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PubMedDate not supplied

Stereospecific reduction of R(+)-thioctic acid by porcine heart lipoamide dehydrogenase/diaphorase.

R(+)-thioctic acid is the naturally occurring cofactor in alpha-ketoacid dehydrogenases. We show both photometrically by NADH+H+ oxidation and by HPLC product analysis that this enantiomer is rapidly reduced by NADH+H+ catalyzed by porcine heart lipoamide dehydrogenase/diaphorase. The racemate exhibits approximately 40% activity as compared to the R(+) form while the S(-) enantiomer photometrically shows little activity and yields no detectable reduced lipoic acid.

Animals↗
PubMed2003

Targets of stress-induced oxidative damage in plant mitochondria and their impact on cell carbon/nitrogen metabolism.

Plant mitochondria link the cellular processes of carbon and nitrogen metabolism through the tricarboxylic acid cycle and the photorespiratory cycle. Environmental stresses lead to damage of specific mitochondrial targets through the direct action of reactive oxygen species and indirect action of lipid peroxidation products. Uncovering the extent of this damage, the exact sites of damage and the mechanisms of avoidance and/or repair remains a largely unresearched challenge for plant scientists. Damage to Fe-S centres and proteins containing lipoic acid moieties appear to predominate in current reports. Substantial evidence that both TCA cycle and photorespiratory capacity of mitochondria are sensitive sites for damage is highlighted and the implications for mitochondrial-dependent carbon and nitrogen metabolism are discussed.

Carbon↗
PubMed1995

Inhibition of rat liver mitochondrial permeability transition by respiratory substrates.

The mitochondrial inner membrane can undergo a permeability increase known as "permeability transition" elicited by Ca2+ and several other inducing agents. In general, the condition of oxidative stress acts as an inducer, at variance with antioxidants and reducing agents that inhibit the permeability transition. The action of mitochondrial respiratory substrates in preventing the permeability transition induced by Ca2+ and phosphate was examined; pyruvate, isocitrate, and glutamate proved to be particularly effective. The effect of substrates was evident also in the presence of an uncoupler, and, in addition, they were able to counteract the swelling stimulated by acetoacetate and tert-butylhydroperoxide. In the presence of various pyridine nucleotide-dependent substrates, mitochondria are able to reduce the disulfide 5,5'-dithiobis (2-nitrobenzoic acid) (DTNB) to an extent far larger than that calculated from the theoretical amount of total mitochondrial thiol groups, indicating the occurrence of a catalytic system. Similarly, the enzymes of the mitochondrial matrix in the presence of either NADH or NADPH are able to reduce DTNB. The results are discussed considering the existence of a close redox communication between pyridine nucleotides and membrane thiol groups, possibly mediated by dithiols such as thioredoxin and lipoic acid.

Animals↗
PubMed2004

Cu2+ toxicity inhibition of mitochondrial dehydrogenases in vitro and in vivo.

Wilson's disease results from mutations in the P-type Cu(2+)-ATPase causing Cu(2+) toxicity. We previously demonstrated that exposure of mixed neuronal/glial cultures to 20 microM Cu(2+) induced ATP loss and death that were attenuated by mitochondrial substrates, activators, and cofactors. Here, we show differential cellular sensitivity to Cu(2+) that was equalized to 5 microM in the presence of the copper exchanger/ionophore, disulfiram. Because Cu(2+) facilitates formation of oxygen radicals (ROS) which inhibit pyruvate dehydrogenase (PDH) and alpha-ketoglutarate dehydrogenase (KGDH), we hypothesized that their inhibition contributed to Cu(2+)-induced death. Toxic CU(2+) exposure was accompanied by early inhibition of neuronal and hepatocellular PDH and KGDH activities, followed by reduced mitochondrial transmembrane potential, DeltaPsi(M). Thiamine (1-6 mM), and dihydrolipoic acid (LA, 50 microM), required cofactors for PDH and KGDH, attenuated this enzymatic inhibition and subsequent death in all cell types. Furthermore, liver PDH and KGDH activities were reduced in the Atp7b mouse model of Wilson's disease prior to liver damage, and were partially restored by oral thiamine supplementation. These data support our hypothesis that Cu(2+)-induced ROS may inhibit PDH and KGDH resulting in neuronal and hepatocellular death. Therefore, thiamine or lipoic acid may constitute potential therapeutic agents for Wilson's disease.

Adenosine Triphosphatases↗
PubMed1997

Cloning and characterization of the lipoyl-protein ligase gene LIPB from the yeast Kluyveromyces lactis: synergistic respiratory deficiency due to mutations in LIPB and mitochondrial F1-ATPase subunits.

