Structural and Biochemical Characterization of Compounds Inhibiting Mycobacterium tuberculosis Pantothenate Kinase

Björkelid, C.; Bergfors, Terese; Raichurkar, Anand Kumar; Mukherjee, Kakoli; Malolanarasimhan, Krishnan; Bandodkar, Balachandra; Jones, T. Alwyn

doi:10.1074/jbc.m113.476473

Cited by 46 publications

(55 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While the original hits inhibited the enzyme at a micromolar concentration, the IC 50 could be improved to 22 nM by systematic changes. True binding of these compounds was confirmed by midpoint (T m ) shift experiments followed by elucidation of cocrystal structures with inhibitors of both triazole and biaryl classes (11). The crystal structures not only gave information about key residues for binding of both classes of inhibitors but also hinted at the observed difference in the modes of inhibition.…”

Section: Discussionmentioning

confidence: 84%

“…The detailed mode of binding of a subset of triazole and biaryl acid inhibitors was determined by crystallographic studies on enzyme-inhibitor complexes. These inhibitors were found to occupy overlapping positions with CoA and each other (11).…”

Section: Identification Of Diverse Chemical Series Targeting Mtpankmentioning

confidence: 99%

“…Crystal structures of protein-inhibitor complexes of MtPanK with triazole and biaryl classes of compounds have previously been described (11). The typical binding modes of the triazole and biaryl compounds are exemplified by compound 7i (PDB identification no.…”

Section: Figmentioning

confidence: 99%

“…Among these, the triazoles were found to be competitive with ATP, while the biaryl acids were mixed noncompetitive. Specific interaction with the target was shown by determining the crystal structures with both types of inhibitors bound in the enzyme (11). These inhibitors were then evaluated for their ability to translate to cellular growth inhibition with in silico predictive tools as well as in vitro experimentation.…”

mentioning

confidence: 99%

See 3 more Smart Citations

Assessment of Mycobacterium tuberculosis Pantothenate Kinase Vulnerability through Target Knockdown and Mechanistically Diverse Inhibitors

Reddy

Landge

Ravishankar

et al. 2014

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 84%

Section: Identification Of Diverse Chemical Series Targeting Mtpankmentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Assessment of Mycobacterium tuberculosis Pantothenate Kinase Vulnerability through Target Knockdown and Mechanistically Diverse Inhibitors

Reddy

Landge

Ravishankar

et al. 2014

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

“…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

View full text Add to dashboard Cite

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.

show abstract

Mycobacterium tuberculosis: Pathogenesis and therapeutic targets

Yang,

Zhang,

Qiao

et al. 2023

MedComm

View full text Add to dashboard Cite

Tuberculosis (TB) remains a significant public health concern in the 21st century, especially due to drug resistance, coinfection with diseases like immunodeficiency syndrome (AIDS) and coronavirus disease 2019, and the lengthy and costly treatment protocols. In this review, we summarize the pathogenesis of TB infection, therapeutic targets, and corresponding modulators, including first‐line medications, current clinical trial drugs and molecules in preclinical assessment. Understanding the mechanisms of Mycobacterium tuberculosis (Mtb) infection and important biological targets can lead to innovative treatments. While most antitubercular agents target pathogen‐related processes, host‐directed therapy (HDT) modalities addressing immune defense, survival mechanisms, and immunopathology also hold promise. Mtb’s adaptation to the human host involves manipulating host cellular mechanisms, and HDT aims to disrupt this manipulation to enhance treatment effectiveness. Our review provides valuable insights for future anti‐TB drug development efforts.

show abstract

Structural and Biochemical Characterization of Compounds Inhibiting Mycobacterium tuberculosis Pantothenate Kinase

Cited by 46 publications

References 35 publications

Assessment of Mycobacterium tuberculosis Pantothenate Kinase Vulnerability through Target Knockdown and Mechanistically Diverse Inhibitors

Assessment of Mycobacterium tuberculosis Pantothenate Kinase Vulnerability through Target Knockdown and Mechanistically Diverse Inhibitors

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

Mycobacterium tuberculosis: Pathogenesis and therapeutic targets

Contact Info

Product

Resources

About