Department of Pathology, Center for Free Radical Biology, University of Alabama at Birmingham, 35294, USA.
Biochem J. 2012 Mar 15;442(3):453-64. doi: 10.1042/BJ20111752.
The process of lipid peroxidation is widespread in biology and is mediated through both enzymatic and non-enzymatic pathways. A significant proportion of the oxidized lipid products are electrophilic in nature, the RLS (reactive lipid species), and react with cellular nucleophiles such as the amino acids cysteine, lysine and histidine. Cell signalling by electrophiles appears to be limited to the modification of cysteine residues in proteins, whereas non-specific toxic effects involve modification of other nucleophiles. RLS have been found to participate in several physiological pathways including resolution of inflammation, cell death and induction of cellular antioxidants through the modification of specific signalling proteins. The covalent modification of proteins endows some unique features to this signalling mechanism which we have termed the 'covalent advantage'. For example, covalent modification of signalling proteins allows for the accumulation of a signal over time. The activation of cell signalling pathways by electrophiles is hierarchical and depends on a complex interaction of factors such as the intrinsic chemical reactivity of the electrophile, the intracellular domain to which it is exposed and steric factors. This introduces the concept of electrophilic signalling domains in which the production of the lipid electrophile is in close proximity to the thiol-containing signalling protein. In addition, we propose that the role of glutathione and associated enzymes is to insulate the signalling domain from uncontrolled electrophilic stress. The persistence of the signal is in turn regulated by the proteasomal pathway which may itself be subject to redox regulation by RLS. Cell death mediated by RLS is associated with bioenergetic dysfunction, and the damaged proteins are probably removed by the lysosome-autophagy pathway.
脂质过氧化作用过程广泛存在于生物学中，并通过酶促和非酶促途径介导。氧化脂质产物的很大一部分具有亲电性，即 RLS（反应性脂质种类），并与细胞亲核试剂如半胱氨酸、赖氨酸和组氨酸反应。亲电物质的细胞信号似乎仅限于蛋白质中半胱氨酸残基的修饰，而非特异性毒性作用则涉及其他亲核试剂的修饰。RLS 已被发现参与几种生理途径，包括通过修饰特定信号蛋白来解决炎症、细胞死亡和诱导细胞抗氧化剂。蛋白质的共价修饰赋予了这种信号机制一些独特的特征，我们称之为“共价优势”。例如，信号蛋白的共价修饰允许信号随时间积累。亲电物质对细胞信号通路的激活是分层的，取决于亲电物质的固有化学反应性、其暴露的细胞内结构域和空间因素等复杂因素的相互作用。这引入了亲电信号域的概念，其中脂质亲电物的产生与含有巯基的信号蛋白紧密相邻。此外，我们提出谷胱甘肽和相关酶的作用是将信号域与不受控制的亲电应激隔离开来。信号的持久性反过来又受到蛋白酶体途径的调节，该途径本身可能受到 RLS 的氧化还原调节。RLS 介导的细胞死亡与生物能功能障碍有关，受损的蛋白质可能通过溶酶体自噬途径被清除。
