Skip Navigation

Nucleic Acids Research 2005 33(22):7090-7101; doi:10.1093/nar/gki1006
This Article
Right arrow Full Text Freely available
Right arrow Print PDF (3147K) Freely available
Right arrow Screen PDF (704K) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (6)
Right arrow Commercial Re-use Guidelines
for Open Access NAR Content
Google Scholar
Right arrow Articles by Srivastava, S. K.
Right arrow Articles by Ramachandran, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Srivastava, S. K.
Right arrow Articles by Ramachandran, R.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Published online 15 December 2005

© The Author 2005. Published by Oxford University Press. All rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions{at}oxfordjournals.org

Article

Mycobacterium tuberculosis NAD+-dependent DNA ligase is selectively inhibited by glycosylamines compared with human DNA ligase I

Sandeep Kumar Srivastava, Divya Dube, Neetu Tewari, Namrata Dwivedi, Rama Pati Tripathi1 and Ravishankar Ramachandran*

Molecular and Structural Biology Division, Central Drug Research Institute PO Box 173, Chattar Manzil, Mahatma Gandhi Marg, Lucknow 226001, India 1Medicinal and Process Chemistry Division, Central Drug Research Institute PO Box 173, Chattar Manzil, Mahatma Gandhi Marg, Lucknow 226001, India

*To whom correspondence should be addressed. Tel: +91 522 2612411, ext. 4442; Fax: +91 522 2623405; Email: ravi_anitha{at}yahoo.com

Received September 30, 2005. Revised October 28, 2005. Accepted November 22, 2005.

DNA ligases are important enzymes which catalyze the joining of nicks between adjacent bases of double-stranded DNA. NAD+-dependent DNA ligases (LigA) are essential in bacteria and are absent in humans. They have therefore been identified as novel, validated and attractive drug targets. Using virtual screening against an in-house database of compounds and our recently determined crystal structure of the NAD+ binding domain of the Mycobacterium tuberculosis LigA, we have identified N1, Nn-bis-(5-deoxy-{alpha}-D-xylofuranosylated) diamines as a novel class of inhibitors for this enzyme. Assays involving M.tuberculosis LigA, T4 ligase and human DNA ligase I show that these compounds specifically inhibit LigA from M.tuberculosis. In vitro kinetic and inhibition assays demonstrate that the compounds compete with NAD+ for binding and inhibit enzyme activity with IC50 values in the µM range. Docking studies rationalize the observed specificities and show that among several glycofuranosylated diamines, bis xylofuranosylated diamines with aminoalkyl and 1, 3-phenylene carbamoyl spacers mimic the binding modes of NAD+ with the enzyme. Assays involving LigA-deficient bacterial strains show that in vivo inhibition of ligase by the compounds causes the observed antibacterial activities. They also demonstrate that the compounds exhibit in vivo specificity for LigA over ATP-dependent ligase. This class of inhibitors holds out the promise of rational development of new anti-tubercular agents.

Correspondence may also be addressed to Rama Pati Tripathi. Tel: +91 522 2612411, ext. 4462; Fax: +91 522 2623405; Email: rpt_56{at}yahoo.com


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 J. Biol. Chem.Home page
S. Shuman
DNA Ligases: Progress and Prospects
J. Biol. Chem., June 26, 2009; 284(26): 17365 - 17369.
[Abstract] [Full Text] [PDF]

Home page
 Antimicrob. Agents Chemother.Home page
M. Korycka-Machala, E. Rychta, A. Brzostek, H. R. Sayer, A. Rumijowska-Galewicz, R. P. Bowater, and J. Dziadek
Evaluation of NAD+-Dependent DNA Ligase of Mycobacteria as a Potential Target for Antibiotics
Antimicrob. Agents Chemother., August 1, 2007; 51(8): 2888 - 2897.
[Abstract] [Full Text] [PDF]

Home page
 J Biomol ScreenHome page
U. Singh and D. Sarkar
Development of a Simple High-Throughput Screening Protocol Based on Biosynthetic Activity of Mycobacterium tuberculosis Glutamine Synthetase for the Identification of Novel Inhibitors
J Biomol Screen, December 1, 2006; 11(8): 1035 - 1042.
[Abstract] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.