Structures of HO2-Co(III)bleomycin A2 bound to d(GAGCTC)2 and d(GGAAGCTTCC)2: structure–reactivity relationships of Co and Fe bleomycins

Zhao, Chunqing; Xia, Chuanwu; Mao, Qunkai; Försterling, Holger; DeRose, Eugene F.; Antholine, William E.; Subczynski, Witold K.; Petering, David H.

doi:10.1016/s0162-0134(02)00420-8

Cited by 30 publications

(58 citation statements)

References 44 publications

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“…The initial Cartesian coordinates were taken from NMR structures [PDB 1GJ2 (43) and 1MXK (27)] of ðBLMÞCo III ─OOH, and the Co was replaced by Fe and the nature of the axial ligand was varied as described below. The DNA binding domain and carbohydrate domain (Fig.…”

Section: Methodsmentioning

confidence: 99%

“…S1. α conformation was found in one NMR structure of ðBLMÞCo III ─OOH (43) and the β conformation was found in one NMR structure (27) and a crystal structure (7) of ðBLMÞCo III ─OOH. The nomenclature used here is such that OH-90-syn-α describes a BLM model with OH − as the axial ligand with θ ¼ 90°, syn orientation of the amide in methylvalerate, and the α conformation of the axial chelate.…”

Section: Methodsmentioning

confidence: 99%

“…Starting from the NMR structure of ðBLMÞCo III ─OOH (PDB ID 1MXK) (27) as an initial structual model of ABLM, the first shell of the EXAFS data was systematically fit to determine the coordination number and shell splitting pattern. Fit values are listed in SI Appendix: Table S3.…”

Section: Ablm Exafsmentioning

confidence: 99%

“…Based on the final overall error, the first shell is best fit to a 1∶5 split coordination with a short distance of 1.87 Å, indicating that ABLM also has a short (27), which has an α axial chelate conformation (see SI Appendix: Fig. S1).…”

Section: Ablm Exafsmentioning

confidence: 99%

“…A ðBLMÞFe III ðη 1 -OOHÞ model, OOH-69-syn-α, was optimized based on the NMR structure of ðBLMÞCo III ─OOH (PDB ID 1MXK) (27). Four additional models of ðBLMÞFe III ðη 1 -OOHÞ were also obtained, based on optimizations of the three structural perturbations in the computational details in SI Appendix.…”

Section: Ablm Exafsmentioning

confidence: 99%

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Definition of the intermediates and mechanism of the anticancer drug bleomycin using nuclear resonance vibrational spectroscopy and related methods

Liu

Bell

Wong

et al. 2010

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

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Bleomycin (BLM) is a glycopeptide anticancer drug capable of effecting single-and double-strand DNA cleavage. The last detectable intermediate prior to DNA cleavage is a low spin Fe III peroxy level species, termed activated bleomycin (ABLM). DNA strand scission is initiated through the abstraction of the C-4′ hydrogen atom of the deoxyribose sugar unit. Nuclear resonance vibrational spectroscopy (NRVS) aided by extended X-ray absorption fine structure spectroscopy and density functional theory (DFT) calculations are applied to define the natures of Fe III BLM and ABLM as ðBLMÞFe III ─ OH and ðBLMÞFe III ðη 1 ─OOHÞ species, respectively. The NRVS spectra of Fe III BLM and ABLM are strikingly different because in ABLM the δFe─O─O bending mode mixes with, and energetically splits, the doubly degenerate, intense O─Fe─N ax transaxial bends. DFT calculations of the reaction of ABLM with DNA, based on the species defined by the NRVS data, show that the direct H-atom abstraction by ABLM is thermodynamically favored over other proposed reaction pathways.nonheme iron | structure/reactivity T he glycopeptide antibiotic bleomycin (BLM) exhibits high intrinsic anticancer cytotoxicity, and is used in chemotherapy against head, neck, and testicular cancers as well as Hodgkin lymphoma (1, 2). Its cytotoxicity is due to its ability to effect singleand double-strand cleavage of DNA with a number of reduced metal ions and dioxygen (3-5); Fe II displays the highest in vivo activity (6). BLM provides five nitrogen-based ligands ( Fig. 1 A and B) for coordination to the metal ion based on a crystal structure of peroxy Co III BLM (7). The four equatorial ligands are an imidazole nitrogen, a deprotonated amide, a pyrimidine nitrogen, and the secondary amine of the β-aminoalanine. The axial ligand is the primary amine of the β-aminoalanine.Activated BLM (ABLM) is the final intermediate detected before DNA double-strand scission (8). ABLM is proposed to be a low spin (ls) Fe III ─OOH species (9-11), that can be formed via the reaction of Fe III BLM with O 2 and an electron or through a shunt reaction between Fe III BLM and H 2 O 2 (8, 12).A prominent issue has been whether ABLM, a nonheme iron complex, performs heme type chemistry similar to P450 and peroxidase in which heterolytic cleavage of the O─O bond results in an Fe IV species with a radical on the BLM ligand. Experiments and calculations have argued against this heterolytic mechanism and suggested a mechanism where ABLM reacts directly in H-atom abstraction from the DNA backbone sugar (10,13,14). However, a recent theoretical study has postulated that ABLM formation involves reaction of the ðBLMÞFe III ─OH 2 complex with H 2 O 2 to form a ðBLMÞFe III ─O 2 H 2 complex (15). This study found the heterolytic cleavage pathway for the ðBLMÞFe III ─ H 2 O 2 complex to be thermoneutral and therefore feasible. Because ABLM is inaccessible to vibrational characterization by resonance Raman (rR) spectroscopy due to photodecay (16), we employed nuclear resonance vibrational spectroscopy (...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Ablm Exafsmentioning

