Natural Engineering of Multi-Electron Biological Oxidation & Reduction

描述（由申请人提供）：氧化还原酶超家族在整个生物学中负责非常广泛的氧化和还原化学转化以及能量转换。许多关键分子将辅助因子如氯、血红素、铁硫簇、黄素、醌和金属排列在一起，在多纳米距离上通过蛋白质形成单电子转移链。在它们的末端，电子与可扩散的单电子载体（如细胞色素c、质体青素）或双电子载体（黄素、醌和烟酰胺）或四电子载体（氧）进行氧化和还原催化交换。随着共同的催化特征和共享的电子隧道工程被理解到一个有用的实用水平，我们已经学会了如何通过从头构建的完全人工蛋白质的实际组装来重现选定的天然氧化还原酶功能。我们现在准备将这些组件组装成扩展的单电子转移链，构建类似于自然界中看到的操作双电子催化终端，并在功能上连接这些链和终端。我们利用这些人造蛋白质的简单性和适应性，我们称之为小模型，它们不像天然蛋白质那样复杂和脆弱。这些模型形成了一种实验室形式，揭示了呼吸过程中自然电子传递系统正常运行时氧化代谢和能量转换的新见解，揭示了生理操作过程中氧化损伤的脆弱性，以及它们在应激或疾病条件下的失效。我们还旨在弥合希望的生物灵感与自然氧化还原酶在可用于人类需求的环境中显着催化能力的实际再现的现实之间的差距。

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. PUBLIC HEALTH RELEVANCE: Reproduction of natural enzyme function in a man-made material remains a major challenge to biological chemists. The benefits of such achievement include the development of new medical interventions, and clinical devices, and an array of new inexpensive green catalysts important in ecology, agriculture and solar energy conversions.