Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 26, Pages 10603-10608Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0903809106
Keywords
computational biochemistry; enzymology; flavin; oxygen reactivity
Categories
Funding
- National Science Foundation [PHY-0822283]
- National Institutes of Health
- Howard Hughes Medical Institute
- American Chemical Society Petroleum Research Fund [46271-C4]
- Ministero dell'Istruzione
- dell'Universita e della Ricerca
- EU-FP7
- Carbohydrate Research Center Wageningen
- Thailand Research Fund [BRG5180002]
- Faculty of Science
- Mahidol University
- Institute for the Promotion of Teaching Science and Technology
- Royal Golden Jubilee PhD Program [PHD/0008/2549]
- Dutch Technology Foundation Stichting Technische Wetenschappen [7726]
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek applied science division
- Technology Program of the Ministry of Economic Affairs
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Dioxygen (O-2) and other gas molecules have a fundamental role in a variety of enzymatic reactions. However, it is only poorly understood which O-2 uptake mechanism enzymes employ to promote efficient catalysis and how general this is. We investigated O-2 diffusion pathways into monooxygenase and oxidase flavoenzymes, using an integrated computational and experimental approach. Enhanced-statistics molecular dynamics simulations reveal spontaneous protein-guided O-2 diffusion from the bulk solvent to preorganized protein cavities. The predicted protein-guided diffusion paths and the importance of key cavity residues for oxygen diffusion were verified by combining site-directed mutagenesis, rapid kinetics experiments, and high-resolution X-ray structures. This study indicates that monooxygenase and oxidase flavoenzymes employ multiple funnel-shaped diffusion pathways to absorb O-2 from the solvent and direct it to the reacting C4a atom of the flavin cofactor. The difference in O-2 reactivity among dehydrogenases, monooxygenases, and oxidases ultimately resides in the fine modulation of the local environment embedding the reactive locus of the flavin.
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