Mycobacterium tuberculosis Rv0198c, a putative matrix metalloprotease is involved in pathogenicity

Muttucumaru, D.G.Niranjala; Smith, Debbie A.; McMinn, Elizabeth J.; Reese, Valerie A.; Coler, Rhea N.; Parish, Tanya

doi:10.1016/j.tube.2010.11.010

Cited by 21 publications

(15 citation statements)

References 29 publications

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“…A recent paper (17) shows that zmp1-deleted M. tuberculosis strains are hypervirulent, which contrasts with the work of Master et al (12), as they propose that zmp1 deletion leads to virulence attenuation. Although the issue awaits a definitive answer, the structure of Zmp1 reported here will help the developing of specific inhibitors that may prove useful both as a tool for further investigation of the biological functions of Zmp1 and as compounds of potential pharmaceutical interest.…”

Section: Discussionmentioning

confidence: 73%

Crystal Structure of Mycobacterium tuberculosis Zinc-dependent Metalloprotease-1 (Zmp1), a Metalloprotease Involved in Pathogenicity

Ferraris

Sbardella

Petrera

et al. 2011

Journal of Biological Chemistry

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Mycobacterium tuberculosis, the causative agent of tuberculosis, parasitizes host macrophages. The resistance of the tubercle bacilli to the macrophage hostile environment relates to their ability to impair phagosome maturation and its fusion with the lysosome, thus preventing the formation of the phago-lysosome and eventually arresting the process of phagocytosis. The M. tuberculosis zinc-dependent metalloprotease Zmp1 has been proposed to play a key role in the process of phagosome maturation inhibition and emerged as an important player in pathogenesis. Here, we report the crystal structure of wild-type Zmp1 at 2.6 Å resolution in complex with the generic zinc metalloprotease inhibitor phosphoramidon, which we demonstrated to inhibit the enzyme potently. Our data represent the first structural characterization of a bacterial member of the zinc-dependent M13 endopeptidase family and revealed a significant degree of conservation with eukaryotic enzymes. However, structural comparison of the Zmp1-phosphoramidon complex with homologous human proteins neprilysin and endothelinconverting enzyme-1 revealed unique features of the Zmp1 active site to be exploited for the rational design of specific inhibitors that may prove useful as a pharmacological tool for better understanding Zmp1 biological function.

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Section: Discussionmentioning

confidence: 73%

Crystal Structure of Mycobacterium tuberculosis Zinc-dependent Metalloprotease-1 (Zmp1), a Metalloprotease Involved in Pathogenicity

Ferraris

Sbardella

Petrera

et al. 2011

Journal of Biological Chemistry

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“…Interestingly, these sub-family proteins from M. tuberculosis have been mentioned in previously published studies, although none of these studies was specifically focused on these proteins or in their putative QS facets. The gene coding for one of the proteins, Rv2488c, was found to be 59-fold upregulated in a putative metalloendopeptidase (Rv0918c) mutant with an hypervirulent phenotype in mouse models [39]. That same gene was 2-fold downregulated in a mutant strain lacking the 2-component system senX3 - regX3 , which had an intramacrophage growth defect and attenuated virulence phenotype [40].…”

Section: Resultsmentioning

confidence: 99%

A Walk into the LuxR Regulators of Actinobacteria: Phylogenomic Distribution and Functional Diversity

et al. 2012

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LuxR regulators are a widely studied group of bacterial helix-turn-helix (HTH) transcription factors involved in the regulation of many genes coding for important traits at an ecological and medical level. This regulatory family is particularly known by their involvement in quorum-sensing (QS) mechanisms, i.e., in the bacterial ability to communicate through the synthesis and binding of molecular signals. However, these studies have been mainly focused on Gram-negative organisms, and the presence of LuxR regulators in the Gram-positive Actinobacteria phylum is still poorly explored. In this manuscript, the presence of LuxR regulators among Actinobacteria was assayed using a domain-based strategy. A total of 991 proteins having one LuxR domain were identified in 53 genome-sequenced actinobacterial species, of which 59% had an additional domain. In most cases (53%) this domain was REC (receiver domain), suggesting that LuxR regulators in Actinobacteria may either function as single transcription factors or as part of two-component systems. The frequency, distribution and evolutionary stability of each of these sub-families of regulators was analyzed and contextualized regarding the ecological niche occupied by each organism. The results show that the presence of extra-domains in the LuxR-regulators was likely driven by a general need to physically uncouple the signal sensing from the signal transduction. Moreover, the total frequency of LuxR regulators was shown to be dependent on genetic, metabolic and ecological variables. Finally, the functional annotation of the LuxR regulators revealed that the bacterial ecological niche has biased the specialization of these proteins. In the case of pathogens, our results suggest that LuxR regulators can be involved in virulence and are therefore promising targets for future studies in the health-related biotechnology field.

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“…The absence of Zmp1 led to changes in the expression of other genes in the same pathway or in compensatory pathways. Yet, the mechanism by which the deletion of zmp1 leads to changes in gene expression is not known, but it is likely that the absence of this protease and its proteolytic activity results in the lack of the cleavage of a substrate signal for one regulatory protein, which in turn modulates the expression of other genes 341 . The discrepancies between these two studies are not well understood, but it could be due to the nature of the different M. tuberculosis mutants.…”

Section: Proteasesmentioning

confidence: 99%

Virulence factors of theMycobacterium tuberculosiscomplex

et al. 2013

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The Mycobacterium tuberculosis complex (MTBC) consists of closely related species that cause tuberculosis in both humans and animals. This illness, still today, remains to be one of the leading causes of morbidity and mortality throughout the world. The mycobacteria enter the host by air, and, once in the lungs, are phagocytated by macrophages. This may lead to the rapid elimination of the bacillus or to the triggering of an active tuberculosis infection. A large number of different virulence factors have evolved in MTBC members as a response to the host immune reaction. The aim of this review is to describe the bacterial genes/proteins that are essential for the virulence of MTBC species, and that have been demonstrated in an in vivo model of infection. Knowledge of MTBC virulence factors is essential for the development of new vaccines and drugs to help manage the disease toward an increasingly more tuberculosis-free world.

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Mycobacterium tuberculosis Rv0198c, a putative matrix metalloprotease is involved in pathogenicity

Cited by 21 publications

References 29 publications

Crystal Structure of Mycobacterium tuberculosis Zinc-dependent Metalloprotease-1 (Zmp1), a Metalloprotease Involved in Pathogenicity

Crystal Structure of Mycobacterium tuberculosis Zinc-dependent Metalloprotease-1 (Zmp1), a Metalloprotease Involved in Pathogenicity

A Walk into the LuxR Regulators of Actinobacteria: Phylogenomic Distribution and Functional Diversity

Virulence factors of theMycobacterium tuberculosiscomplex

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