Functional Active-Site Models of Cytochrome c Oxidase

描述(申请人提供)：我们体内的大部分能量是通过称为氧化磷酸化的呼吸过程在线粒体内产生的。这种能量来源于氧气的活化和还原。这种四电子还原过程是由呼吸末端酶--细胞色素c氧化酶(CcO)催化的。重要的医学疾病与氧/能量代谢有关。氧化应激在许多疾病的病理中都很重要，如神经系统疾病、阿尔茨海默病、中风、心血管疾病和细胞死亡。引起炎症和细胞损伤的活性氧物种主要是在线粒体中形成的！新陈代谢。人类消耗的氧气有95%以上用于呼吸。在线粒体中，酶促产生的还原当量(电子)与氧气在一系列电子转移反应中发生反应，形成质子梯度，最终产生生物能源货币三磷酸腺苷。释放能量的电子/质子转移到分子氧与其他质子通过线粒体膜的转移相耦合。随后通过ATPase的这种质子梯度的松弛提供了ATP中的能量存储。氧的4电子还原以惊人的速度发生；每秒可以转化多达250个氧分子(1000个电子)。该项目旨在发明和合成模拟CcO中活性中心的化合物。这些化合物具有接近的血红素和铜，其功能类似于酶，在生理条件下催化分子氧的电化学还原，而不释放活性氧物种，如超氧化物和过氧化氢。通过仔细研究这些合成的功能性酶模拟还原氧气的机制，我们打算对描述酶本身功能的机制有一个了解。铜离子(CuB)和氨基酸酪氨酸(Tyr244)中的酚基在CcO的催化功能中所起的作用是特别有趣的。

DESCRIPTION (provided by applicant): Most of the energy in our bodies is generated within the mitochondria by a respiratory process called oxidative phosphorylation. This energy derives from the activation and reduction of dioxygen. This four-electron reduction process is catalyzed by the terminal respiratory enzyme, cytochrome c oxidase (CcO). Important medical disorders are related to oxygen/energy metabolism. Oxidative stress is important in the pathology of many diseases, such as those of the nervous system, Alzheimer's disease, stroke, cardiovascular disorders, and cell death. The reactive oxygen species, which cause inflammation and cell damage, are primarily formed during mitochondria! metabolism. Over 95 percent of the oxygen consumed by humans is used in respiration. In the mitochondria, reducing equivalents (electrons) derived enzymatically from food, react with dioxygen in a series of electron-transfer reactions to develop a proton gradient that ultimately produces ATP, the biological energy currency. Energy releasing electron/proton transfers to molecular oxygen are coupled to the transfer of other protons across the mitochondrial membrane. Subsequent relaxation of this proton gradient through ATPase provides energy storage in ATP. This 4-electron reduction of dioxygen occurs at remarkably fast rates; up to 250 dioxygen molecules (1000 electrons) can be transformed per second. This project is directed towards the invention and synthesis of compounds that imitate the active site in CcO. These compounds, which have a heme and a copper in close proximity, are intended to function like the enzyme by catalyzing the electrochemical reduction of molecular oxygen under physiological conditions without releasing reactive oxygen species such as superoxide and hydrogen peroxide. Through careful study of the mechanisms by which these synthetic, functional enzyme-mimics, reduce dioxygen, we intend to gain an understanding of the mechanisms that describe the function of the enzyme itself. The role that the copper ion (CuB) and a phenolic group, in the amino acid tyrosine (Tyr244) play in the catalytic function of CcO are of particular interest.