Targeting the Histidine Pathway in Mycobacterium tuberculosis

Lunardi, Juleane; Nunes, J.; Bizarro, Cristiano Valim; Basso, Luiz Augusto; Santos, Daniel Silas Veras dos; Machado, Pablo

doi:10.2174/15680266113136660203

Cited by 29 publications

(24 citation statements)

References 131 publications

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“…Another top ranking pathway is the one responsible for histidine biosynthesis, which has been suggested as harboring potential drug targets due to its absence in mammals [62]. The pathway is composed by eight essential proteins.…”

Section: Construction and Incorporation Of Mtb Metabolic Network Analmentioning

confidence: 99%

A whole genome bioinformatic approach to determine potential latent phase specific targets in Mycobacterium tuberculosis

et al. 2016

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Current Tuberculosis treatment is long and expensive, faces the increasing burden of MDR/XDR strains and lack of effective treatment against latent form, resulting in an urgent need of new anti-TB drugs. Key to TB biology is its capacity to fight the host's RNOS mediated attack. RNOS are known to display a concentration dependent mycobactericidal activity, which leads to the following hypothesis "if we know which proteins are targeted by RNOS and kill TB, we we might be able to inhibit them with drugs resulting in a synergistic bactericidal effect". Based on this idea, we performed an Mtb metabolic network whole proteome analysis of potential RNOS sensitive and relevant targets which includes target druggability and essentiality criteria. Our results, available at http://tuberq.proteinq.com.ar yield new potential TB targets, like I3PS, while also providing and updated view of previous proposals becoming an important tool for researchers looking for new ways of killing TB.

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Section: Construction and Incorporation Of Mtb Metabolic Network Analmentioning

confidence: 99%

A whole genome bioinformatic approach to determine potential latent phase specific targets in Mycobacterium tuberculosis

et al. 2016

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“…ATP‐PRT acts as the gateway into His biosynthesis and as such plays an important metabolic role. It has been the focus of several studies and identified as a potential target of new antibiotic therapies . The nature of the active species in solution of the long form of this enzyme and the details of allostery have been unclear; with early solution studies favoring a change in quaternary structure from active dimer to inactive His‐bound oligomer .…”

Section: Discussionmentioning

confidence: 99%

“…It has been the focus of several studies and identified as a potential target of new antibiotic therapies. 26,27 The nature of the active species in solution of the long form of this enzyme and the details of allostery have been unclear; with early solution studies favoring a change in quaternary structure from active dimer to inactive His-bound oligomer. 21,22 The loose hexameric structure observed in the absence of His for the MtuATP-PRT and EcoATP-PRT was interpreted as consistent with an inactive hexamer.…”

Section: Discussionmentioning

confidence: 99%

Campylobacter jejuni adenosine triphosphate phosphoribosyltransferase is an active hexamer that is allosterically controlled by the twisting of a regulatory tail

