The common aromatic amino acid biosynthesis pathway is essential in Mycobacterium tuberculosis

Parish, Tanya; Stoker, Neil G.

doi:10.1099/00221287-148-10-3069

Cited by 171 publications

(145 citation statements)

References 24 publications

(22 reference statements)

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“…Several other metabolic pathways have been ranked high in RPI for M. tuberculosis H37Rv despite their low RPI values for other species. Experiments demonstrated that the chorismate biosynthesis pathway (62) is essential for the viability of M. tuberculosis H37Rv (Parish and Stoker 2002) and that the aspargine degradation pathway (66), pyridoxal 5-phosphate biosynthesis (52), valine degradation (not shown in Fig. 1), and leucine biosynthesis (31) are also essential pathways (Sassetti et al 2003).…”

Section: Discussionmentioning

confidence: 99%

Insights on the Evolution of Metabolic Networks of Unicellular Translationally Biased Organisms from Transcriptomic Data and Sequence Analysis

Carbone

Madden

2005

J Mol Evol

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Abstract. Codon bias is related to metabolic functions in translationally biased organisms, and two facts are argued about. First, genes with high codon bias describe in meaningful ways the metabolic characteristics of the organism; important metabolic pathways corresponding to crucial characteristics of the lifestyle of an organism, such as photosynthesis, nitrification, anaerobic versus aerobic respiration, sulfate reduction, methanogenesis, and others, happen to involve especially biased genes. Second, gene transcriptional levels of sets of experiments representing a significant variation of biological conditions strikingly confirm, in the case of Saccharomyces cerevisiae, that metabolic preferences are detectable by purely statistical analysis: the high metabolic activity of yeast during fermentation is encoded in the high bias of enzymes involved in the associated pathways, suggesting that this genome was affected by a strong evolutionary pressure that favored a predominantly fermentative metabolism of yeast in the wild. The ensemble of metabolic pathways involving enzymes with high codon bias is rather well defined and remains consistent across many species, even those that have not been considered as translationally biased, such as Helicobacter pylori, for instance, reveal some weak form of translational bias for this genome. We provide numerical evidence, supported by experimental data, of these facts and conclude that the metabolic networks of translationally biased genomes, observable today as projections of eons of evolutionary pressure, can be analyzed numerically and predictions of the role of specific pathways during evolution can be derived. The new concepts of Comparative Pathway Index, used to compare organisms with respect to their metabolic networks, and Evolutionary Pathway Index, used to detect evolutionarily meaningful bias in the genetic code from transcriptional data, are introduced.

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Section: Discussionmentioning

confidence: 99%

Insights on the Evolution of Metabolic Networks of Unicellular Translationally Biased Organisms from Transcriptomic Data and Sequence Analysis

Carbone

Madden

2005

J Mol Evol

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“…This pathway is absent in humans, and inhibitors of amino acid biosynthesis have been shown to be effective antimicrobial and herbicidal agents (8,9). Gene disruption studies have demonstrated that M. tuberculosis is not viable if the shikimate pathway is not operational (10). These findings make DAH7PS an attractive target for drug development.…”

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confidence: 95%

Potent Inhibitors of a Shikimate Pathway Enzyme from Mycobacterium tuberculosis

Reichau

Jiao

Walker

et al. 2011

Journal of Biological Chemistry

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Tuberculosis remains a serious global health threat, with the emergence of multidrug-resistant strains highlighting the urgent need for novel antituberculosis drugs. The enzyme 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase (DAH7PS) catalyzes the first step of the shikimate pathway for the biosynthesis of aromatic compounds. This pathway has been shown to be essential in Mycobacterium tuberculosis, the pathogen responsible for tuberculosis. DAH7PS catalyzes a condensation reaction between P-enolpyruvate and erythrose 4-phosphate to give 3-deoxy-D-arabino-heptulosonate 7-phosphate. The enzyme reaction mechanism is proposed to include a tetrahedral intermediate, which is formed by attack of an active site water on the central carbon of P-enolpyruvate during the course of the reaction. Molecular modeling of this intermediate into the active site reported in this study shows a configurational preference consistent with water attack from the re face of P-enolpyruvate. Based on this model, we designed and synthesized an inhibitor of DAH7PS that mimics this reaction intermediate. Both enantiomers of this intermediate mimic were potent inhibitors of M. tuberculosis DAH7PS, with inhibitory constants in the nanomolar range. The crystal structure of the DAH7PS-inhibitor complex was solved to 2.35 Å . Both the position of the inhibitor and the conformational changes of active site residues observed in this structure correspond closely to the predictions from the intermediate modeling. This structure also identifies a water molecule that is located in the appropriate position to attack the re face of P-enolpyruvate during the course of the reaction, allowing the catalytic mechanism for this enzyme to be clearly defined.Tuberculosis remains a serious global health threat with over a million deaths per year. The recent emergence of multidrugresistant strains of Mycobacterium tuberculosis, the pathogen that causes the lung disease, highlights the need for rapid development of new antibacterial drugs to combat tuberculosis (1-4).3-Deoxy-D-arabino-heptulosonate 7-phosphate synthase (DAH7PS) 4 is an important enzyme in M. tuberculosis and other pathogens. It catalyzes the first committed step in the shikimate pathway, which is responsible for the biosynthesis of aromatic amino acids and other essential aromatic metabolites in microorganisms, plants, and apicomplexan parasites (5-7). This pathway is absent in humans, and inhibitors of amino acid biosynthesis have been shown to be effective antimicrobial and herbicidal agents (8, 9). Gene disruption studies have demonstrated that M. tuberculosis is not viable if the shikimate pathway is not operational (10). These findings make DAH7PS an attractive target for drug development.DAH7PS catalyzes the aldol-like condensation of P-enolpyruvate and D-erythrose 4-phosphate (E4P) to yield 3-deoxy-Darabino-heptulusonate 7-phosphate (Fig. 1a). The reaction mechanism has been subject to extensive study, and many of the key details of the mechanism have been elucidated (11-16). The reactio...

