Open AccessThe carbohydrate domain of calicheamicin gamma I1 determines its sequence specificity for DNA cleavage.
Author(s) -
Jacqueline Drak,
Nobuharu Iwasawa,
Samuel J. Danishefsky,
Donald M. Crothers
Publication year - 1991
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.88.17.7464
Subject(s) - dna , calicheamicin , chemistry , stereochemistry , aglycone , carbohydrate , natural product , moiety , hydrogen atom abstraction , biochemistry , combinatorial chemistry , biology , glycoside , genetics , antibody , radical
We have investigated the DNA cleaving properties of calicheamicinone, the synthetic core aglycone of calicheamicin gamma I1, a natural product with extremely potent antitumor activity. Our experiments have shown that the synthetic analog binds and cleaves DNA, albeit without any sequence selectivity and with less efficiency than the natural compound. We propose that a key element in the sequence recognition process is the thiobenzoate ring present in the natural compound. We have demonstrated by one-dimensional NMR that there is direct hydrogen abstraction from DNA by calicheamicinone, with enhanced binding affinity contributed by the carbohydrate domain. The reduced efficiency of hydrogen abstraction from DNA by bound calicheamicinone, compared with the natural compound, implicates the carbohydrate moiety in positioning the drug for hydrogen abstraction.