regulation of accumulation of G, C mutations and protection against oxidative stress in mycobacteria. 1769 24

In Mycobacterium tuberculosis (MTB), rifampicin resistance is almost invariably due to mutations in the rpoB gene, whose function is critical for cell viability. Most of these mutations, at least initially, impair the fitness of the bacteria but confer a selective advantage when antibiotic pressure is exerted. Subsequent adaptation may be critical to restore fitness. The possibility was considered that MTB with mutations in the rpoB gene elicits a constitutive stress response, increasing the probability of subsequent adaptation. In order to test this hypothesis, the expression of recA and dnaE2, an inducible putative error-prone DNA polymerase, was determined in six different isogenic laboratory-generated rpoB-mutants of MTB. Expression levels were determined with real-time PCR and the data obtained were compared with those of the wild-type parent. In four of the six rpoB mutants, a two- to fivefold induction of dnaE2 was detected (P<0.05). Thus, the presence of specific mutations in rpoB is not only associated with impaired fitness but also results in a detectable, moderate yet persistent increase in the expression of dnaE2 but not recA.
...
PMID:Specific mutations in the Mycobacterium tuberculosis rpoB gene are associated with increased dnaE2 expression. 1786 60

Leprosy affects skin and peripheral nerves, and acute inflammatory type 1 reactions (reversal reaction) can cause neurologic impairment and disabilities. Single skin lesion paucibacillary leprosy volunteers (N = 135) recruited in three Brazilian endemic regions, treated with single-dose rifampin, ofloxacin, and minocycline (ROM), were monitored for 3 years. Poor outcome was defined as type 1 reactions with or without neuritis. IgM anti-phenolic glycolipid I, histopathology, Mitsuda test, and Mycobacterium leprae DNA polymerase chain reaction (ML-PCR) were performed at baseline. chi(2) test, Kaplan-Meir curves, and Cox proportional hazards were applied. The majority of volunteers were adults with a mean age of 30.5 +/- 15.4 years; 44.4% were ML-PCR positive. During follow-up, 14.8% of the patients had a poor clinical outcome, classified as a type 1 reaction. Older age (> or = 40 years), ML-PCR positivity, and lesion size > 5 cm were associated with increased risk. In multivariate analysis, age (> or = 40 years) and ML-PCR positivity remained baseline predictors of type 1 reaction among monolesion leprosy patients.
...
PMID:Mycobacterium leprae DNA associated with type 1 reactions in single lesion paucibacillary leprosy treated with single dose rifampin, ofloxacin, and minocycline. 1798 36


<< Previous 1 2 3 4 5 6 7 8 Next >>

---