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“…The pathway is absent in higher organisms, making the enzymes of this pathway attractive as targets for the development of antimicrobial agents. Recent gene disruption studies have shown that operation of the shikimate pathway is essential for the viability of Mycobacterium tuberculosis (5), the causative agent of tuberculosis, a disease that remains a significant world-wide health risk (6). Although effective anti-tuberculosis drugs exist, the long treatment times required, the problems of latent or persistent tuberculosis (7), and the proliferation of multidrug-resistant strains of M. tuberculosis (8) have all created an urgent need for the development of new antimycobacterial agents.…”

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confidence: 99%

Synergistic Allostery, a Sophisticated Regulatory Network for the Control of Aromatic Amino Acid Biosynthesis in Mycobacterium tuberculosis

Webby

Jiao

Hutton

et al. 2010

Journal of Biological Chemistry

111

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The shikimate pathway is the biosynthetic route that is responsible for the production of essential aromatic compounds (1). These include the aromatic amino acids tryptophan, tyrosine, and phenylalanine, folic acid, an essential cofactor for many enzymatic processes, and salicylate, used for the biosynthesis of the siderophores through which bacteria acquire iron (2). The pathway is found in microorganisms and plants and has more recently been discovered in apicomplexan parasites (3, 4). The pathway is absent in higher organisms, making the enzymes of this pathway attractive as targets for the development of antimicrobial agents. Recent gene disruption studies have shown that operation of the shikimate pathway is essential for the viability of Mycobacterium tuberculosis (5), the causative agent of tuberculosis, a disease that remains a significant world-wide health risk (6). Although effective anti-tuberculosis drugs exist, the long treatment times required, the problems of latent or persistent tuberculosis (7), and the proliferation of multidrug-resistant strains of M. tuberculosis (8) have all created an urgent need for the development of new antimycobacterial agents.The first committed step in the shikimate pathway is the stereospecific aldol reaction between phosphoenolpyruvate (PEP) 4 and erythrose 4-phosphate (E4P) to produce 3-deoxy-Darabino-heptulosonate 7-phosphate (DAH7P), catalyzed by the enzyme DAH7P synthase (Fig. 1). DAH7P is converted into chorismate, the product of the main shikimate pathway, via six further enzyme-catalyzed reactions. At this point the pathway to the aromatic amino acids branches, with chorismate converted either to anthranilate by anthranilate synthase or to prephenate by chorismate mutase. Anthranilate ultimately produces Trp, whereas prephenate is converted into Phe and Tyr.As the first enzyme, DAH7P synthase, is a major control point for shikimate pathway flux. Several organisms express two or more isozymes of this enzyme that show different sensitivity to the pathway end products. Escherichia coli and Neurospora crassa each produce three isozymes, with each enzyme individually inhibited by either Phe, Tyr, or Trp (9,10

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The common aromatic amino acid biosynthesis pathway is essential in Mycobacterium tuberculosis

Cited by 171 publications

References 24 publications

Insights on the Evolution of Metabolic Networks of Unicellular Translationally Biased Organisms from Transcriptomic Data and Sequence Analysis

Insights on the Evolution of Metabolic Networks of Unicellular Translationally Biased Organisms from Transcriptomic Data and Sequence Analysis

Potent Inhibitors of a Shikimate Pathway Enzyme from Mycobacterium tuberculosis

Synergistic Allostery, a Sophisticated Regulatory Network for the Control of Aromatic Amino Acid Biosynthesis in Mycobacterium tuberculosis

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