How do reactive oxygen species affect the active sites of metalloproteins?

随着有氧环境的出现，生物体被迫制定策略来应对暴露于分子氧（O2）和被称为活性氧（ROS）的高活性O2衍生物的有害影响。几种含有过渡金属络合物的金属蛋白对分子O2表现出高灵敏度。对酶破坏的机制研究仅限于少数几个例子，如蛋白质乌头酸酶或富马酸硝酸还原酶调节剂（FNR）。含有更复杂的金属络合物的酶，如固氮酶和氢化酶，也会很快被双氧破坏，但由于它们的复杂性，获得对其反应性的结构见解更具挑战性。在现有的三种氢化酶中，[FeFe]氢化酶表现出最高的产氢催化活性，但同时也具有最高的O2-敏感性。在所提出的项目中，O2诱导的[FeFe]氢化酶活性位点的失活将在理论和实验科学家之间的协同合作中得到阐明。一个系统的方法来氧诱导抑制的一般问题，需要一个详细的理论理解所涉及的反应事件和发展合适的计算方法，在音乐会与实验验证打开了一个定制的，更氧稳定的酶的路径。

With the emergence of an aerobic atmosphere, organisms were forced to develop strategies to deal with the deleterious effects of exposition to dioxygen (O2) and highly reactive O2 derivatives designated as reactive oxygen species (ROS). Several metalloproteins which contain transition metal complexes exhibit a high sensitivity against molecular O2. Mechanistic studies on the enzyme destruction are restricted to only a few examples like the proteins aconitase or the fumarate nitrate reductase regulator (FNR). Enzymes that contain more intricate metal complexes like nitrogenases and hydrogenase are also quickly destroyed by dioxygen but due to their complexity it is more challenging to obtain structural insights into their reactivity. Out of the three existing hydrogenase classes, [FeFe] hydrogenases exhibit the highest catalytical activity for hydrogen production but at the same time also the highest O2-sensitivity. In the presented project the O2 induced inactivation of the [FeFe] hydrogenase active site will be elucidated in a synergistic cooperation between theoretical and experimental scientists. A systematical approach to the general problem of oxygen induced inhibition requires a detailed theoretical understanding of the reaction events involved and the development of suitable computational methods that in concert with experimental verification opens the path to a tailored, more oxygen stable enzyme.