et al. 2016

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Adenosine triphosphate phosphoribosyltransferase (ATP-PRT) catalyzes the first committed step of the histidine biosynthesis in plants and microorganisms. Here, we present the functional and structural characterization of the ATP-PRT from the pathogenic e-proteobacteria Campylobacter jejuni (CjeATP-PRT). This enzyme is a member of the long form (HisG L ) ATP-PRT and is allosterically inhibited by histidine, which binds to a remote regulatory domain, and competitively inhibited by AMP. In the crystalline form, CjeATP-PRT was found to adopt two distinctly different hexameric conformations, with an open homohexameric structure observed in the presence of substrate ATP, and a more compact closed form present when inhibitor histidine is bound. CjeATP-PRT was observed to adopt only a hexameric quaternary structure in solution, contradicting previous hypotheses favoring an allosteric mechanism driven by an oligomer equilibrium.Abbreviations: ATP-PRT, adenosine triphosphate phosphoribosyltransferase; BTP, 1,3-bis[tris(hydroxymethyl)methylamino]propane; CjeATP-PRT, ATP-PRT from Campylobacter jejuni; EcoATP-PRT, Escherichia coli ATP-PRT; His, l-histidine; ITC, isothermal titration calorimetry; MtuATP-PRT, Mycobacterium tuberculosis ATP-PRT; PDB, Protein Data Bank; PR-ATP, phosphoribosyl ATP; PRPP, phosphoribosyl pyrophosphate; PRT, phosphoribosyltransferase; RMSD, root-mean-square difference; SenATP-PRT, Salmonella enterica subsp. enterica Typhimurium ATP-PRT Additional Supporting Information may be found in the online version of this article.Significance Statement: ATP-phosphoribosyltransferase catalyzes the first dedicated step in the biosynthesis of the essential amino acid histidine in microorganisms. We report the functional characterization of this enzyme from human pathogen Campylobacter jejuni. The enzyme is inhibited by histidine, allowing for tuned production of histidine in response to cellular demands. Our results reveal how the enzyme structure becomes compressed when histidine binds and exposes the molecular details of how this enzyme performs its function. Instead, this study supports the conclusion that the ATP-PRT long form hexamer is the active species; the tightening of this structure in response to remote histidine binding results in an inhibited enzyme.

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“…The domain possessing the phosphatase activity was conserved within the bifunctional HisB of modern bacterial clades such as Gammaproteobacteria (Escherichia and Salmonella), whereas in clades such as Actinomycetales (Mycobacteria, Corynebacterium, and Streptomyces), the phosphatase activity was performed by a unique monofunctional enzyme. Interestingly, Rv0114, which is annotated as a D-glycero-␣-D-mannoheptose 1,7-bisphosphate phosphatase (gmhB) (17), also speculated to be a probable HolPase (18) has diverged separately from both the bifunctional HisB and monofunctional HisN, suggesting a possibly different role of this protein other than that of a HolPase (Fig. 1A).…”

Section: Rv3137 Is the Mtb Holpase And Not An Impasementioning

confidence: 99%

Identification and structural characterization of a histidinol phosphate phosphatase from Mycobacterium tuberculosis

Jha

Kumar

Sharma

et al. 2018

Journal of Biological Chemistry

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The absence of a histidine biosynthesis pathway in humans, coupled with histidine essentiality for survival of the important human pathogen (), underscores the importance of the bacterial enzymes of this pathway as major antituberculosis drug targets. However, the identity of the mycobacterial enzyme that functions as the histidinol phosphate phosphatase (HolPase) of this pathway remains to be established. Here, we demonstrate that the enzyme encoded by the gene, belonging to the inositol monophosphatase (IMPase) family, functions as the HolPase and specifically dephosphorylates histidinol phosphate. The crystal structure of Rv3137 in apo form enabled us to dissect its distinct structural features. Furthermore, the holo-complex structure revealed that a unique cocatalytic multizinc-assisted mode of substrate binding and catalysis is the hallmark of HolPase. Interestingly, the enzyme-substrate complex structure unveiled that although monomers possess individual catalytic sites they share a common product-exit channel at the dimer interface. Furthermore, target-based screening against HolPase identified several small-molecule inhibitors of this enzyme. Taken together, our study unravels the missing enzyme link in the histidine biosynthesis pathway, augments our current mechanistic understanding of histidine production in , and has helped identify potential inhibitors of this bacterial pathway.

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Targeting the Histidine Pathway in Mycobacterium tuberculosis

Cited by 29 publications

References 131 publications

A whole genome bioinformatic approach to determine potential latent phase specific targets in Mycobacterium tuberculosis

A whole genome bioinformatic approach to determine potential latent phase specific targets in Mycobacterium tuberculosis

Campylobacter jejuni adenosine triphosphate phosphoribosyltransferase is an active hexamer that is allosterically controlled by the twisting of a regulatory tail

Identification and structural characterization of a histidinol phosphate phosphatase from Mycobacterium tuberculosis

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