Site-specific atom transfer from DNA to a bound ligand defines the geometry of a DNA-calicheamicin .gamma.1I complex

Voss, James J. De; Townsend, Craig A.; Ding, Wen; Morton, George O.; Ellestad, George A.; Zein, Nada; Tabor, Alethea B.; Schreiber, Stuart L.

doi:10.1021/ja00182a053

Cited by 105 publications

(61 citation statements)

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“…Therefore, the carbohydrate moiety not only enhances DNA binding affinity but also acts to position the biradical for optimum reactivity with DNA. This conclusion is in accord with the low frequency of double-stranded DNA cutting by calicheamicinone and is consistent with the results of De Voss et al (22), who showed that calicheamicin VY is specifically oriented with respect to the cleavage site.…”

Section: Resultssupporting

confidence: 92%

The carbohydrate domain of calicheamicin gamma I1 determines its sequence specificity for DNA cleavage.

Drak

Iwasawa

Danishefsky

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

117

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We have investigated the DNA cleaving properties of calicheamicinone, the synthetic core aglycone of calicheamicin y', 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.

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Section: Resultssupporting

confidence: 92%

The carbohydrate domain of calicheamicin gamma I1 determines its sequence specificity for DNA cleavage.

Drak

Iwasawa

Danishefsky

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

117

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“…De Voss et al (17) have confirmed that a C-5' hydrogen atom is abstracted from the second nucleotide within the oligopyrimidine strand of the recognition sequence, strengthening these assignments. The fragments whose mobilities are unaltered upon base treatment were assumed to be produced by cleavage of the purine-rich complementary strand, where a different hydrogen atom is apparently abstracted (cleavage is staggered 3 bp in the 3' direction, so that it is actually in the flanking sequence).…”

Section: Methodsmentioning

confidence: 88%

Cleavage behavior of calicheamicin gamma 1 and calicheamicin T.

Walker

Landovitz

Ding

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

128

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Calicheamicin y"is a potent antitumor antibiotic that cleaves DNA with a high degree of specificity; there is much interest in the recognition process. We have investigated the DNA-cleaving properties of calicheamicin T, a truncated derivative of calicheamicin. We show that calicheamicin T cleaves DNA in a double-stranded fashion, indicating that the first two sugars are sufficient to facilitate binding of the aglycone in the minor groove. However, calicheamicin T cleaves DNA nonselectively. This result suggests that cyclization kinetics do not determine the cleavage speiflcity of the intact drug. Instead, cleavage specificity probably reflects binding specificity. Because of the recognition sites reported in the original cleavage paper, calicheamicin has been assumed to recognize oligopyrimidine DNA sequences containing G-C base pailrs. We show here that calicheamicin also cuts efficiently at APT tracts, sometimes in preference to G-C-rich homopyrimidine tracts. Crystallographic data and experiments with chemical probes indicate that DNA sequences including GC base pairs have significantly different local conformations from DNA sequences containing several (four or more) sequential A-T base pairs. This difference makes it unlikely that calicheamicin simply senses inherent groove conformation and suggests that there is some degree of "induced fit." The ability to recognize both AFT-and G C-rich oligopyrimidine sequences with a high degree of specificity makes calicheamicin an unusual minor-groove binder.

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“…This strain is completely relieved by the enediyne undergoing the Bergman reaction, generating a highly reactive benzenoid diradical (12). The calicheamicin diradical abstracts hydrogen atoms from duplex DNA at the C-5' position of the cytidine in 5'-TCCT-3' and the C-4' position ofthe nucleotide three base pairs removed on the 3' side of the complementary strand (21,22), leading to cleavage of both strands of DNA. The mechanism of action of the structurally similar esperamicins is thought to be essentially the same as that of the calicheamicins.…”

mentioning

confidence: 99%