Involvement of amino acids 361 to 364 of human topoisomerase I in camptothecin resistance and enzyme catalysis

Xi Guang Li, Paul Haluska, Yaw Huei Hsiang, Ajit K. Bharti, Donald W. Kufe, Leroy-Fong Liu, Eric H. Rubin

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37 引文 斯高帕斯(Scopus)

摘要

Camptothecins are antineoplastic drugs that specifically target the enzyme DNA topoisomerase I. Prior work has identified a human topoisomerase I mutation, F361S, that confers resistance to camptothecin. We now demonstrate that substitutions in the 361-364 region can alter DNA cleavage/ligation by the enzyme. The defective catalysis exhibited by certain mutants likely relates to an impaired interaction with DNA, since these enzymes are more sensitive to the inhibitory effects of DNA binding ligands. Moreover, studies with peptides and fusion proteins suggest that the 361-364 region may bind DNA directly. The finding that the 361-364 region is involved in both enzyme catalysis and camptothecin resistance suggests that this region is part of the active site of human topoisomerase I and that camptothecin may interact with the enzyme at this site.

原文英語
頁(從 - 到)1019-1027
頁數9
期刊Biochemical Pharmacology
53
發行號7
DOIs
出版狀態已發佈 - 四月 4 1997
對外發佈Yes

ASJC Scopus subject areas

  • Pharmacology

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