Replacement of the Human Topoisomerase Linker Domain with the Plasmodial Counterpart Renders the Enzyme Camptothecin Resistant

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2013 Jul 12

PMID 23844196

Citations 9

Authors

Barbara Arno

Ilda DAnnessa

Cinzia Tesauro

Laura Zuccaro

Alessio Ottaviani

Birgitta Knudsen

Paola Fiorani

Alessandro Desideri

Affiliations

Soon will be listed here.

Abstract

A human/plasmodial hybrid enzyme, generated by swapping the human topoisomerase IB linker domain with the corresponding domain of the Plasmodium falciparum enzyme, has been produced and characterized. The hybrid enzyme displays a relaxation activity comparable to the human enzyme, but it is characterized by a much faster religation rate. The hybrid enzyme is also camptothecin resistant. A 3D structure of the hybrid enzyme has been built and its structural-dynamical properties have been analyzed by molecular dynamics simulation. The analysis indicates that the swapped plasmodial linker samples a conformational space much larger than the corresponding domain in the human enzyme. The large linker conformational variability is then linked to important functional properties such as an increased religation rate and a low drug reactivity, demonstrating that the linker domain has a crucial role in the modulation of the topoisomerase IB activity.

Citing Articles

A tale of topoisomerases and the knotty genetic material in the backdrop of Plasmodium biology.

Singh P, Rani K, Gotmare A, Bhattacharyya S Biosci Rep. 2022; 42(6).

PMID: 35699968 PMC: 9261774. DOI: 10.1042/BSR20212847.

Topoisomerase IB: a relaxing enzyme for stressed DNA.

Soren B, Dasari J, Ottaviani A, Iacovelli F, Fiorani P Cancer Drug Resist. 2022; 3(1):18-25.

PMID: 35582040 PMC: 9094055. DOI: 10.20517/cdr.2019.106.

Topoisomerase I (TOP1) dynamics: conformational transition from open to closed states.

Takahashi D, Gadelle D, Agama K, Kiselev E, Zhang H, Yab E Nat Commun. 2022; 13(1):59.

PMID: 35013228 PMC: 8748870. DOI: 10.1038/s41467-021-27686-7.

In Vitro and In Silico Characterization of an Antimalarial Compound with Antitumor Activity Targeting Human DNA Topoisomerase IB.

Soren B, Dasari J, Ottaviani A, Messina B, Andreotti G, Romeo A Int J Mol Sci. 2021; 22(14).

PMID: 34299074 PMC: 8306514. DOI: 10.3390/ijms22147455.

Swapping of The N-Terminal Domain of Human Topoisomerase 1B with the Corresponding Counterpart Strongly Impairs Enzyme Activity.

Dasari J, Soren B, Ottaviani A, Tesauro C, Marino S, Messina B Rep Biochem Mol Biol. 2020; 8(4):366-375.

PMID: 32582794 PMC: 7275839.

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