Identification of the dihydrolipoamide acetyltransferase subunit of the human pyruvate dehydrogenase complex as an autoantigen in halothane hepatitis. Molecular mimicry of trifluoroacetyl-lysine by lipoic acid.
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.
Christen
U
U
Department of Pharmacology, Biocenter of the University, Basel, Switzerland.
Quinn
J
J
Yeaman
S J
SJ
Kenna
J G
JG
Clarke
J B
JB
Gandolfi
A J
AJ
Gut
J
J
D000123:Acetyltransferases / Q000276:immunology*; D000595:Amino Acid Sequence; D001324:Autoantigens / Q000276:immunology*; D001327:Autoimmune Diseases / Q000209:etiology / Q000276:immunology*; D001667:Binding, Competitive; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000276:immunology*; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; D000939:Epitopes / Q000276:immunology; D006221:Halothane / Q000009:adverse effects*; D006801:Humans; D015151:Immunoblotting; D008099:Liver / Q000201:enzymology / Q000276:immunology; D008239:Lysine / Q000031:analogs & derivatives / Q000737:chemistry / Q000276:immunology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000378:metabolism; D011768:Pyruvate Dehydrogenase Complex / Q000276:immunology*; D008063:Thioctic Acid / Q000737:chemistry / Q000276:immunology
D001324:Autoantigens; D000939:Epitopes; C072409:N-epsilon-trifluoro-lysine; D009842:Oligopeptides; D011768:Pyruvate Dehydrogenase Complex; C088853:glutamyl-threonyl-aspartyl-lysyl(lipoyl)alanyl-threonyl-isoleucyl-glycine; D008063:Thioctic Acid; D000123:Acetyltransferases; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; D008239:Lysine; D006221:Halothane