confidence: 99%

Section: Ablm Exafsmentioning

confidence: 99%

Section: Ablm Exafsmentioning

confidence: 99%

See 3 more Smart Citations

Definition of the intermediates and mechanism of the anticancer drug bleomycin using nuclear resonance vibrational spectroscopy and related methods

Liu

Bell

Wong

et al. 2010

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

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Oxidative DNA Damage Mediated by Transition Metal Ions and Their Complexes

Pratviel

2011

Metal Ions in Life Sciences

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DNA damage by redox-active metal complexes depends on the interaction of the metal complex with DNA together with the mechanism of oxygen activation. Weak interaction, tight binding, and direct involvement of DNA in the coordination sphere of the metal are described. Metal complexes acting through the production of diffusing radicals and metal complexes oxidizing DNA by metal-centered active species are compared. Metal complexes able to form high-valent metal-oxo species in close contact with DNA and perform DNA oxidation in a way reminiscent of enzymatic chemistry are the most elegant systems.

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The metal bonding domain of the antitumor drug Fe(II)-bleomycin: a DFT investigation

Karawajczyk

Buda

2004

J Biol Inorg Chem

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The geometric and electronic structure of ferrous complexes of bleomycin (Fe(II)BLM) has been investigated by means of density functional theory (DFT) calculations. The active site of this antitumor drug is a highly distorted octahedral complex, with the coordination sphere completed by the five known endogenous ligands, including pyrimidine, imidazole, deprotonated amide, and secondary and primary amines. We have addressed the controversial issue of the nature of the sixth axial ligand, which we have identified as the oxygen of the carbamoyl group. Our conclusions are further validated by a comparison with structural data derived from NMR experiments. Moreover, because of the high sensitivity of structural data on the pH of the environment, we have investigated the effect of a different protonation state of the histidine amide on the geometric structure of the Fe(II)BLM complex. The extensive model of the active site of bleomycin considered in this work allows us to check the limitations of previous investigations based on simplified models.

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Structures of HO2-Co(III)bleomycin A2 bound to d(GAGCTC)2 and d(GGAAGCTTCC)2: structure–reactivity relationships of Co and Fe bleomycins

Cited by 30 publications

References 44 publications

Definition of the intermediates and mechanism of the anticancer drug bleomycin using nuclear resonance vibrational spectroscopy and related methods

Definition of the intermediates and mechanism of the anticancer drug bleomycin using nuclear resonance vibrational spectroscopy and related methods

Oxidative DNA Damage Mediated by Transition Metal Ions and Their Complexes

The metal bonding domain of the antitumor drug Fe(II)-bleomycin: a DFT investigation

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