Open AccessIdentification of the dihydrolipoamide acetyltransferase subunit of the human pyruvate dehydrogenase complex as an autoantigen in halothane hepatitis
Author(s) -
CHRISTEN Urs,
QUINN Janet,
YEAMAN Stephen J.,
KENNA J. Gerald,
CLARKE Janet B.,
GANDOLFI A. Jay,
GUT Josef
Publication year - 1994
Publication title -
european journal of biochemistry
Language(s) - English
Resource type - Journals
eISSN - 1432-1033
pISSN - 0014-2956
DOI - 10.1111/j.1432-1033.1994.tb19082.x
Subject(s) - pyruvate dehydrogenase complex , protein subunit , dihydrolipoyl transacetylase , pyruvate dehydrogenase phosphatase , dihydrolipoamide dehydrogenase , biochemistry , chemistry , halothane , enzyme , organic chemistry , gene
Trifluoroacetylated (CF 3 CO‐) proteins, elicited upon exposure of animals or humans to halothane, were recognized by anti‐CF 3 CO antibody, monospecific for the hapten derivative N 6 ‐trifluoroacetyl‐ l ‐lysine. Anti‐CF 3 CO 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 CF 3 CO‐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‐CF 3 CO antibody. Furthermore, based on a high degree of structural relatedness, both CF 3 CO‐Lys and (6 RS )‐lipoic acid, as well as the lipoylated peptide ETDK (lipoyl) ATIG specifically inhibited the recognition by anti‐CF 3 CO antibody of the E2 subunit of pyruvate dehydrogenase, of trifluoroacetylated rabbit serum albumin and of human liver CF 3 CO‐proteins. In sera of patients was halothane hepatitis, autoantibodies with properties identical to those of anti‐CF 3 CO antibody were identified which could not discriminate between CF 3 CO‐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 CF 3 CO‐proteins by the E2 subunit of pyruvate dehydrogenase is due to the similar structures of CF 3 CO‐Lys and lipoic acid.