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The use of divalent metal ions by type II topoisomerases.

ABSTRACT: Type II topoisomerases are essential enzymes that regulate DNA under- and overwinding and remove knots and tangles from the genetic material. In order to carry out their critical physiological functions, these enzymes utilize a double-stranded DNA passage mechanism that requires them to generate a transient double-stranded break. Consequently, while necessary for cell survival, type II topoisomerases also have the capacity to fragment the genome. This feature of the prokaryotic and eukaryotic enzymes, respectively, is exploited to treat a variety of bacterial infections and cancers in humans. All type II topoisomerases require divalent metal ions for catalytic function. These metal ions function in two separate active sites and are necessary for the ATPase and DNA cleavage/ligation activities of the enzymes. ATPase activity is required for the strand passage process and utilizes the metal-dependent binding and hydrolysis of ATP to drive structural rearrangements in the protein. Both the DNA cleavage and ligation activities of type II topoisomerases require divalent metal ions and appear to utilize a novel variant of the canonical two-metal-ion phosphotransferase/hydrolase mechanism to facilitate these reactions. This article will focus primarily on eukaryotic type II topoisomerases and the roles of metal ions in the catalytic functions of these enzymes.

SUBMITTER: Deweese JE

PROVIDER: S-EPMC2918885 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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The use of divalent metal ions by type II topoisomerases.

Deweese Joseph E JE Osheroff Neil N

Metallomics : integrated biometal science 20100521 7

Type II topoisomerases are essential enzymes that regulate DNA under- and overwinding and remove knots and tangles from the genetic material. In order to carry out their critical physiological functions, these enzymes utilize a double-stranded DNA passage mechanism that requires them to generate a transient double-stranded break. Consequently, while necessary for cell survival, type II topoisomerases also have the capacity to fragment the genome. This feature of the prokaryotic and eukaryotic en ...[more]

PMID: 20703329

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Project description:Chelation complexes of the histidine-containing tripeptides HisAlaAla, AlaHisAla, and AlaAlaHis with Ni(II) and Cu(II) having a -1 net charge are characterized in the gas phase by infrared multiple-photon dissociation (IRMPD) spectroscopy and density functional theory calculations. We address the question of whether the gas-phase complexes carry over characteristics from the corresponding condensed-phase species. We focus particularly on three aspects of their structure: (i) square-planar chelation by the deprotonated amide nitrogens around the metal ion (low-spin for the Ni case), (ii) metal-ion coordination of the imidazole side chain nitrogen, and (iii) the exceptional preference for metal-ion chelation by peptides with His in the third position from the N-terminus, as in the amino terminal Cu and Ni (ATCUN) motif. We find that square-planar binding around the metal ion, involving bonds to both deprotonated backbone nitrogens, one of the carboxylate oxygens and the N-terminal nitrogen, is the dominant binding motif for all three isomers. In contrast to the condensed-phase behavior, the dominant mode of binding for all three isomers does not involve the imidazole side chain, which is instead placed outside the coordination zone. Only for the AlaAlaHis isomer, the imidazole-bound structure is also detected as a minority population, as identified from a distinctive short-wavelength IR absorption. The observation that this conformation exists only for AlaAlaHis correlates with condensed-phase behavior at neutral-to-basic pH, in the sense that the isomer with His in the third position is exceptionally disposed to metal ion chelation by four nitrogen atoms (4N) when compared with the other isomers. These results also emphasize the divergence between the conformational stabilities in the gas phase and in solution or crystalline environments: in the gas phase, direct metal binding of the imidazole is overall less favorable than the alternative of a remote imidazole that can act as an intramolecular H-bond donor enhancing the gas-phase stability.

Dataset Information

The use of divalent metal ions by type II topoisomerases.

Publications

The use of divalent metal ions by type II topoisomerases.

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