Natural Engineering of Multi-Electron Biological Oxidation & Reduction

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DESCRIPTION (provided by applicant): The oxidoreductase superfamily is responsible for a very broad range of oxidative and reductive chemical transformations and energy conversions throughout biology. Many key members align cofactors such as chlorins, hemes, iron-sulfur clusters, flavins, quinones and metals to form single-electron-transfer chains through protein over multi-nanometer distances. At their termini, electrons exchange with sites of diffusible one-electron carriers (e. g. cytochrome c, plastocyanin) or sites of two-electron (flavin, quinone and nicotinamide) or four-electron (oxygen) oxidative and reductive catalysis. With the common catalytic features and a shared electron-tunneling engineering understood to a useful practical level, we have learned how to reproduce selected natural oxidoreductases functions by practical assembly in completely artificial proteins built from scratch. We are now poised to assemble the components into extended single-electron-transfer chains, to construct operating two-electron catalytic termini akin to those seen in Nature, and to functionally connect these chains and termini. We exploit the simplicity and adaptability of these artificial proteins we call maquettes, and their freedom from the obscuring complexity and fragility of natural proteins. The maquettes form a type of laboratory to uncover new insights into oxidative metabolism and energy conversion during normal operation of natural electron-transfer systems in respiration, into the vulnerabilities to oxidative damage during physiological operation and into their failure under conditions of stress or disease. We also aim to bridge the gap between hopeful bio-inspiration and the reality of practical reproduction of the remarkable catalytic capability of natural oxidoreductases in settings that can be put to work for human needs.