The mgi1-4 and mgi2-1 mutants of the petite-negative yeast Kluyveromyces lactis have mutations in the beta- and alpha-subunits of the mitochondrial F1-ATPase, respectively. The mutants are respiratory competent but can form petites with deletions in mitochondrial DNA. In this study a cryptic nuclear mutation (lipB-1) was identified which, in combination with the mgi alleles, displays a synergistic respiratory-deficient phenotype on glycerol medium. The gene defined by the mutation was cloned and shown to encode a polypeptide of 332 amino acids with an N-terminal sequence characteristic of a mitochondrial targeting signal. The deduced protein shares 27% sequence identity with the product of the Escherichia coli lipB gene, which encodes a lipoyl-protein ligase involved in the attachment of lipoyl groups to lipoate-dependent apoproteins. A K. lactis strain carrying a disrupted lipB allele is severely compromised for growth on glycerol medium. The growth defect cannot be rescued by addition of lipoic acid, but cell growth can be restored on medium containing ethanol plus succinate. In addition, it was observed that lipB mutants of K. lactis, unlike the wild-type, are unable to utilize glycine as sole nitrogen source, indicating that activity of the glycine decarboxylase complex (GDC) is also affected. Taken together, these findings suggest that LIPB is the main determinant of the lipoyl-protein ligase activity required for lipoylation of enzymes such as alpha-ketoacid dehydrogenases and GDC.

Amino Acid Sequence↗
PubMed2006

A zebrafish assay for identifying neuroprotectants in vivo.

In this study, we developed an in vivo method to determine drug effects on oxidation-induced apoptosis in the zebrafish brain caused by treatment with L-hydroxyglutaric acid (LGA). We confirmed that LGA-induced apoptosis was caused by oxidation by examining the presence of an oxidative product, nitrotyrosine. Next, we examined the effects of 14 characterized neuroprotectants on LGA-treated zebrafish, including: D-methionine (D-Met), Indole-3-carbinol, deferoxamine (DFO), dihydroxybenzoate (DHB), deprenyl, L-NAME (N(G)-nitro-L-arginine methyl ester), n-acetyl L-cysteine (L-NAC), 2-oxothiazolidine-4-carboxylate (OTC), lipoic acid, minocycline, isatin, cortisone, ascorbic acid and alpha-tocopherol. Eleven of 14 neuroprotectants and 7 of 7 synthetic anti-oxidants exhibit significant protection in zebrafish. Buthionine sulfoximine (BSO), used as a negative control, exhibited no significant protective effects. In addition, three blood-brain barrier (BBB) impermeable compounds exhibited no significant effects. Our results in zebrafish were similar to results reported in mammals supporting the utility of this in vivo method for identifying potential neuroprotective anti-oxidants.

Acridines↗
PubMed1999

Biotin biochemistry and human requirements.

Human biotin turnover and requirements can be estimated on the basis of (1) concentrations of biotin and metabolites in body fluids, (2) activities of biotin-dependent carboxylases, and (3) the urinary excretion of organic acids that are formed at increased rates if carboxylase activities are reduced. Recent studies suggest that the urinary excretions of biotin and its metabolite bisnorbiotin, activities of propionyl-CoA carboxylase and beta-methylcrotonyl-CoA carboxylase in lymphocytes, and urinary excretion of 3-hydroxyisovaleric acid are good indicators of marginal biotin deficiency. On the basis of studies using these indicators of biotin deficiency, an adequate intake of 30 microg (123 nmoles) of biotin per day is currently recommended for adults. The dietary biotin intake in Western populations has been estimated to be 35 to 70 microg/d (143-287 nmol/d). Recent studies suggest that humans absorb biotin nearly completely. Conditions that may increase biotin requirements in humans include pregnancy, lactation, and therapy with anticonvulsants or lipoic acid.

Journal Article↗
PubMed2002

Altered arachidonic acid biosynthesis and antioxidant protection mechanisms in Schwann cells grown in elevated glucose.

