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

Urs CHRISTEN, Janet QUINN, Stephen J. YEAMAN, J. Gerald KENNA, Janet B. CLARKE, A. Jay GANDOLFI, Josef GUT

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

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 unlipoylated 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 ETDKlipoylATIG 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 was 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.

Original languageEnglish (US)
Pages (from-to)1035-1047
Number of pages13
JournalEuropean Journal of Biochemistry
Volume223
Issue number3
DOIs
StatePublished - Aug 1994

ASJC Scopus subject areas

  • Biochemistry

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