The lipoic acid containing components of the 2-oxoacid dehydrogenase complexes mimic trifluoroacetylated proteins and are autoantigens associated with halothane hepatitis

Nora Frey, Urs Christen, Paul Jenö, Stephen J. Yeaman, Yoshiharu Shimomura, J. Gerald Kenna, A. Jay Gandolfi, A Jay Gandolfi, Josef Gut

Research output: Contribution to journalArticle

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Abstract

Anti-CF3CO antibodies, monospecific toward trifluoroacetylated proteins (CF3CO-proteins), which are elicited in experimental animals and humans exposed to the anesthetic agent halothane, cross-react with an unknown protein of approximately 52 kDa, constitutively expressed in tissues of experimental animals and humans not previously exposed to the agent. Using anti-CF3CO antibody, the protein(s) of 52 kDa could be immunoprecipitated from solubilized rat heart homogenate. Two-dimensional gel electrophoretic analysis revealed the presence of distinct major (P1, P2) and minor (P3, P4, P5) protein components with apparent molecular masses of 52 kDa. From each of the components P1 and P2, the amino acid sequences of three peptides were determined and found to exhibit 100% identity with the corresponding amino acid sequences of the E2 subunit of the rat 2-oxoglutarate dehydrogenase complex (OGDC). Additionally to the E2 subunit of OGDC, anti-CF3CO antibody also recognized on immunoblots the purified E2 subunit of the branched chain 2-oxoacid dehydrogenase complex (BCOADC) and protein X, a constituent of the pyruvate dehydrogenase complex (PDC), in a manner sensitive to competition N6-(trifluoroacetyl)-L-lysine (CF3CO-Lys), 6(RS)-lipoic acid, and N6(6(RS)-lipoyl)-L-lysine (lipoyl-Lys). Furthermore, a discrete population of autoantibodies was identified in sera of patients with halothane hepatitis which could not discriminate between the lipoylated target epitope present on the E2 subunit of OGDC and epitopes on CF3CO-RSA, used as model for CF3CO-proteins. These data suggest that the autoantigenicity of these proteins in halothane hepatitis is based on the molecular mimicry of CF3CO-LyS by lipoic acid, the prosthetic group common to protein X and the E2 subunits of OGDC and BCOADC.

Original languageEnglish (US)
Pages (from-to)736-746
Number of pages11
JournalChemical Research in Toxicology
Volume8
Issue number5
StatePublished - 1995

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Keto Acids
Thioctic Acid
Autoantigens
Halothane
Oxidoreductases
Ketoglutarate Dehydrogenase Complex
Proteins
Anti-Idiotypic Antibodies
Lysine
Rats
Epitopes
Amino Acid Sequence
Animals
Pyruvate Dehydrogenase Complex
Molecular Mimicry
Halothane Hepatitis
Amino Acids
Molecular mass
Prosthetics
Autoantibodies

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Chemistry(all)
  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

The lipoic acid containing components of the 2-oxoacid dehydrogenase complexes mimic trifluoroacetylated proteins and are autoantigens associated with halothane hepatitis. / Frey, Nora; Christen, Urs; Jenö, Paul; Yeaman, Stephen J.; Shimomura, Yoshiharu; Gerald Kenna, J.; Jay Gandolfi, A.; Gandolfi, A Jay; Gut, Josef.

In: Chemical Research in Toxicology, Vol. 8, No. 5, 1995, p. 736-746.

Research output: Contribution to journalArticle

Frey, Nora ; Christen, Urs ; Jenö, Paul ; Yeaman, Stephen J. ; Shimomura, Yoshiharu ; Gerald Kenna, J. ; Jay Gandolfi, A. ; Gandolfi, A Jay ; Gut, Josef. / The lipoic acid containing components of the 2-oxoacid dehydrogenase complexes mimic trifluoroacetylated proteins and are autoantigens associated with halothane hepatitis. In: Chemical Research in Toxicology. 1995 ; Vol. 8, No. 5. pp. 736-746.
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abstract = "Anti-CF3CO antibodies, monospecific toward trifluoroacetylated proteins (CF3CO-proteins), which are elicited in experimental animals and humans exposed to the anesthetic agent halothane, cross-react with an unknown protein of approximately 52 kDa, constitutively expressed in tissues of experimental animals and humans not previously exposed to the agent. Using anti-CF3CO antibody, the protein(s) of 52 kDa could be immunoprecipitated from solubilized rat heart homogenate. Two-dimensional gel electrophoretic analysis revealed the presence of distinct major (P1, P2) and minor (P3, P4, P5) protein components with apparent molecular masses of 52 kDa. From each of the components P1 and P2, the amino acid sequences of three peptides were determined and found to exhibit 100{\%} identity with the corresponding amino acid sequences of the E2 subunit of the rat 2-oxoglutarate dehydrogenase complex (OGDC). Additionally to the E2 subunit of OGDC, anti-CF3CO antibody also recognized on immunoblots the purified E2 subunit of the branched chain 2-oxoacid dehydrogenase complex (BCOADC) and protein X, a constituent of the pyruvate dehydrogenase complex (PDC), in a manner sensitive to competition N6-(trifluoroacetyl)-L-lysine (CF3CO-Lys), 6(RS)-lipoic acid, and N6(6(RS)-lipoyl)-L-lysine (lipoyl-Lys). Furthermore, a discrete population of autoantibodies was identified in sera of patients with halothane hepatitis which could not discriminate between the lipoylated target epitope present on the E2 subunit of OGDC and epitopes on CF3CO-RSA, used as model for CF3CO-proteins. These data suggest that the autoantigenicity of these proteins in halothane hepatitis is based on the molecular mimicry of CF3CO-LyS by lipoic acid, the prosthetic group common to protein X and the E2 subunits of OGDC and BCOADC.",
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T1 - The lipoic acid containing components of the 2-oxoacid dehydrogenase complexes mimic trifluoroacetylated proteins and are autoantigens associated with halothane hepatitis

