M. tuberculosis Pantothenate Kinase: Dual Substrate Specificity and Unusual Changes in Ligand Locations

Chetnani, B.; Kumar, P. Rajesh; Surolia, Avadhesha; Vijayan, M.

doi:10.1016/j.jmb.2010.04.064

Cited by 32 publications

(29 citation statements)

References 38 publications

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“…Crystal structures are reported for Type I PanK isoforms from four species: Escherichia coli (EcPanK), 14,28 Mycobacterium tuberculosis (MtPanK), [29][30][31] Coxiella burnetii (CbPanK; PDB 3TQC), and Klebsiella pneumoniae (KpPanK). 24 The reported crystal structure of EcPanK in complex with pantothenate predicts several amino acids involved in stabilizing pantothenate binding.…”

Section: Discussionmentioning

confidence: 99%

Exploring structural motifs necessary for substrate binding in the active site of Escherichia coli pantothenate kinase

Awuah¹,

Ma²,

Hoegl³

et al. 2014

Bioorganic & Medicinal Chemistry

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The coenzyme A (CoA) biosynthetic enzymes have been used to produce various CoA analogues, including mechanistic probes of CoA-dependent enzymes such as those involved in fatty acid biosynthesis. These enzymes are also important for the activation of the pantothenamide class of antibacterial agents, and of a recently reported family of antibiotic resistance inhibitors. Herein we report a study on the selectivity of pantothenate kinase, the first and rate limiting step of CoA biosynthesis. A robust synthetic route was developed to allow rapid access to a small library of pantothenate analogs diversified at the β-alanine moiety, the carboxylate or the geminal dimethyl group. All derivatives were tested as substrates of Escherichia coli pantothenate kinase (EcPanK). Four derivatives, all N-aromatic pantothenamides, proved to be equivalent to the benchmark Npentylpantothenamide (N5-pan) as substrates of EcPanK, while two others, also with N-aromatic groups, were some of the best substrates reported for this enzyme. This collection of data provides insight for the future design of PanK substrates in the production of useful CoA analogues. Graphical abstractThe promiscuity of E. coli PanK has limits! We report the synthesis of pantothenate analogs diversified at the β-alanine moiety, the carboxylate or the geminal dimethyl group. Interestingly, some of these are among the best substrates reported for E. coli PanK.

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Section: Discussionmentioning

confidence: 99%

Exploring structural motifs necessary for substrate binding in the active site of Escherichia coli pantothenate kinase

Awuah¹,

Ma²,

Hoegl³

et al. 2014

Bioorganic & Medicinal Chemistry

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“…Both trpD and coaA of M. tuberculosis lack homolog proteins in the human genome. For both of these two proteins, three dimensional structures are available in the Protein Data Bank (Castell et al, 2013 andChetnani et al, 2010). All these factors encouraged us to select trpD and coaA as target proteins against which molecular docking was performed.…”

Section: Introductionmentioning

confidence: 99%

In silico and in vitro screening of FDA-approved drugs for potential repurposing against tuberculosis

Brindha¹,

Sundaramurthi

Vincent³

et al. 2017

Preprint

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MotivationRepurposing of known drugs to newer clinical conditions is a promising avenue for finding novel therapeutic applications for tuberculosis. MethodsWe performed docking-based virtual screening for 1554 known drugs against two of the potential drug targets, namely trpD and coaA of M. tuberculosis. In the first round of in silico screening we used rigid docking using Glide and AutoDock Vina. We subjected the consistently ranked drugs for induced-fit docking by these tools against the same target proteins. We performed luciferase reporter phage (LRP) assay to determine the biological activity of five selected drugs against M. tuberculosis. ResultsWe observed lymecycline and cefpodoxime to be active against drug susceptible and drug resistant strains of M. tuberculosis. In addition, lymecycline and cefpodoxime showed synergistic activity with rifampin and isoniazid against M. tuberculosis. ConclusionOur results suggest that lymecycline and cefpodoxime have potential to be repurposed for the treatment of tuberculosis.

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“…It functions as a homodimer. MtPanK has been the target for extensive structural studies and has been crystallized in complex with its substrates, products, adenosine or guanosine cofactors, and feedback inhibitor CoA (13)(14)(15)(16). The MtPanK structures in this study represent the first complexes with engineered inhibitory compounds and provide a starting point for development of novel antibiotics targeting pathogens that are dependent on type I PanK.…”

mentioning

confidence: 99%

Structural and Biochemical Characterization of Compounds Inhibiting Mycobacterium tuberculosis Pantothenate Kinase

Björkelid

Bergfors

Raichurkar

et al. 2013

Journal of Biological Chemistry

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M. tuberculosis Pantothenate Kinase: Dual Substrate Specificity and Unusual Changes in Ligand Locations

Cited by 32 publications

References 38 publications

Exploring structural motifs necessary for substrate binding in the active site of Escherichia coli pantothenate kinase

Exploring structural motifs necessary for substrate binding in the active site of Escherichia coli pantothenate kinase

In silico and in vitro screening of FDA-approved drugs for potential repurposing against tuberculosis

Structural and Biochemical Characterization of Compounds Inhibiting Mycobacterium tuberculosis Pantothenate Kinase

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