In cultured Schwann cells, elevated glucose induces alterations in arachidonic acid metabolism that cause a decrease in the content of glycerophospholipid arachidonoyl-containing molecular species (ACMS). This could result from decreased de novo arachidonic acid biosynthesis, or increased arachidonic acid release from phospholipids. Incorporation of radioactive 8,11,14-eicosatrienoic acid into ACMS was lower for cells grown in 30 mm versus 5 mm glucose, consistent with a decrease in delta5 desaturase activity. However, neither basal arachidonic acid release from prelabeled cells nor stimulated generation of arachidonic acid in the presence of the reacylation inhibitor, thimerosal, the phosphotyrosine phosphatase inhibitor, bipyridyl peroxovanadium, or both together, were altered by varying the glucose concentrations, indicating that arachidonic acid turnover did not contribute to ACMS depletion. Free cytosolic NAD+ /NADH decreased, whereas NADP+ /NADPH remained unchanged for cells grown in elevated glucose, implying that decreased desaturase activity is a result of metabolic changes other than cofactor availability. Schwann cells in elevated glucose were susceptible to oxidative stress, as shown by increased malondialdehyde, depleted glutathione levels, and reduced cytosolic superoxide dismutase activity. Glutathione-altering compounds had no effect on ACMS levels, in contrast to N -acetylcysteine and alpha-lipoic acid, which partly corrected ACMS depletion in phosphatidylcholine. These findings suggest that in the Schwann cell cultures, a high glucose level elicits oxidative stress and weakens antioxidant protection mechanisms which could decrease arachidonic acid biosynthesis and that this deficit can be partly corrected by treatment with exogenous antioxidants.

Animals↗
PubMed2004

Sidechain biology and the immunogenicity of PDC-E2, the major autoantigen of primary biliary cirrhosis.

The E2 component of mitochondrial pyruvate dehydrogenase complex (PDC-E2) is the immunodominant autoantigen of primary biliary cirrhosis. Whereas lipoylation of PDC-E2 is essential for enzymatic activity and predominates under normal conditions, other biochemical systems exist that also target the lysine residue, including acylation of fatty acids or xenobiotics and ubiquitinylation. More importantly, the immunogenicity can be affected by derivatization of the lysine residue, as the recognition of lipoylated PDC-E2 by patient autoantibodies is enhanced compared with octanoylated PDC-E2. Furthermore, our laboratory has shown that various xenobiotic modifications of a peptide representing the immunodominant region of PDC-E2 are immunoreactive against patient sera. The only purported regulatory system that prevents the accumulation of potentially autoreactive PDC-E2 is glutathionylation, in which the lysine-lipoic acid moiety is further modified with glutathione during apoptosis. Interestingly, this system is found in several cell lines, including HeLa, Jurkat, and Caco-2 cells, but not in cholangiocytes and salivary gland epithelial cells, both of which are targets for destruction in primary biliary cirrhosis. Hence, the failure of this or other regulatory system(s) may overwhelm the immune system with immunogenic PDC-E2 that can initiate the breakdown of tolerance in a genetically susceptible individual. In this review the authors survey the data available on the biochemical life of PDC-E2, with particular emphasis on the lysine residue and its known interactions with machinery involved in various posttranslational modifications.

Amino Acid Sequence↗
PubMed2003

Acrolein inhibits NADH-linked mitochondrial enzyme activity: implications for Alzheimer's disease.

In Alzheimer's disease (AD) brain increased lipid peroxidation and decreased energy utilization are found. Mitochondria membranes contain a significant amount of arachidonic and linoleic acids, precursors of lipid peroxidation products, 4-hydroxynonenal (HNE) and 2-propen-1-al (acrolein), that are extremely reactive. Both alkenals are increased in AD brain. In this study, we examined the effects of nanomolar levels of acrolein on the activities of pyruvate dehydrogenase (PDH) and Alpha-ketoglutarate dehydrogenase (KGDH), both reduced nicotinamide adenine dinucleotide (NADH)-linked mitochondrial enzymes. Acrolein decreased PDH and KGDH activities significantly in a dose-dependent manner. Using high performance liquid chromatography coupled to mass spectrometry (HPLC-MS), acrolein was found to bind lipoic acid, a component in both the PDH and KGDH complexes, most likely explaining the loss of enzyme activity. Acrolein also interacted with oxidized nicotinamide adenine dinucleotide (NAD(+)) in such a way as to decrease the production of NADH. Acrolein, which is increased in AD brain, may be partially responsible for the dysfunction of mitochondria and loss of energy found in AD brain by inhibition of PDH and KGDH activities, potentially contributing to the neurodegeneration in this disorder.

Acrolein↗
PubMed2005

Mitochondrial myopathies: diagnosis, exercise intolerance, and treatment options.

