Abstract:
:Bisdioxopiperazine anti-cancer agents are catalytic inhibitors of topoisomerase II which by unknown means lock the enzyme in a closed clamp form and inhibit its ATPase activity. In order to demarcate a putative pharmacophore, we here describe a novel Tyr165Ser mutation in the enzyme's Walker A ATP binding site leading to specific bisdioxopiperazine resistance when transformed into a temperature-conditional yeast system. The Tyr165Ser mutation differed from a previously described Arg162Gln by being heterozygous and by purified Tyr165Ser enzyme being drug-resistant in a kinetoplast DNA decatenation enzymatic assay. This suggested dominant nature of Tyr165Ser was supported by co-transformation studies in yeast of plasmids carrying wild type and mutant genes. These results enable a model of the bisdioxopiperazine pharmacophore using the proposed asymmetric ATP hydrolysis of the enzyme.
journal_name
FEBS Lettjournal_title
FEBS lettersauthors
Wessel I,Jensen LH,Renodon-Corniere A,Sorensen TK,Nitiss JL,Jensen PB,Sehested Mdoi
10.1016/s0014-5793(02)02805-3keywords:
subject
Has Abstractpub_date
2002-06-05 00:00:00pages
161-6issue
1-3eissn
0014-5793issn
1873-3468pii
S0014579302028053journal_volume
520pub_type
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