Characterization of the
            <i>Mycobacterium tuberculosis</i>
            4-Diphosphocytidyl-2-
            <i>C</i>
            -Methyl-
            <scp>d</scp>
            -Erythritol Synthase: Potential for Drug Development

Eoh, Hyungjin; Brown, Alexander; Buetow, Lori; Hunter, William N.; Parish, Tanya; Kaur, Devinder; Brennan, Patrick J.; Crick, Dean C.

doi:10.1128/jb.00925-07

Cited by 46 publications

(44 citation statements)

References 42 publications

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“…Several genes encoding enzymes of the DOXP pathway are essential for the viability of M. tuberculosis in culture (6,7,14). However, we had not previously investigated dxs1 or gcpE.…”

Section: Resultsmentioning

confidence: 99%

“…Recombinant proteins have been produced, and enzymatic activities have been confirmed for Dxs1 (2), Dxr (11,18), IspD (14), and IspF (7). In addition, previous work demonstrated that Dxr, IspD, and IspF are all essential for the in vitro growth of M. tuberculosis (6,7,14). M. tuberculosis genome has two homologs of dxs (dxs1, Rv2682c; and dxs2, Rv3379c) and lytB (lytB1, Rv3382c; and lytB2, Rv1110).…”

mentioning

confidence: 99%

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The Nonmevalonate Pathway of Isoprenoid Biosynthesis in Mycobacterium tuberculosis Is Essential and Transcriptionally Regulated by Dxs

et al. 2010

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Mycobacterium tuberculosis synthesizes isoprenoids via the nonmevalonate or DOXP pathway. Previous work demonstrated that three enzymes in the pathway (Dxr, IspD, and IspF) are all required for growth in vitro. We demonstrate the essentiality of the key genes dxs1 and gcpE, confirming that the pathway is of central importance and that the second homolog of the synthase (dxs2) cannot compensate for the loss of dxs1. We looked at the effect of overexpression of Dxr, Dxs1, Dxs2, and GcpE on viability and on growth in M. tuberculosis. Overexpression of dxs1 or dxs2 was inhibitory to growth, whereas overexpression of dxr or gcpE was not. Toxicity is likely to be, at least partially, due to depletion of pyruvate from the cells. Overexpression of dxs1 or gcpE resulted in increased flux through the pathway, as measured by accumulation of the metabolite 4-hydroxy-3-methyl-but-2-enyl pyrophosphate. We identified the functional translational start site and promoter region for dxr and demonstrated that it is expressed as part of a polycistronic mRNA with gcpE and two other genes. Increased expression of this operon was seen in cells overexpressing Dxs1, indicating that transcriptional control is effected by the first enzyme of the pathway via an unknown regulator.Mycobacterium tuberculosis, the causative agent of human tuberculosis, poses an increasing threat to health. The escalating incidence of drug resistant strains provides a new impetus to understand this complex pathogen and to identify metabolic targets for novel therapeutics. As a first step toward this aim, we have been directing our efforts to identifying metabolic pathways essential for bacterial viability.

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“…Several genes encoding enzymes of the DOXP pathway are essential for the viability of M. tuberculosis in culture (6,7,14). However, we had not previously investigated dxs1 or gcpE.…”

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

The Nonmevalonate Pathway of Isoprenoid Biosynthesis in Mycobacterium tuberculosis Is Essential and Transcriptionally Regulated by Dxs

et al. 2010

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“…The Rv3582c gene product has approximately 31% identity with E. coli IspD and recombinant Rv3582c protein was shown to be a functional IspD in Mtb [58]. …”

Section: Isoprenoids and Related Lipidsmentioning

confidence: 99%

Genetics of Capsular Polysaccharides and Cell Envelope (Glyco)lipids

2014

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This chapter summarizes what is currently known of the structures, physiological roles, involvement in pathogenicity and biogenesis of a variety of non-covalently bound cell envelope lipids and glycoconjugates of Mycobacterium tuberculosis and other Mycobacterium species. Topics addressed in this chapter include phospholipids; phosphatidylinositol mannosides; triglycerides; isoprenoids and related compounds (polyprenyl phosphate, menaquinones, carotenoids, non-carotenoid cyclic isoprenoids); acyltrehaloses (lipooligosaccharides, trehalose mono- and di-mycolates, sulfolipids, di- and poly-acyltrehaloses); mannosyl-beta-1-phosphomycoketides; glycopeptidolipids; phthiocerol dimycocerosates, para-hydroxybenzoic acids and phenolic glycolipids; mycobactins; mycolactones; and capsular polysaccharides.

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“…While sequence similarity with counterparts in other species is restricted to M. tuberculosis and M. bovis for ML0405, it extends to M. avium, M. smegmatis and M. marinum for ML2331. In this regard, other candidate gene lists have been put forth, including genes with occurrences in more than one sequenced mycobacetria [92].…”

Section: Defi Ning Mycobacterium Leprae Tnmentioning

confidence: 99%

Defining mycobacteria: Shared and specific genome features for different lifestyles

Vissa

Sakamuri

et al. 2009

Indian J Microbiol

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During the last decade, the combination of rapid whole genome sequencing capabilities, application of genetic and computational tools, and establishment of model systems for the study of a range of species for a spectrum of biological questions has enhanced our cumulative knowledge of mycobacteria in terms of their growth properties and requirements. The adaption of the corynebacterial surrogate system has simplifi ed the study of cell wall biosynthetic machinery common to actinobacteria. Comparative genomics supported by experimentation reveals that superimposed on a common core of 'mycobacterial' gene set, pathogenic mycobacteria are endowed with multiple copies of several protein families that encode novel secretion and transport systems such as mce and esx; immunomodulators named PE/PPE proteins, and polyketide synthases for synthesis of complex lipids. The precise timing of expression, engagement and interactions involving one or more of these redundant proteins in their host environments likely play a role in the defi nition and differentiation of species and their disease phenotypes. Besides these, only a few species specifi c 'virulence' factors i.e., macromolecules have been discovered. Other subtleties may also arise from modifi cations of shared macromolecules. In contrast, to cope with the broad and changing growth conditions, their saprophytic relatives have larger genomes, in which the excess coding capacity is dedicated to transcriptional regulators, transporters for nutrients and toxic metabolites, biosynthesis of secondary metabolites and catabolic pathways. In this review, we present a sampling of the tools and techniques that are being implemented to tease apart aspects of physiology, phylogeny, ecology and pathology and illustrate the dominant genomic characteristics of representative species. The investigation of clinical isolates, natural disease states and discovery of new diagnostics, vaccines and drugs for existing and emerging mycobacterial diseases, particularly for multidrug resistant strains are the challenges in the coming decades.

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Characterization of the Mycobacterium tuberculosis 4-Diphosphocytidyl-2- C -Methyl- d -Erythritol Synthase: Potential for Drug Development

Cited by 46 publications

References 42 publications

The Nonmevalonate Pathway of Isoprenoid Biosynthesis in Mycobacterium tuberculosis Is Essential and Transcriptionally Regulated by Dxs

The Nonmevalonate Pathway of Isoprenoid Biosynthesis in Mycobacterium tuberculosis Is Essential and Transcriptionally Regulated by Dxs

Genetics of Capsular Polysaccharides and Cell Envelope (Glyco)lipids

Defining mycobacteria: Shared and specific genome features for different lifestyles

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