Mitochondrial myopathies are caused by genetic mutations that directly influence the functioning of the electron transport chain (ETC). It is estimated that 1 of 8,000 people have pathology inducing mutations affecting mitochondrial function. Diagnosis often requires a multifaceted approach with measurements of serum lactate and pyruvate, urine organic acids, magnetic resonance spectroscopy (MRS), muscle histology and ultrastructure, enzymology, genetic analysis, and exercise testing. The ubiquitous distribution of the mitochondria in the human body explains the multiple organ involvement. Exercise intolerance is a common but often an overlooked hallmark of mitochondrial myopathies. The muscle consequences of ETC dysfunction include increased reliance on anaerobic metabolism (lactate generation, phosphocreatine degradation), enhanced free radical production, reduced oxygen extraction and electron flux through ETC, and mitochondrial proliferation or biogenesis (see article by Hood in current issue). Treatments have included antioxidants (vitamin E, alpha lipoic acid), electron donors and acceptors (coenzyme Q10, riboflavin), alternative energy sources (creatine monohydrate), lactate reduction strategies (dichloroacetate) and exercise training. Exercise is a particularly important modality in diagnosis as well as therapy (see article by Taivassalo in current issue). Increased awareness of these disorders by exercise physiologists and sports medicine practitioners should lead to more accurate and more rapid diagnosis and the opportunity for therapy and genetic counseling.

Antioxidants↗
PubMed1990

Lipoamidase (lipoyl-X hydrolase) from pig brain.

Although the optimum substrate for lipoamidase (lipoyl-X hydrolase) has not yet been determined, it is known that lipoamidase activity, as determined by hydrolysis of the synthetic substrate lipoyl 4-aminobenzoate (LPAB), is widely distributed in pig brain tissues, i.e. in the cerebrum, cerebellum and medulla. Over 95% of the enzyme activity is present in the membrane subfractions, indicating that brain lipoamidase is an integral membrane protein enzyme. To elucidate the chemical nature and the optimum substrate of the abundant lipoamidase in the brain, we isolated it from the membrane subfractions. After an 8-step purification procedure, brain lipoamidase was purified 601-fold and identified as a 140 kDa glycoprotein by SDS/PAGE. A mechanistic study to determine Km and Vmax, values was carried out using various synthetic compounds. Lipoyl-lysine, which is generally believed to be a naturally occurring substrate of lipoamidase, was first compared with biotinyl-lysine, because these two vitamins have reactive sulphur atoms and are similar in molecular mass and structure. The Km for lipoyl-lysine was 333 microM, whereas biotinyl-lysine was not hydrolysed. Stringent specificity for the lipoyl moiety is demonstrated, as expected. Dipeptides of amino acid-lysine structures were studied, and dipeptides of aspartyl- and glutamyl-lysine hydrolysis occurred at high Km (3 mM) values. Thus lysine in the moiety is not very effective as an optimum substrate. The chemical bond structures of the amide bond (lipoyl-lysine) and peptide bond (aspartyl-lysine) were hydrolysed. Next, the ester bond compound was tested, and it was observed that lipolylmethyl ester was hydrolysed at high specificity. These findings indicate that this enzyme has broad specificities with respect to bond structure; it therefore is a unique hydrolase having stringent specificity for lipoic acid and relatively broad specificity for the chemical bond and the X moiety. Various inhibitors were tested; a few reagents, such as organic mercurials, di-isopropylfluorophosphate, 1,10-phenanthroline, sodium azide and angiotensin-converting enzyme inhibitor exhibited some inhibition (not more than 60%). Thus the active centre of this enzyme is a complex type. Although ATP is not hydrolysed and the lowest Km value is exhibited by the synthetic substrate reduced from LPAB (12 microM), some other compounds may still be expected to be hydrolysed by this unique and abundant brain lipoamidase.

Amidohydrolases↗
PubMed2001

Characterization of 16 novel human genes showing high similarity to yeast sequences.

The entire set of open reading frames (ORFs) of Saccharomyces cerevisiae has been used to perform systematic similarity searches against nucleic acid and protein databases: with the aim of identifying interesting homologies between yeast and mammalian genes. Many similarities were detected: mostly with known genes. However: several yeast ORFs were only found to match human partial sequence tags: indicating the presence of human transcripts still uncharacterized that have a homologous counterpart in yeast. About 30 such transcripts were further studied and named HUSSY (human sequence similar to yeast). The 16 most interesting are presented in this paper along with their sequencing and mapping data. As expected: most of these genes seem to be involved in basic metabolic and cellular functions (lipoic acid biosynthesis: ribulose-5-phosphate-3-epimerase: glycosyl transferase: beta-transducin: serine-threonine-kinase: ABC proteins: cation transporters). Genes related to RNA maturation were also found (homologues to DIM1: ROK1-RNA-elicase and NFS1). Furthermore: five novel human genes were detected (HUSSY-03: HUSSY-22: HUSSY-23: HUSSY-27: HUSSY-29) that appear to be homologous to yeast genes whose function is still undetermined. More information on this work can be obtained at the website http://grup.bio.unipd.it/hussy

