School of Life Sciences, University of Essex, Wivenhoe Park, Colchester, Essex, CO4 3SQ, UK.
Mol Aspects Med. 2022 Apr;84:101045. doi: 10.1016/j.mam.2021.101045. Epub 2021 Oct 13.
Under those pathological conditions in which Myoglobin and Hemoglobin escape their cellular environments and are thus separated from cellular reductive/protective systems, the inherent peroxidase activities of these proteins can be expressed. This activity leads to the formation of the highly oxidizing oxo-ferryl species. Evidence that this happens in vivo is provided by the formation of a covalent bond between the heme group and the protein and this acts as an unambiguous biomarker for the presence of the oxo ferryl form. The peroxidatic activity also leads to the oxidation of lipids, the products of which can be powerful vasoconstrictive agents (e.g. isoprostanes, neuroprostanes). Here we review the evidence that lipid oxidation occurs following rhabdomyolysis and sub-arachnoid hemorrhage and that the products formed from arachidonic acid chains of phospholipids lead, through vasoconstriction, to kidney failure and brain vasospasm. Intervention in these pathological conditions through administration of reducing agents to remove ferryl heme is discussed. Through-protein electron transfer pathways that facilitate ferryl reduction at low reductant concentration have been identified. We conclude with consideration of the therapeutic use of Hemoglobin Based Oxygen carriers and how the toxicity of these may be reduced by engineering such electron transfer pathways into hemoglobin.
在肌红蛋白和血红蛋白从其细胞环境中逸出并因此与细胞还原/保护系统分离的病理条件下，这些蛋白质固有的过氧化物酶活性可以被表达。这种活性导致高度氧化的氧合铁物种的形成。体内发生这种情况的证据是血红素基团与蛋白质之间形成共价键，这是氧合铁形式存在的明确生物标志物。过氧化物酶活性也导致脂质的氧化，其产物可以是强大的血管收缩剂（例如，异前列腺素，神经前列腺素）。在这里，我们回顾了肌红蛋白尿和蛛网膜下腔出血后发生脂质氧化的证据，以及磷脂中花生四烯酸链形成的产物通过血管收缩导致肾衰竭和脑血管痉挛。通过向患者施用还原剂以去除铁血红素来干预这些病理条件的方法正在被讨论。已经确定了在低还原剂浓度下促进铁血红素还原的蛋白内电子转移途径。最后，我们考虑了血红蛋白基氧载体的治疗用途，以及如何通过工程设计将这些电子转移途径引入血红蛋白来降低其毒性。
