Spectroscopic Evidence for a Cobalt-Bound Peroxyhemiacetal Intermediate
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ABSTRACT:
SUBMITTER: Son Y
PROVIDER: S-EPMC8549039 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Copper-zinc superoxide dismutase (SOD) is of fundamental importance to our understanding of oxidative damage. Its primary function is catalysing the dismutation of superoxide to O(2) and H(2)O(2). SOD also reacts with H(2)O(2), leading to the formation of a strong copper-bound oxidant species that can either inactivate the enzyme or oxidise other substrates. In the presence of bicarbonate (or CO(2)) and H(2)O(2), this peroxidase activity is enhanced and produces the carbonate radical. This freely diffusible reactive oxygen species is proposed as the agent for oxidation of large substrates that are too bulky to enter the active site. Here, we provide direct structural evidence, from a 2.15 Å resolution crystal structure, of (bi)carbonate captured at the active site of reduced SOD, consistent with the view that a bound carbonate intermediate could be formed, producing a diffusible carbonate radical upon reoxidation of copper. The bound carbonate blocks direct access of substrates to Cu(I), suggesting that an adjunct to the accepted mechanism of SOD catalysed dismutation of superoxide operates, with Cu(I) oxidation by superoxide being driven via a proton-coupled electron transfer mechanism involving the bound carbonate rather than the solvent. Carbonate is captured in a different site when SOD is oxidised, being located in the active site channel adjacent to the catalytically important Arg143. This is the probable route of diffusion from the active site following reoxidation of the copper. In this position, the carbonate is poised for re-entry into the active site and binding to the reduced copper.
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Project description:The EutT enzyme from Listeria monocytogenes ( LmEutT) is a member of the family of ATP:cobalt(I) corrinoid adenosyltransferase (ACAT) enzymes that catalyze the biosynthesis of adenosylcobalamin (AdoCbl) from exogenous Co(II)rrinoids and ATP. Apart from EutT-type ACATs, two evolutionary unrelated types of ACATs have been identified, termed PduO and CobA. Although the three types of ACATs are nonhomologous, they all generate a four-coordinate cob(II)alamin (4C Co(II)Cbl) species to facilitate the formation of a supernucleophilic Co(I)Cbl intermediate capable of attacking the 5'-carbon of cosubstrate ATP. Previous spectroscopic studies of the EutT ACAT from Salmonella enterica ( SeEutT) revealed that this enzyme requires a divalent metal cofactor for the conversion of 5C Co(II)Cbl to a 4C species. Interestingly, LmEutT does not require a divalent metal cofactor for catalytic activity, which exemplifies an interesting phylogenetic divergence among the EutT enzymes. To explore if this disparity in the metal cofactor requirement among EutT enzymes correlates with differences in substrate specificity or the mechanism of Co(II)Cbl reduction, we employed various spectroscopic techniques to probe the interaction of Co(II)Cbl and cob(II)inamide (Co(II)Cbi+) with LmEutT in the absence and presence of cosubstrate ATP. Our data indicate that LmEutT displays a similar substrate specificity as SeEutT and can bind both Co(II)Cbl and Co(II)Cbi+ when complexed with MgATP, though it exclusively converts Co(II)Cbl to a 4C species. Notably, LmEutT is the most effective ACAT studied to date in generating the catalytically relevant 4C Co(II)Cbl species, achieving a >98% 5C → 4C conversion yield on the addition of just over one mol equiv of cosubstrate MgATP.
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Project description:Dacarbazine (DAC) 5-(3,3-dimethyl-1-triazenyl)imidazole-4-carboxamide is an imidazole-carboxamide derivative that is structurally related to purines. DAC belongs to the triazene compounds, which are a group of alkylating agents with antitumor and mutagenic properties. DAC is a non-cell cycle specific drug, active in all phases of the cellular cycle. In the frame of this work the 3d metal complexes (cobalt and copper) with dacarbazine were synthesized. Their spectroscopic properties by the use of FT-IR, FT-Raman, and 1HNMR were studied. The structures of dacarbazine and its complexes with copper(II) and cobalt(II) were calculated using DFT methods. The effect of metals on the electronic charge distribution of dacarbazine was discussed on the basis of calculated NBO atomic charges. The reactivity of metal complexes in relation to ligand alone was estimated on the basis of calculated energy of HOMO and LUMO orbitals. The aromaticity of the imidazole ring in dacarbazine and the complexes were compared (on the basis of calculated geometric indices of aromaticity). Thermal stability of the investigated 3d-metal complexes with dacarbazine and the products of their thermal decomposition were analyzed.
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Project description:The role of copper during the reoxidation of substrate-reduced amine oxidases by O(2) has not yet been definitively established. Both outer-sphere and inner-sphere pathways for the reduction of O(2) to H(2)O(2) have been proposed. A key step in the inner-sphere mechanism is the reaction of O(2) directly with the Cu(I) center of a Cu(I)-semiquinone intermediate. To thoroughly examine this possibility, we have measured the spectral changes associated with single-turnover reoxidation by O(2) of substrate-reduced Arthrobacter globiformis amine oxidase (AGAO) under a wide range of conditions. We have previously demonstrated that the internal electron-transfer reaction [Cu(II)-TPQ(AMQ) --> Cu(I)-TPQ(SQ)] (where TPQ(AMQ) is the aminoquinol form of reduced TPQ and TPQ(SQ) is the semiquinone form) occurs at a rate that could permit the reaction of O(2) with both species to be observed on the stopped-flow time scale [Shepard, E. M., and Dooley, D. M. (2006) J. Biol. Inorg. Chem. 11, 1039-1048]. The transient absorption spectra observed for the reaction of O(2) with substrate-reduced AGAO provide compelling support for the reaction of the Cu(I)-TPQ(SQ) form. Further, global analysis of the kinetics and the transient absorption spectra are fully consistent with an inner-sphere reaction of the Cu(I)-semiquinone intermediate with O(2) and are inconsistent with an outer-sphere mechanism for the reaction of the reduced enzyme with O(2).
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