Structural insight of DNA topoisomerases I from camptothecin-producing plants revealed by molecular dynamics simulations

Phytochemistry
Supaart SirikantaramasKazuki Saito

Abstract

DNA topoisomerase I (Top1) catalyzes changes in DNA topology by cleaving and rejoining one strand of the double stranded (ds)DNA. Eukaryotic Top1s are the cellular target of the plant-derived anticancer indole alkaloid camptothecin (CPT), which reversibly stabilizes the Top1-dsDNA complex. However, CPT-producing plants, including Camptotheca acuminata, Ophiorrhiza pumila and Ophiorrhiza liukiuensis, are highly resistant to CPT because they possess point-mutated Top1. Here, the adaptive convergent evolution is reported between CPT production ability and mutations in their Top1, as a universal resistance mechanism found in all tested CPT-producing plants. This includes Nothapodytes nimmoniana, one of the major sources of CPT. To obtain a structural insight of the resistance mechanism, molecular dynamics simulations of CPT- resistant and -sensitive plant Top1s complexed with dsDNA and topotecan (a CPT derivative) were performed, these being compared to that for the CPT-sensitive human Top1. As a result, two mutations, Val617Gly and Asp710Gly, were identified in O. pumila Top1 and C. acuminata Top1, respectively. The substitutions at these two positions, surprisingly, are the same as those found in a CPT derivative-resistant human ...Continue Reading

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Citations

Jan 11, 2017·Journal of Medicinal Chemistry·Giovanni CapranicoGiovanni Chillemi
Jan 10, 2018·Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan·Kazuki Saito
Nov 28, 2019·Journal of Computer-aided Molecular Design·Chonnikan HanpaiboolThanyada Rungrotmongkol

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