The lipoic acid containing components of the 2-oxoacid dehydrogenase complexes mimic trifluoroacetylated proteins and are autoantigens associated with halothane hepatitis.
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 by 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.
Frey
N
N
Department of Pharmacology, Biocenter of the University, Basel, Switzerland.
Christen
U
U
Jenö
P
P
Yeaman
S J
SJ
Shimomura
Y
Y
Kenna
J G
JG
Gandolfi
A J
AJ
Ranek
L
L
Gut
J
J
D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide); D000595:Amino Acid Sequence; D000818:Animals; D001323:Autoantibodies / Q000097:blood; D001324:Autoantigens; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000276:immunology; D003429:Cross Reactions; D015180:Electrophoresis, Gel, Two-Dimensional; D000939:Epitopes / Q000276:immunology; D005463:Fluoroacetates; D006221:Halothane / Q000009:adverse effects*; D006801:Humans; D015151:Immunoblotting; D007655:Ketoglutarate Dehydrogenase Complex / Q000737:chemistry / Q000276:immunology*; D007658:Ketone Oxidoreductases / Q000737:chemistry / Q000276:immunology*; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000737:chemistry / Q000276:immunology*; D011506:Proteins / Q000737:chemistry* / Q000276:immunology; D051381:Rats; D012709:Serum Albumin / Q000737:chemistry / Q000276:immunology; D008063:Thioctic Acid / Q000032:analysis*; D014269:Trifluoroacetic Acid / Q000737:chemistry / Q000276:immunology
D001323:Autoantibodies; D001324:Autoantigens; D000939:Epitopes; D005463:Fluoroacetates; D009097:Multienzyme Complexes; D011506:Proteins; D012709:Serum Albumin; C053344:trifluoroacetyl-serum albumin; D008063:Thioctic Acid; D014269:Trifluoroacetic Acid; D007658:Ketone Oxidoreductases; D007655:Ketoglutarate Dehydrogenase Complex; D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide); D006221:Halothane