Department of Experimental Medicine and Biochemical Sciences, University of Rome TorVergata, via Montpellier 1, 00133 Rome, Italy.
Arch Biochem Biophys. 2012 Jun 1;522(1):62-9. doi: 10.1016/j.abb.2012.03.028. Epub 2012 Apr 9.
A further function of cytochrome c (cyt c), beyond respiration, is realized outside mitochondria in the apoptotic program. In the early events of apoptosis, the interaction of cyt c with a mitochondrion-specific phospholipid, cardiolipin (CL), brings about a conformational transition of the protein and acquirement of peroxidase activity. The hallmark of cyt c with peroxidase activity is its partial unfolding accompanied by loosening of the Fe sixth axial bond and an enhanced access of the heme catalytic site to small molecules like H2O2. To investigate the peroxidase activity of non-native cyt c, different forms of the protein were analyzed with the aim to correlate their structural features with the acquired enzymatic activity and apoptogenic properties (wt cyt c/CL complex and two single cyt c variants, H26Y and Y67H, free and bound to CL). The results suggest that cyt c may respond to different environments by changing its fold thus favouring the exertion of different biological functions in different pathophysiological cell conditions. Transitions among different conformations are regulated by endogenous molecules such as ATP and may be affected by synthetic molecules such as minocycline, thus suggesting a mechanism explaining its use as therapeutic agent impacting on disease-associated oxidative and apoptotic mechanisms.
细胞色素 c（cyt c）除了呼吸作用之外，还有一个功能，就是在线粒体之外的凋亡程序中发挥作用。在细胞凋亡的早期事件中，cyt c 与一种线粒体特异性磷脂，心磷脂（CL）的相互作用导致蛋白质构象发生转变，并获得过氧化物酶活性。具有过氧化物酶活性的 cyt c 的标志是其部分展开，同时伴随着 Fe 第六轴向键的松动和血红素催化位点对小分子（如 H2O2）的更容易接近。为了研究非天然 cyt c 的过氧化物酶活性，分析了不同形式的蛋白质，目的是将其结构特征与获得的酶活性和促凋亡特性（wt cyt c/CL 复合物和两种单独的 cyt c 变体，H26Y 和 Y67H，游离和与 CL 结合）相关联。结果表明，cyt c 可能通过改变其折叠来响应不同的环境，从而有利于在不同的病理生理细胞条件下发挥不同的生物学功能。不同构象之间的转变受内源性分子（如 ATP）调节，并且可能受到合成分子（如米诺环素）的影响，这表明一种解释其作为治疗剂影响与疾病相关的氧化和凋亡机制的机制。
