Catalytic Mechanism of L,D-Transpeptidase 2 from Mycobacterium tuberculosis Described by a Computational Approach: Insights for the Design of New Antibiotics Drugs

2014 ◽  
Vol 54 (9) ◽  
pp. 2402-2410 ◽  
Author(s):  
José Rogério A. Silva ◽  
Adrian E. Roitberg ◽  
Cláudio Nahum Alves
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Catalytic Mechanism ◽  
Computational Approach ◽  
New Antibiotics

Crystal Structure of the Mycobacterium tuberculosis dUTPase: Insights into the Catalytic Mechanism

2004 ◽  
Vol 341 (2) ◽  
pp. 503-517 ◽  
Author(s):  
Sum Chan ◽  
Brent Segelke ◽  
Timothy Lekin ◽  
Heike Krupka ◽  
Uhn Soo Cho ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Mycobacterium Tuberculosis ◽  
Catalytic Mechanism

Structural investigation of inhibitor designs targeting 3-dehydroquinate dehydratase from the shikimate pathway of Mycobacterium tuberculosis

2011 ◽  
Vol 436 (3) ◽  
pp. 729-739 ◽  
Author(s):  
Marcio V. B. Dias ◽  
William C. Snee ◽  
Karen M. Bromfield ◽  
Richard J. Payne ◽  
Satheesh K. Palaninathan ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Targets ◽  
Structural Investigation ◽  
Catalytic Mechanism ◽  
Shikimate Pathway ◽  
Structural Rearrangement ◽  
Competitive Inhibitors ◽  
Structural Insights ◽  
Potential Drug Targets

The shikimate pathway is essential in Mycobacterium tuberculosis and its absence from humans makes the enzymes of this pathway potential drug targets. In the present paper, we provide structural insights into ligand and inhibitor binding to 3-dehydroquinate dehydratase (dehydroquinase) from M. tuberculosis (MtDHQase), the third enzyme of the shikimate pathway. The enzyme has been crystallized in complex with its reaction product, 3-dehydroshikimate, and with six different competitive inhibitors. The inhibitor 2,3-anhydroquinate mimics the flattened enol/enolate reaction intermediate and serves as an anchor molecule for four of the inhibitors investigated. MtDHQase also forms a complex with citrazinic acid, a planar analogue of the reaction product. The structure of MtDHQase in complex with a 2,3-anhydroquinate moiety attached to a biaryl group shows that this group extends to an active-site subpocket inducing significant structural rearrangement. The flexible extensions of inhibitors designed to form π-stacking interactions with the catalytic Tyr24 have been investigated. The high-resolution crystal structures of the MtDHQase complexes provide structural evidence for the role of the loop residues 19–24 in MtDHQase ligand binding and catalytic mechanism and provide a rationale for the design and efficacy of inhibitors.

Crystal structure of hexanoyl-CoA bound to β-ketoacyl reductase FabG4 of Mycobacterium tuberculosis

2013 ◽  
Vol 450 (1) ◽  
pp. 127-139 ◽  
Author(s):  
Debajyoti Dutta ◽  
Sudipta Bhattacharyya ◽  
Amlan Roychowdhury ◽  
Rupam Biswas ◽  
Amit Kumar Das
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Active Site ◽  
Ternary Complex ◽  
Catalytic Mechanism ◽  
Acyl Carrier Protein ◽  
Structural Data ◽  
Acid Synthesis ◽  
Binary Complex ◽  
C Terminus ◽  
Covalently Linked

