Molecular Mimicry of CF3CO-Lysine by Lipoic Acid I: The Dihydrolipoamide Acetyltransferase Subunit of the Human Pyruvate Dehydrogenase as Autoantigen in Halothane Hepatitis

Abstract

Trifluoroaeetylated proteins (CF3CO-proteins), elicited in animals or humans exposed to halothane, were recognized by anti-CF3CO antibody, monospecific N6-trifluoroacetyl-L-lysine (CF3CO-Lys). Anti-CF3CO antibodies cross-reacted with the dihydrolipoamide acetyltransferase (E2 subunit) of pyruvate dehydrogenase (PDH), indicating that epitopes of the E2 subunit of PDH molecularly mimic those on CF3CO-proteins. Lipoic acid, the prosthetic group of the E2 subunit was essential in that only the lipoylated (Llip) form the recombinantly expressed inner lipoyl domain of the human E2 subunit, but not the unlipoylated (Ulip) form, was recognized by anti-CF3CO antibodies. Based on a high degree of structural relatedness, both CF3CO-Lys and (6RS)-lipoic acid, as well as the lipoylated peptide ETDK (lipoyl)ATIG, inhibited the recognition by anti-CF3CO-antibody of the E2 subunit of PDH 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 discriminiate between CF3CO-proteins and E2 subunit of PDH. These data suggest that the E2 subunit of PDH is an autoantigen in halothane hepatitis and that molecular mimicry of CF3CO-proteins by the E2 subunit of PDH is due to the similar structures of CF3CO-Lys and lipoic acid.