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A water-soluble supramolecular complex that mimics the heme/copper hetero-binuclear site of cytochrome c oxidase.

ABSTRACT: In mitochondria, cytochrome c oxidase (CcO) catalyses the reduction of oxygen (O2) to water by using a heme/copper hetero-binuclear active site. Here we report a highly efficient supramolecular approach for the construction of a water-soluble biomimetic model for the active site of CcO. A tridentate copper(ii) complex was fixed onto 5,10,15,20-tetrakis(4-sulfonatophenyl)porphinatoiron(iii) (FeIIITPPS) through supramolecular complexation between FeIIITPPS and a per-O-methylated ?-cyclodextrin dimer linked by a (2,2':6',2''-terpyridyl)copper(ii) complex (CuIITerpyCD2). The reduced FeIITPPS/CuITerpyCD2 complex reacted with O2 in an aqueous solution at pH 7 and 25 °C to form a superoxo-type FeIII-O2-/CuI complex in a manner similar to CcO. The pH-dependent autoxidation of the O2 complex suggests that water molecules gathered at the distal Cu site are possibly involved in the FeIII-O2-/CuI superoxo complex in an aqueous solution. Electrochemical analysis using a rotating disk electrode demonstrated the role of the FeTPPS/CuTerpyCD2 hetero-binuclear structure in the catalytic O2 reduction reaction.

SUBMITTER: Kitagishi H

PROVIDER: S-EPMC5892347 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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A water-soluble supramolecular complex that mimics the heme/copper hetero-binuclear site of cytochrome c oxidase.

Kitagishi Hiroaki H Shimoji Daiki D Ohta Takehiro T Kamiya Ryo R Kudo Yasuhiro Y Onoda Akira A Hayashi Takashi T Weiss Jean J Wytko Jennifer A JA Kano Koji K

Chemical science 20180115 7

In mitochondria, cytochrome c oxidase (CcO) catalyses the reduction of oxygen (O2) to water by using a heme/copper hetero-binuclear active site. Here we report a highly efficient supramolecular approach for the construction of a water-soluble biomimetic model for the active site of CcO. A tridentate copper(ii) complex was fixed onto 5,10,15,20-tetrakis(4-sulfonatophenyl)porphinatoiron(iii) (FeIIITPPS) through supramolecular complexation between FeI ...[more]

PMID: 29675246

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Project description:UnlabelledCopper is an essential micronutrient used as a metal cofactor by a variety of enzymes, including cytochrome c oxidase (Cox). In all organisms from bacteria to humans, cellular availability and insertion of copper into target proteins are tightly controlled due to its toxicity. The major subunit of Cox contains a copper atom that is required for its catalytic activity. Previously, we identified CcoA (a member of major facilitator superfamily transporters) as a component required for cbb3-type Cox production in the Gram-negative, facultative phototroph Rhodobacter capsulatus. Here, first we demonstrate that CcoA is a cytoplasmic copper importer. Second, we show that bypass suppressors of a ccoA deletion mutant suppress cbb3-Cox deficiency by increasing cellular copper content and sensitivity. Third, we establish that these suppressors are single-base-pair insertion/deletions located in copA, encoding the major P1B-type ATP-dependent copper exporter (CopA) responsible for copper detoxification. A copA deletion alone has no effect on cbb3-Cox biogenesis in an otherwise wild-type background, even though it rescues the cbb3-Cox defect in the absence of CcoA and renders cells sensitive to copper. We conclude that a hitherto unknown functional interplay between the copper importer CcoA and the copper exporter CopA controls intracellular copper homeostasis required for cbb3-Cox production in bacteria like R. capsulatus.ImportanceCopper (Cu) is an essential micronutrient required for many processes in the cell. It is found as a cofactor for heme-copper containing cytochrome c oxidase enzymes at the terminus of the respiratory chains of aerobic organisms by catalyzing reduction of dioxygen (O2) to water. Defects in the biogenesis and copper insertion into cytochrome c oxidases lead to mitochondrial diseases in humans. This work shows that a previously identified Cu transporter (CcoA) is a Cu importer and illustrates the link between two Cu transporters, the importer CcoA and the exporter CopA, required for Cu homeostasis and Cu trafficking to cytochrome c oxidase in the cell.

Project description:Dioxygen reduction by heme-copper oxidases is a critical biochemical process, wherein hydrogen bonding is hypothesized to participate in the critical step involving the active-site reductive cleavage of the O-O bond. Sixteen novel synthetic heme-(μ-O2 2-)-Cu(XTMPA) complexes, whose design is inspired by the cytochrome c oxidase active site structure, were generated in an attempt to form the first intramolecular H-bonded complexes. Derivatives of the "parent" ligand (XTMPA, TMPA = (tris((2-pyridyl)methyl)amine)) possessing one or two amine pendants preferentially form an H-bond with the copper-bound O-atom of the peroxide bridge. This is evidenced by a characteristic blue shift in the ligand-to-metal charge transfer (LMCT) bands observed in UV-vis spectroscopy (consistent with lowering of the peroxo π* relative to the iron orbitals) and a weakening of the O-O bond determined by resonance Raman spectroscopy (rR), with support from Density Functional Theory (DFT) calculations. Remarkably, with the TMPA-based infrastructure (versus similar heme-peroxo-copper complexes with different copper ligands), the typically undetected Cu-O stretch for these complexes was observed via rR, affording critical insights into the nature of the O-O peroxo core for the complexes studied. While amido functionalities have been shown to have greater H-bonding capabilities than their amino counterparts, in these heme-peroxo-copper complexes amido substituents distort the local geometry such that H-bonding with the peroxo core only imparts a weak electronic effect; optimal H-bonding interactions are observed by employing two amino groups on the copper ligand. The amino-substituted systems presented in this work reveal a key orientational anisotropy in H-bonding to the peroxo core for activating the O-O bond, offering critical insights into effective O-O cleavage chemistry. These findings indirectly support computational and protein structural studies suggesting the presence of an interstitial H-bonding water molecule in the CcO active site, which is critical for the desired reactivity. The results are evaluated with appropriate controls and discussed with respect to potential O2-reduction capabilities.

Dataset Information

A water-soluble supramolecular complex that mimics the heme/copper hetero-binuclear site of cytochrome c oxidase.

Publications

A water-soluble supramolecular complex that mimics the heme/copper hetero-binuclear site of cytochrome <i>c</i> oxidase.

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