Dataset Information

Cytochrome aa3 Oxygen Reductase Utilizes the Tunnel Observed in the Crystal Structures To Deliver O2 for Catalysis.

ABSTRACT: Cytochrome aa3 is the terminal respiratory enzyme of all eukaryotes and many bacteria and archaea, reducing O2 to water and harnessing the free energy from the reaction to generate the transmembrane electrochemical potential. The diffusion of O2 to the heme-copper catalytic site, which is buried deep inside the enzyme, is the initiation step of the reaction chemistry. Our previous molecular dynamics (MD) study with cytochrome ba3, a homologous enzyme of cytochrome aa3 in Thermus thermophilus, demonstrated that O2 diffuses from the lipid bilayer to its reduction site through a 25 Å long tunnel inferred by Xe binding sites detected by X-ray crystallography [Mahinthichaichan, P., Gennis, R., and Tajkhorshid, E. (2016) Biochemistry 55, 1265-1278]. Although a similar tunnel is observed in cytochrome aa3, this putative pathway appears partially occluded between the entrances and the reduction site. Also, the experimentally determined second-order rate constant for O2 delivery in cytochrome aa3 (?108 M-1 s-1) is 10 times slower than that in cytochrome ba3 (?109 M-1 s-1). A question to be addressed is whether cytochrome aa3 utilizes this X-ray-inferred tunnel as the primary pathway for O2 delivery. Using complementary computational methods, including multiple independent flooding MD simulations and implicit ligand sampling calculations, we probe the O2 delivery pathways in cytochrome aa3 of Rhodobacter sphaeroides. All of the O2 molecules that arrived in the reduction site during the simulations were found to diffuse through the X-ray-observed tunnel, despite its apparent constriction, supporting its role as the main O2 delivery pathway in cytochrome aa3. The rate constant for O2 delivery in cytochrome aa3, approximated using the simulation results, is 10 times slower than in cytochrome ba3, in agreement with the experimentally determined rate constants.

SUBMITTER: Mahinthichaichan P

PROVIDER: S-EPMC5936630 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Cytochrome aa3 Oxygen Reductase Utilizes the Tunnel Observed in the Crystal Structures To Deliver O2 for Catalysis.

Mahinthichaichan Paween P Gennis Robert B RB Tajkhorshid Emad E

Biochemistry 20180329 14

Cytochrome aa3 is the terminal respiratory enzyme of all eukaryotes and many bacteria and archaea, reducing O2 to water and harnessing the free energy from the reaction to generate the transmembrane electrochemical potential. The diffusion of O2 to the heme-copper catalytic site, which is buried deep inside the enzyme, is the initiation step of the reaction chemistry. Our previous molecular dynamics (MD) study with cytochrome ba3, a homologous enzyme o ...[more]

PMID: 29546752

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Project description:Membrane cytochrome b5 reductase is a pleiotropic oxidoreductase that uses primarily soluble reduced nicotinamide adenine dinucleotide (NADH) as an electron donor to reduce multiple biological acceptors localized in cellular membranes. Some of the biological acceptors of the reductase and coupled redox proteins might eventually transfer electrons to oxygen to form reactive oxygen species. Additionally, an inefficient electron transfer to redox acceptors can lead to electron uncoupling and superoxide anion formation by the reductase. Many efforts have been made to characterize the involved catalytic domains in the electron transfer from the reduced flavoprotein to its electron acceptors, such as cytochrome b5, through a detailed description of the flavin and NADH-binding sites. This information might help to understand better the processes and modifications involved in reactive oxygen formation by the cytochrome b5 reductase. Nevertheless, more than half a century since this enzyme was first purified, the one-electron transfer process toward potential electron acceptors of the reductase is still only partially understood. New advances in computational analysis of protein structures allow predicting the intramolecular protein dynamics, identifying potential functional sites, or evaluating the effects of microenvironment changes in protein structure and dynamics. We applied this approach to characterize further the roles of amino acid domains within cytochrome b5 reductase structure, part of the catalytic domain, and several sensors and structural domains involved in the interactions with cytochrome b5 and other electron acceptors. The computational analysis results allowed us to rationalize some of the available spectroscopic data regarding ligand-induced conformational changes leading to an increase in the flavin adenine dinucleotide (FAD) solvent-exposed surface, which has been previously correlated with the formation of complexes with electron acceptors.

Dataset Information

Cytochrome aa3 Oxygen Reductase Utilizes the Tunnel Observed in the Crystal Structures To Deliver O2 for Catalysis.

Publications

Cytochrome aa<sub>3</sub> Oxygen Reductase Utilizes the Tunnel Observed in the Crystal Structures To Deliver O<sub>2</sub> for Catalysis.

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