Institute for Translational Medicine, MSH Medical School Hamburg, Hamburg, Germany.
Evolutionary Biochemistry and Redox Medicine, Institute for Pathobiochemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
Free Radic Res. 2023 Feb;57(2):105-114. doi: 10.1080/10715762.2023.2201391. Epub 2023 Apr 19.
Lipid peroxidation is a biochemically adverse phenomenon with key involvement in many different diseases including premature infant blindness, nonalcoholic steatohepatitis, or Parkinson's disease. Moreover, lipid peroxidation may be the most important universal driver of the biological aging process. Canonic lipid peroxidation is a free radical chain reaction consisting of three kinetically independent steps, initiation, propagation, and termination. During the bulk propagation phase, only lipids and oxygen are consumed as substrates and maintain the chain reaction. In native biological membranes, however, lipid peroxidation takes place in direct vicinity to high concentrations of inserted membrane proteins with their exposed hydrophobic amino acid side chains. In the following, we review the evidence that redox-active intramembrane amino acid residues have a profound impact on the course and extent of lipid peroxidation . Specifically, tyrosine and tryptophan are concluded to be chain-breaking antioxidants that effectuate termination, whereas cysteine is a chain-transfer catalyst that accelerates propagation and thereby promotes lipid peroxidation. Methionine, in turn, is highly accumulated in mitochondrial membrane proteins of animal species with high metabolic rates and imminent danger of lipid peroxidation, though its specific role has not been entirely defined. Potentially, it interferes with initiation on the membrane protein surface. Nevertheless, all four residues are distinguished by their clear relevance to lipid peroxidation as deduced from either experimental or genetic and comparative data. The latter have uncovered distinct evolutionary pressures in favor or against each residue in lipid membranes and have shed light on formerly unacknowledged chemical mechanisms.
脂质过氧化是一种生化上不利的现象，它主要涉及许多不同的疾病，包括早产儿失明、非酒精性脂肪性肝炎或帕金森病。此外，脂质过氧化可能是生物衰老过程中最重要的普遍驱动因素。经典的脂质过氧化是一个自由基链式反应，由三个动力学上独立的步骤组成，即引发、传播和终止。在大量传播阶段，只有脂质和氧气作为底物被消耗，并维持链式反应。然而，在天然生物膜中，脂质过氧化发生在插入膜蛋白的高浓度附近，这些蛋白的暴露疏水性氨基酸侧链。在下面，我们回顾了证据表明，氧化还原活性的跨膜氨基酸残基对脂质过氧化的过程和程度有深远的影响。具体来说，酪氨酸和色氨酸被认为是终止链反应的链断裂抗氧化剂，而半胱氨酸是一种促进传播的链转移催化剂，从而促进脂质过氧化。另一方面，蛋氨酸在代谢率高且脂质过氧化风险高的动物物种的线粒体膜蛋白中高度积累，尽管其具体作用尚未完全确定。它可能会干扰膜蛋白表面的引发。然而，所有这四个残基都因其在脂质过氧化中的明显相关性而被区分开来，这是根据实验或遗传和比较数据推断出来的。后者揭示了在脂质膜中每个残基的有利或不利的独特进化压力，并阐明了以前未被承认的化学机制。
