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Inhibition of type IA topoisomerase by a monoclonal antibody through perturbation of DNA cleavage-religation equilibrium

Leelaram, Majety Naga and Bhat, Anuradha Gopal and Hegde, Shivanand Manjunath and Manjunath, Ramanathapuram and Nagaraja, Valakunja (2012) Inhibition of type IA topoisomerase by a monoclonal antibody through perturbation of DNA cleavage-religation equilibrium. In: FEBS Journal, 279 (1). pp. 55-65.

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Official URL: http://onlinelibrary.wiley.com/doi/10.1111/j.1742-...

Abstract

Type IA DNA topoisomerases, typically found in bacteria, are essential enzymes that catalyse the DNA relaxation of negative supercoils. DNA gyrase is the only type II topoisomerase that can carry out the opposite reaction (i.e. the introduction of the DNA supercoils). A number of diverse molecules target DNA gyrase. However, inhibitors that arrest the activity of bacterial topoisomerase I at low concentrations remain to be identified. Towards this end, as a proof of principle, monoclonal antibodies that inhibit Mycobacterium smegmatis topoisomerase I have been characterized and the specific inhibition of Mycobacterium smegmatis topoisomerase I by a monoclonal antibody, 2F3G4, at a nanomolar concentration is described. The enzyme-bound monoclonal antibody stimulated the first transesterification reaction leading to enhanced DNA cleavage, without significantly altering the religation activity of the enzyme. The stimulated DNA cleavage resulted in perturbation of the cleavagereligation equilibrium, increasing single-strand nicks and proteinDNA covalent adducts. Monoclonal antibodies with such a mechanism of inhibition can serve as invaluable tools for probing the structure and mechanism of the enzyme, as well as in the design of novel inhibitors that arrest enzyme activity.

Item Type: Journal Article
Additional Information: Copyright of this article belongs to John Wiley and Sons.
Keywords: monoclonal antibody;mycobacteria;protein-DNA complex; topoisomerase I;transesterification
Department/Centre: Division of Biological Sciences > Biochemistry
Division of Biological Sciences > Microbiology & Cell Biology
Date Deposited: 03 Feb 2012 12:19
Last Modified: 03 Feb 2012 12:19
URI: http://eprints.iisc.ernet.in/id/eprint/43388

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