Amino Acid Sequence↗
PubMed1991

Maple syrup urine disease: domain structure, mutations and exon skipping in the dihydrolipoyl transacylase (E2) component of the branched-chain alpha-keto acid dehydrogenase complex.

Maple syrup urine disease (MSUD) is an autosomal recessive disorder in the oxidative decarboxylation of the branched-chain alpha-keto acids derived from leucine, isoleucine and valine. The enzyme deficient in MSUD, the branched-chain alpha-keto acid dehydrogenase (BCKAD) complex, is a mitochondrial multienzyme complex consisting of at least six distinct subunits. MSUD is genetically heterogeneous as manifested by lesions in different subunits of the BCKAD complex among unrelated patients. To approach the biochemical basis of MSUD involving the dihydrolipoyl transacylase (E2) subunit, the domain structure of this polypeptide from human and bovine livers has been defined by limited proteolysis and cDNA cloning. The assembly of 24 E2 subunits into a cubic structure, forming the core of the mammalian BCKAD complex, was established by electron microscopy and sedimentation equilibrium analysis. Highly assembled bovine E2 devoid of prosthetic lipoic acid has been overexpressed in Escherichia coli. Studies carried out with this bacterial expression system have provided insights into the lipoylation process of E2, and the involvement of the His391 residue in the transacylation reaction. At the genetic level, the human E2 gene (DBT) has been regionally assigned to chromosome 1p31, and a related E2 pseudogene to chromosome 3q24 by in situ hybridization. Genomic cloning has shown that the human E2 gene undergoes premature transcriptional termination and alternate splicing as normal events, although its functional significance is unknown. Through the use of the polymerase chain reaction and other recombinant DNA methods, several compound heterozygous mutations at the E2 locus have been identified in classical as well as thiamine-responsive MSUD patients. These mutations would appear to be useful genetic models, which will facilitate investigations into macromolecular organization and protein-protein interactions. Moreover, an array of precise single and multiple exon deletions has been observed in the amplified mutant E2 transcripts. The results represent unexpected secondary effects that are apparently associated with the above primary mutations in the E2 gene.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed2003

Anti-AGEing defences against Alzheimer's disease.

Accumulation of insoluble protein deposits and their cross-linking by AGEs (advanced glycation end products) in the brain is a feature of aging and neurodegeneration, especially in AD (Alzheimer's disease). In AD, two types of fibrillar protein aggregates are present: extracellular deposits (plaques) consisting mainly of Abeta (beta-amyloid peptide), and intracellular deposits (tangles) composed predominantly of microtubule-associated protein tau. Both plaques and tangles are modified by AGEs, which occurs particularly at lysine and arginine residues. Interaction of a synthetic amyloid plaque (fibrillar Abeta) with microglia leads to a strong pro-inflammatory response, indicating that priming of immune cells with beta-amyloid potentiates their response to secondary stimuli such as AGE and cytokines such as interferon-gamma. Formation of hyperphosphorylated and cross-linked microtubule-associated protein tau aggregates, especially tau dimers as the first step in tangle formation, can be induced in vitro by the combination of okadaic acid, a PP2A phosphatase inhibitor, and methylglyoxal. These results suggest that excess production of reactive carbonyl compound ("carbonyl stress") and subsequent AGE formation can contribute to cross-linking of protein fibrils and to pathological pro-inflammatory signalling, which all contribute to pathological changes and dementia progression in AD. However, the human brain has developed the glyoxalase system, a most effective defence system to scavenge small dicarbonyl compounds such as glyoxal and methylglyoxal. Very importantly, this system needs GSH as a rate-limiting cofactor. Since GSH is limited under conditions of oxidative stress and inflammation, supplementation with antioxidants such as lipoic acid, vitamin E or flavonoids could indirectly strengthen the anti-glycation defence system in AD. In addition, synthetic carbonyl scavengers and anti-inflammatory drugs could also be valuable drugs for the "anti-glycation" treatment of AD.

Alzheimer Disease↗
PubMed1999

The role of oxidative stress and NF-kappaB activation in late diabetic complications.