FabGs, or β-oxoacyl reductases, are involved in fatty acid synthesis. The reaction entails NADPH/NADH-mediated conversion of β-oxoacyl-ACP (acyl-carrier protein) into β-hydroxyacyl-ACP. HMwFabGs (high-molecular-weight FabG) form a phylogenetically separate group of FabG enzymes. FabG4, an HMwFabG from Mycobacterium tuberculosis, contains two distinct domains, an N-terminal ‘flavodoxintype’ domain and a C-terminal oxoreductase domain. The catalytically active C-terminal domain utilizes NADH to reduce β-oxoacyl-CoA to β-hydroxyacyl-CoA. In the present study the crystal structures of the FabG4–NADH binary complex and the FabG4–NAD+–hexanoyl-CoA ternary complex have been determined to understand the substrate specificity and catalytic mechanism of FabG4. This is the first report to demonstrate how FabG4 interacts with its coenzyme NADH and hexanoyl-CoA that mimics an elongating fattyacyl chain covalently linked with CoA. Structural analysis shows that the binding of hexanoyl-CoA within the active site cavity of FabG significantly differs from that of the C16 fattyacyl substrate bound to mycobacterial FabI [InhA (enoyl-ACP reductase)]. The ternary complex reveals that both loop I and loop II interact with the phosphopantetheine moiety of CoA or ACP to align the covalently linked fattyacyl substrate near the active site. Structural data ACP inhibition studies indicate that FabG4 can accept both CoA- and ACP-based fattyacyl substrates. We have also shown that in the FabG4 dimer Arg146 and Arg445 of one monomer interact with the C-terminus of the second monomer to play pivotal role in substrate association and catalysis.

Structural insights of catalytic mechanism in mutant pyrazinamidase of Mycobacterium tuberculosis

2020 ◽  
pp. 1-14
Author(s):  
Muhammad Junaid ◽  
Cheng-Dong Li ◽  
Jiayi Li ◽  
Abbas Khan ◽  
Syed Shujait Ali ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Catalytic Mechanism ◽  
Structural Insights

Structural and computational dissection of the catalytic mechanism of the inorganic pyrophosphatase from Mycobacterium tuberculosis

2015 ◽  
Vol 192 (1) ◽  
pp. 76-87 ◽  
Author(s):  
Andrew C. Pratt ◽  
Sajeewa W. Dewage ◽  
Allan H. Pang ◽  
Tapan Biswas ◽  
Sandra Barnard-Britson ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Catalytic Mechanism ◽  
Inorganic Pyrophosphatase ◽  
Computational Dissection

Elucidating the biosynthetic pathways of volatile organic compounds in Mycobacterium tuberculosis through a computational approach

2017 ◽  
Vol 13 (4) ◽  
pp. 750-755 ◽  
Author(s):  
Purva Bhatter ◽  
Karthik Raman ◽  
Vani Janakiraman
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Volatile Organic Compounds ◽  
Organic Compounds ◽  
Computational Approach ◽  
Biosynthetic Pathways ◽  
First Report ◽  
Volatile Organic

A first report on the biosynthetic origin ofMycobacterium tuberculosisspecific small volatile molecules.

scholarly journals Itaconate is a covalent inhibitor of the Mycobacterium tuberculosis isocitrate lyase

2020 ◽  
Author(s):  
Brooke X. C. Kwai ◽  
Annabelle J. Collins ◽  
Martin J. Middleditch ◽  
Jonathan Sperry ◽  
Ghader Bashiri ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Catalytic Mechanism ◽  
Isocitrate Lyase ◽  
Cysteine Residue ◽  
Covalent Adduct ◽  
Catalytic Cysteine ◽  
Covalent Inhibitor

Mycobacterium tuberculosis isocitrate lyases (ICLs) form a covalent adduct with itaconate through their catalytic cysteine residue. These results reveal atomic details of itaconate inhibition and provide insights into the catalytic mechanism of ICLs.

Inhibition of Mycobacterium tuberculosis tRNA-Ligases Using siRNA-Based Gene Silencing Method: A Computational Approach

2020 ◽  
Vol 27 (1) ◽  
pp. 91-99
Author(s):  
Partha Sarathi Mohanty ◽  
Sandeep Sharma ◽  
Farah Naaz ◽  
Dilip Kumar ◽  
Archana Raikwar ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Gene Silencing ◽  
Computational Approach
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