Natural Engineering of Multi-Electron Biological Oxidation & Reduction

描述(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和能量转换。许多关键成员通过蛋白质在多纳米距离上排列辅因子，如氯素、血红素、铁硫簇、黄素、醌和金属，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、胞质蓝素)或两电子(黄素、醌和烟酰胺)或四电子(氧)的位置交换氧化和还原催化作用。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在从头开始构建的完全人工蛋白质中的实际组装来复制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的双电子催化末端，并在功能上连接这些链和末端。我们利用这些人造蛋白质的简单性和适应性，我们称之为Maquettes，以及它们不受天然蛋白质令人费解的复杂性和脆弱性的影响。这些模型形成了一种实验室，以揭示呼吸中自然电子转移系统正常运行期间的氧化新陈代谢和能量转换，生理运行期间对氧化损伤的脆弱性，以及在压力或疾病条件下的失败。我们还旨在弥合希望的生物灵感与实际复制之间的差距，在可用于人类需求的环境中，自然氧化还原酶具有显着的催化能力。

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.