A common endpoint of hyperglycemia dependent cellular changes is the generation of reactive oxygen intermediates (ROIs) and the presence of elevated oxidative stress. Therefore, oxidative stress is supposed to play an important role in the development of late diabetic complications. Formation of advanced glycation end products (AGE's) due to elevated nonenzymatic glycation of proteins, lipids and nucleic acids is accompanied by oxidative, radical-generating reactions and thus represents a major source for oxygen free radicals under hyperglycemic conditions. Once formed, AGE's can influence cellular function by binding to several binding sites including the receptor for AGE's, RAGE. Binding of AGE's (and other ligands) to RAGE results in generation of intracellular oxidative stress and subsequent activation of the redox-sensitive transcription factor NF-kappaB in vitro and in vivo. Consistently, activation of NF-kappaB in diabetic patients correlates with the quality of glycemic control and can be reduced by treatment with the antioxidant alpha-lipoic acid. The development of techniques allowing for a tissue culture independent measurement of NF-kappaB activation in patients with diabetes mellitus gives insights into the molecular mechanisms linking diabetes mellitus and hyperglycemia with formation of advanced glycated endproducts and generation of oxidative stress finally resulting in oxidative stress mediated cellular activation.

Animals↗
PubMed2003

Molecular mechanisms, diagnosis, and rational approaches to management of and therapy for Charcot-Marie-Tooth disease and related peripheral neuropathies.

During the last decade, 18 genes and 11 additional loci harboring candidate genes have been associated with Charcot-Marie-Tooth disease (CMT) and related peripheral neuropathies. Ten of these 18 genes have been identified in the last 2 years. This phenomenal pace of CMT gene discovery has fomented an unprecedented explosion of information regarding peripheral nerve biology and its pathologic manifestations in CMT. This review integrates molecular genetics with the clinical phenotypes and provides a flowchart for molecular-based diagnostics. In addition, we discuss rational approaches to molecular therapeutics, including novel biologic molecules (eg, small interfering ribonucleic acid [siRNA], antisense RNA, and ribozymes) that potentially could be used as drugs in the future. These may be applicable in attempts to normalize gene expression in cases of CMT type 1A, wherein a 1.5 Mb genomic duplication causes an increase in gene dosage that is associated with the majority of CMT cases. Aggresome formation by the PMP22 gene product, the disease-associated gene in the duplication cases, could thus be avoided. We also discuss alternative therapeutics, in light of other neurodegenerative disorders, to disrupt such aggresomes. Finally, we review rational therapeutic approaches, including the use of antioxidants such as vitamin E, coenzyme Q10, or lipoic acid to relax potential oxidative stress in peripheral nerves, for CMT management.

Charcot-Marie-Tooth Disease↗
PubMed2005

Chemical xenobiotics and mitochondrial autoantigens in primary biliary cirrhosis: identification of antibodies against a common environmental, cosmetic, and food additive, 2-octynoic acid.

Emerging evidence has suggested environmental factors as causative agents in the pathogenesis of primary biliary cirrhosis (PBC). We have hypothesized that in PBC the lipoyl domain of the immunodominant E2 component of pyruvate dehydrogenase (PDC-E2) is replaced by a chemical xenobiotic mimic, which is sufficient to break self-tolerance. To address this hypothesis, based upon our quantitative structure-activity relationship data, a total of 107 potential xenobiotic mimics were coupled to the lysine residue of the immunodominant 15 amino acid peptide of the PDC-E2 inner lipoyl domain and spotted on microarray slides. Sera from patients with PBC (n = 47), primary sclerosing cholangitis (n = 15), and healthy volunteers (n = 20) were assayed for Ig reactivity. PBC sera were subsequently absorbed with native lipoylated PDC-E2 peptide or a xenobiotically modified PDC-E2 peptide, and the remaining reactivity analyzed. Of the 107 xenobiotics, 33 had a significantly higher IgG reactivity against PBC sera compared with control sera. In addition, 9 of those 33 compounds were more reactive than the native lipoylated peptide. Following absorption, 8 of the 9 compounds demonstrated cross-reactivity with lipoic acid. One compound, 2-octynoic acid, was unique in both its quantitative structure-activity relationship analysis and reactivity. PBC patient sera demonstrated high Ig reactivity against 2-octynoic acid-PDC-E2 peptide. Not only does 2-octynoic acid have the potential to modify PDC-E2 in vivo but importantly it was/is widely used in the environment including perfumes, lipstick, and many common food flavorings.

Amino Acid Sequence↗