Mechanism of Phosphoryl Transfer Catalyzed by Shikimate Kinase from Mycobacterium tuberculosis

2006 ◽  
Vol 364 (3) ◽  
pp. 411-423 ◽  
Author(s):  
Marcus D. Hartmann ◽  
Gleb P. Bourenkov ◽  
Attila Oberschall ◽  
Nicolai Strizhov ◽  
Hans D. Bartunik
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Phosphoryl Transfer ◽  
Shikimate Kinase

scholarly journals Study of the Phosphoryl-Transfer Mechanism of Shikimate Kinase by NMR Spectroscopy

2016 ◽  
Vol 22 (8) ◽  
pp. 2758-2768 ◽  
Author(s):  
Verónica Prado ◽  
Emilio Lence ◽  
Juan A. Vallejo ◽  
Alejandro Beceiro ◽  
Paul Thompson ◽  
...  
Keyword(s):  
Nmr Spectroscopy ◽  
Transfer Mechanism ◽  
Phosphoryl Transfer ◽  
Shikimate Kinase

DevR–DevS is a bona fide two-component system of Mycobacterium tuberculosis that is hypoxia-responsive in the absence of the DNA-binding domain of DevR

Microbiology ◽  
2004 ◽  
Vol 150 (4) ◽  
pp. 865-875 ◽  
Author(s):  
Deepak Kumar Saini ◽  
Vandana Malhotra ◽  
Deepanwita Dey ◽  
Neha Pant ◽  
Taposh K. Das ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Pathogenic Bacteria ◽  
Response Regulator ◽  
Regulatory System ◽  
Site Directed Mutagenesis ◽  
Phosphoryl Transfer ◽  
Dependent Manner ◽  
Two Component System ◽  
Component System ◽  
Two Component

Two-component systems play a central role in the adaptation of pathogenic bacteria to the environment prevailing within host tissues. The genes encoding the response regulator DevR (Rv3133c/DosR) and the cytoplasmic portion (DevS201) of the histidine kinase DevS (Rv3132c/DosS), a putative two-component system of Mycobacterium tuberculosis, were cloned and the protein products were overexpressed, purified and refolded as N-terminally His6-tagged proteins from Escherichia coli. DevS201 underwent autophosphorylation and participated in rapid phosphotransfer to DevR in a Mg2+-dependent manner. Chemical stability analysis and site-directed mutagenesis implicated the highly conserved residues His395 and Asp54 as the sites of phosphorylation in DevS and DevR, respectively. Mutations in Asp8 and Asp9 residues, postulated to form the acidic Mg2+-binding pocket, and the invariant Lys104 of DevR, abrogated phosphoryl transfer from DevS201 to DevR. DevR–DevS was thus established as a typical two-component regulatory system based on His-to-Asp phosphoryl transfer. Expression of the Rv3134c–devR–devS operon was induced at the RNA level in hypoxic cultures of M. tuberculosis H37Rv and was associated with an increase in the level of DevR protein. However, in a devR mutant strain expressing the N-terminal domain of DevR, induction was observed at the level of RNA expression but not at that of protein. DevS was translated independently of DevR and induction of devS transcripts was not associated with an increase in protein level in either wild-type or mutant strains, reflecting differential regulation of this locus during hypoxia.

scholarly journals Virtual Screening, Molecular Docking and Dynamic Simulation of Shikimate Kinase from Mycobacterium Tuberculosis Using in Silico Approach

2020 ◽  
Author(s):  
Dr. Mustafa Alhaji Isa
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Molecular Docking ◽  
Binding Site ◽  
Md Simulation ◽  
Simulation Analysis ◽  
3D Structure ◽  
Normal Function ◽  
Binding Energies ◽  
Shikimate Kinase ◽  
Lipinski’S Rule

<p>Shikimate kinase (SK) is an enzyme that catalyzes the fifth steps in the shikimate pathway. The enzyme facilitate the transfer of phosphoryl from ATP to shikimate, to produce ADP and shikimate-3-phosphate from <i>Mycobacterium tuberculosis</i> (MTB). The 3D structure of SK bound ligands (4-(2-Hydroxyethyl)-1-Piperazine Ethanesulfonic Acid (EPE)), ADP and metals (Mg2+, Cl- and Pt+) obtained from PDB (PDB ID: 1L4U and resolution 1.8Å). The structural analysis of the SK revealed that it has a substrate or shikimate binding site (Asp34, Arg58, and Lys136) and substrate binding via amide nitrogen (Gly80). It also possessed nucleotide binding region (Gly12─Thr17), the ATP binding site (Arg117 and Arg153) and metallic ion (Mg2+) binding site (Ser16 and Asp32). All these residues mentioned above play an essential role in the catalytic activity of the SK. Therefore inhibition any of these residues serve as a stumbling block for the normal function of the enzyme. A total of eleven thousand three hundred and twenty-three (11323) compounds obtained from two public databases (Zinc Database and PubChem) capable of binding to SK with good binding affinities. These compounds further filtered for Lipinski’s rule of five, drug-likeness, molecular docking analysis, and ADME and toxicity analysis. Three compounds with minimum binding energies─ PubChem15478 (─11.75 kcal/mol), ZINC02838601 (─11.52 kcal/mol), and ZINC11790367 (─9.88 kcal/mol) ─were selected and used for the MD simulation analysis. Also, MD simulation of the SK bound to EPE, ADP, and Mg2+ were carried out to compare their stabilities with the selected protein-ligand complexes. The result showed that the two compounds (ZINC11790367 and PubChem15478) formed stable and rigid complexes comparable to the bound ligand and the cofactors during the 50ns MD simulation. Therefore, it concluded that the above mentioned two compounds capable of inhibiting SK considered as prospective drugs for MTB after successful experimental validation.</p>

Screening of antitubercular compound library identifies novel shikimate kinase inhibitors of Mycobacterium tuberculosis

2016 ◽  
Vol 100 (12) ◽  
pp. 5415-5426 ◽  
Author(s):  
Vikrant S. Rajput ◽  
Rukmankesh Mehra ◽  
Sanjay Kumar ◽  
Amit Nargotra ◽  
Parvinder Pal Singh ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Kinase Inhibitors ◽  
Compound Library ◽  
Shikimate Kinase

scholarly journals Mechanism of irreversible inhibition of Mycobacterium tuberculosis shikimate kinase by ilimaquinone

2018 ◽  
Vol 1866 (5-6) ◽  
pp. 731-739 ◽  
Author(s):  
Johayra Simithy ◽  
Ngolui Rene Fuanta ◽  
Judith V. Hobrath ◽  
Anna Kochanowska-Karamyan ◽  
Mark T. Hamann ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Shikimate Kinase ◽  
Irreversible Inhibition
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