AU - Frey, Nora

AU - Christen, Urs

AU - Jenö, Paul

AU - Yeaman, Stephen J.

AU - Shimomura, Yoshiharu

AU - Gerald Kenna, J.

AU - Jay Gandolfi, A.

AU - Gandolfi, A Jay

AU - Gut, Josef

PY - 1995

Y1 - 1995

N2 - Anti-CF3CO antibodies, monospecific toward trifluoroacetylated proteins (CF3CO-proteins), which are elicited in experimental animals and humans exposed to the anesthetic agent halothane, cross-react with an unknown protein of approximately 52 kDa, constitutively expressed in tissues of experimental animals and humans not previously exposed to the agent. Using anti-CF3CO antibody, the protein(s) of 52 kDa could be immunoprecipitated from solubilized rat heart homogenate. Two-dimensional gel electrophoretic analysis revealed the presence of distinct major (P1, P2) and minor (P3, P4, P5) protein components with apparent molecular masses of 52 kDa. From each of the components P1 and P2, the amino acid sequences of three peptides were determined and found to exhibit 100% identity with the corresponding amino acid sequences of the E2 subunit of the rat 2-oxoglutarate dehydrogenase complex (OGDC). Additionally to the E2 subunit of OGDC, anti-CF3CO antibody also recognized on immunoblots the purified E2 subunit of the branched chain 2-oxoacid dehydrogenase complex (BCOADC) and protein X, a constituent of the pyruvate dehydrogenase complex (PDC), in a manner sensitive to competition N6-(trifluoroacetyl)-L-lysine (CF3CO-Lys), 6(RS)-lipoic acid, and N6(6(RS)-lipoyl)-L-lysine (lipoyl-Lys). Furthermore, a discrete population of autoantibodies was identified in sera of patients with halothane hepatitis which could not discriminate between the lipoylated target epitope present on the E2 subunit of OGDC and epitopes on CF3CO-RSA, used as model for CF3CO-proteins. These data suggest that the autoantigenicity of these proteins in halothane hepatitis is based on the molecular mimicry of CF3CO-LyS by lipoic acid, the prosthetic group common to protein X and the E2 subunits of OGDC and BCOADC.

AB - Anti-CF3CO antibodies, monospecific toward trifluoroacetylated proteins (CF3CO-proteins), which are elicited in experimental animals and humans exposed to the anesthetic agent halothane, cross-react with an unknown protein of approximately 52 kDa, constitutively expressed in tissues of experimental animals and humans not previously exposed to the agent. Using anti-CF3CO antibody, the protein(s) of 52 kDa could be immunoprecipitated from solubilized rat heart homogenate. Two-dimensional gel electrophoretic analysis revealed the presence of distinct major (P1, P2) and minor (P3, P4, P5) protein components with apparent molecular masses of 52 kDa. From each of the components P1 and P2, the amino acid sequences of three peptides were determined and found to exhibit 100% identity with the corresponding amino acid sequences of the E2 subunit of the rat 2-oxoglutarate dehydrogenase complex (OGDC). Additionally to the E2 subunit of OGDC, anti-CF3CO antibody also recognized on immunoblots the purified E2 subunit of the branched chain 2-oxoacid dehydrogenase complex (BCOADC) and protein X, a constituent of the pyruvate dehydrogenase complex (PDC), in a manner sensitive to competition N6-(trifluoroacetyl)-L-lysine (CF3CO-Lys), 6(RS)-lipoic acid, and N6(6(RS)-lipoyl)-L-lysine (lipoyl-Lys). Furthermore, a discrete population of autoantibodies was identified in sera of patients with halothane hepatitis which could not discriminate between the lipoylated target epitope present on the E2 subunit of OGDC and epitopes on CF3CO-RSA, used as model for CF3CO-proteins. These data suggest that the autoantigenicity of these proteins in halothane hepatitis is based on the molecular mimicry of CF3CO-LyS by lipoic acid, the prosthetic group common to protein X and the E2 subunits of OGDC and BCOADC.

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