Christen U, Quinn J, Yeaman S J, Kenna J G, Clarke J B, Gandolfi A J, Gut J
Department of Pharmacology, Biocenter of the University, Basel, Switzerland.
Eur J Biochem. 1994 Aug 1;223(3):1035-47. doi: 10.1111/j.1432-1033.1994.tb19082.x.
Trifluoroacetylated (CF3CO-) proteins, elicited upon exposure of animals or humans to halothane, were recognized by anti-CF3CO antibody, monospecific for the hapten derivative N6-trifluoroacetyl-L-lysine. Anti-CF3CO antibodies cross-reacted with the dihydrolipoamide acetyltransferase (E2 subunit) of pyruvate dehydrogenase, indicating that epitopes on the E2 subunit of pyruvate dehydrogenase molecularly mimic those on CF3CO-proteins. Lipoic acid, the prosthetic group of the E2 subunit of pyruvate dehydrogenase was essential in this process, in that only the lipoylated form of the recombinantly expressed inner lipoyl domain of the human E2 subunit of pyruvate dehydrogenase, but not the unlipolyated form, was recognized by anti-CF3CO antibody. Furthermore, based on a high degree of structural relatedness, both CF3CO-Lys and (6RS)-lipoic acid, as well as the lipoylated peptide ETDK(lipoyl)ATIG specifically inhibited the recognition by anti-CF3CO antibody of the E2 subunit of pyruvate dehydrogenase, of trifluoroacetylated rabbit serum albumin and of human liver CF3CO-proteins. In sera of patients with halothane hepatitis, autoantibodies with properties identical to those of anti-CF3CO antibody were identified which could not discriminate between CF3CO-proteins and the E2 subunit of pyruvate dehydrogenase. These data suggest that the E2 subunit pyruvate of dehydrogenase is an autoantigen in halothane hepatitis and that molecular mimicry of CF3CO-proteins by the E2 subunit of pyruvate dehydrogenase is due to the similar structures of CF3CO-Lys and lipoic acid.
动物或人类接触氟烷后产生的三氟乙酰化（CF3CO-）蛋白可被抗CF3CO抗体识别，该抗体对半抗原衍生物N6-三氟乙酰-L-赖氨酸具有单特异性。抗CF3CO抗体与丙酮酸脱氢酶的二氢硫辛酰胺乙酰转移酶（E2亚基）发生交叉反应，表明丙酮酸脱氢酶E2亚基上的表位在分子水平上模拟了CF3CO-蛋白上的表位。硫辛酸作为丙酮酸脱氢酶E2亚基的辅基在这一过程中至关重要，因为只有重组表达的人丙酮酸脱氢酶E2亚基内部硫辛酰化结构域的硫辛酰化形式，而不是未硫辛酰化形式，能被抗CF3CO抗体识别。此外，基于高度的结构相关性，CF3CO-Lys和（6RS）-硫辛酸以及硫辛酰化肽ETDK（硫辛酰）ATIG均能特异性抑制抗CF3CO抗体对丙酮酸脱氢酶E2亚基、三氟乙酰化兔血清白蛋白和人肝脏CF3CO-蛋白的识别。在氟烷性肝炎患者的血清中，鉴定出了与抗CF3CO抗体性质相同的自身抗体，这些自身抗体无法区分CF3CO-蛋白和丙酮酸脱氢酶E2亚基。这些数据表明，丙酮酸脱氢酶E2亚基是氟烷性肝炎中的自身抗原，且丙酮酸脱氢酶E2亚基对CF3CO-蛋白的分子模拟是由于CF3CO-Lys和硫辛酸结构相似所致。
