Redox equilibration after one-electron reduction of cytochrome c oxidase: Radical formation and a possible hydrogen relay mechanism

Ashe, Damian; Alleyne, Trevor; Wilson, Michael T.; Svistunenko, Dimitri A.; Nicholls, Peter

doi:10.1016/j.abb.2014.04.015

Cited by 5 publications

(7 citation statements)

References 49 publications

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“…that the transfer of electrons in biological systems occur preferentially through bonds rather than through space, we proposed that having arrived at Trp‐104, electrons travel to the binuclear CuA center by stepwise protonation/deprotonation of these conserved amino acids using a mechanism similar to that seen previously for chymotrypsin and subtilisin . We subsequently presented electron paramagnetic resonance (EPR) data captured during enzyme turnover, which detected the formation of one or more tyrosine and or tryptophan radicals in the early electron transfer steps of COX, providing support for the proposed electron relay mechanism . More recently , we conducted an analysis of the structure of the COX oxygen binding site.…”

Section: Introductionsupporting

confidence: 52%

Simulating the slow to fast switch in cytochrome c oxidase catalysis by introducing a loop flip near the enzyme's cytochrome c (substrate) binding site

Alleyne

Ignacio

Sampson

et al. 2017

Biotech and App Biochem

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The mitochondrial enzyme cytochrome c oxidase catalyzes the reduction of molecular oxygen in the critical step of oxidative phosphorylation that links the oxidation of food consumed to ATP production in cells. The enzyme catalyzes the reduction of oxygen at two vastly different rates that are thought to be linked to two different conformations but the conformation of the "fast enzyme" remains obscure. In this study, we demonstrated how oxygen binding at haem a3 could trigger long-distance conformational changes and then simulated a conformational change in an eight-residue loop near the enzyme's substrate (cytochrome c) binding site. We then used this modified cytochrome c oxidase (COX) to simulate a stable COX-cytochrome c enzyme-substrate (ES) complex. Compared to ES complexes formed in the absence of the conformation change, the distance between the redox centers of the two proteins was reduced by half and instead of nine, only four COX amino acid residues were found along the axis linking the electron entry point and the CuA redox center of COX: We proposed that intramolecular electron transfer in COX occurs via a charge/hydrogen relay system involving these four residues. We suggest that the conformational change and resulting shortened electron pathway are features of fast-acting COX.

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Section: Introductionsupporting

confidence: 52%

Simulating the slow to fast switch in cytochrome c oxidase catalysis by introducing a loop flip near the enzyme's cytochrome c (substrate) binding site

Alleyne

Ignacio

Sampson

et al. 2017

Biotech and App Biochem

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“…Furthermore, previous studies have established that the primary effect of ROS production involve peroxidation of lipid in biomembranes (plasma, mitochondria, nuclear and lysosomal membranes) (Ashe et al, 2014;Bhattacharya et al, 2014). Correspondingly, the threshold of ROS production and availability of radical scavengers (SOD, GSH and GPx) determines the extent of the lipid peroxidation observed in neural ischemic injuries.…”

Section: Oxygen-dependent Ros Productionmentioning

confidence: 98%

“…CcOX represents the complex V of the electron transport chain and is responsible for the conversion of molecular oxygen to water in the mitochondria (Ashe et al, 2014;Bhattacharya et al, 2014;Jethava et al, 2014). In addition, the binuclear center of CcOX has a high affinity for oxygen, and cyanide when present; such that CN À in the mitochondria binds the binuclear center and reduces the oxygen conversion capacity of CcOX.…”

Section: Oxygen-dependent Ros Productionmentioning

confidence: 99%

“…The cellular mechanism of ROS production in CN involve the ability of free cyanide (CN À ) to compete with oxygen for the binding site of CcOX Heme a3-Cu binuclear center (Ashe et al, 2014). CcOX represents the complex V of the electron transport chain and is responsible for the conversion of molecular oxygen to water in the mitochondria (Ashe et al, 2014;Bhattacharya et al, 2014;Jethava et al, 2014).…”

Section: Oxygen-dependent Ros Productionmentioning

confidence: 99%

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Differential oxidative stress thresholds distinguishes cellular response to vascular occlusion and chemotoxicityin vivo

Ogundele

Balogun

Cobham

et al. 2016

Drug and Chemical Toxicology

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Although CN and VO induced oxidative stress through ROS production, our findings suggest a difference in the threshold of ROS production and cytotoxicity for both forms of ischemia. However, this threshold is dependent on the availability of oxygen to fuel mitochondria-ROS production in oxidative stress. Ultimately, the difference in oxygen availability in vivo determined the significance of lipid peroxidation, calcium-shift and autophagic cell response associated with the ischemia. CN treatment generated more ROS and was associated with prominent cellular changes when compared with VO.

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“…Kinetic evidence suggests that the pair of copper ions, referred to as CuA, is the first of the Cox redox active centres to receive electrons (17). There is rapid equilibration of these electrons with a second centre, haem a, after which the electrons are transferred to oxygen via a third copper and a second haem but the sequence of events has not been agreed on (18)(19)(20)(21).…”

Section: Introductionmentioning

confidence: 99%

A Bio-computing Analysis of the Resting-to-pulsed Conformational Changes in Cytochrome c Oxidase

Alleyne¹,

Ignacio²,

Ashe³

et al. 2015

West Indian Med J

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Cytochrome c oxidase (Cox) accepts electrons from its substrate, cytochrome c and passes these to oxygen, which is reduced to water. Kinetic studies show that an active form of the enzyme (pulsed) and a slower form (resting) exists. More efficient internal electron transfer and the switching of the enzyme's oxygen/ligand binding site between opened and closed positions are said to account for the different rates of reduction. We employed bio-computing to analyse the structure of the oxygen/ligand binding site of bovine Cox under different redox states; a comparison with Thermus thermophilus Cox was also conducted. The study detected that the ligand binding site of Cox is exposed to the contents of the intermembrane space, and that the side chain of haem a 3 , located at the enzyme's oxygen/ligand binding site, approached Pro-69 and Ile-34 in faraway subunit-II. However, no open-to-closed gating structures were detected at the ligand binding site. We concluded that the resting-to-pulse transition in Cox does not involve opening-up of the ligand binding site. We propose that the rates of ligand/oxygen/cyanide binding are partly controlled by "queuing" near the binding site and that the binding of oxygen to haem a 3-CuB triggers the resting-to-pulsed transition via long-range conformational changes.

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Redox equilibration after one-electron reduction of cytochrome c oxidase: Radical formation and a possible hydrogen relay mechanism

Cited by 5 publications

References 49 publications

Simulating the slow to fast switch in cytochrome c oxidase catalysis by introducing a loop flip near the enzyme's cytochrome c (substrate) binding site

Simulating the slow to fast switch in cytochrome c oxidase catalysis by introducing a loop flip near the enzyme's cytochrome c (substrate) binding site

Differential oxidative stress thresholds distinguishes cellular response to vascular occlusion and chemotoxicityin vivo

A Bio-computing Analysis of the Resting-to-pulsed Conformational Changes in Cytochrome c Oxidase

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