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DLAT  -  dihydrolipoamide S-acetyltransferase

Homo sapiens

 
 
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Disease relevance of DLAT

  • Autoantibodies to the pyruvate dehydrogenase complex (PDC) are present in the serum of more than 95% of patients with primary biliary cirrhosis (PBC), the major epitope being the inner lipoyl domain of the E2 component [1].
  • Moreover, confocal microscopic examination and image analysis revealed that the mRNA signal intensity of each of the 2-OADC components in the bile ducts of PBC was relatively lower in comparison with control liver diseases [2].
  • Of these, three sera were from patients with chronic hepatitis C virus (HCV) infection, and contained IgG class autoantibody to BCOADC-E2 [3].
  • Primary biliary cirrhosis (PBC) is a cholestatic liver disease characterised by immune-mediated destruction of the biliary epithelial cells (BEC) lining the intrahepatic bile ducts (non-suppurative destructive cholangitis (NSDC)) [4].
  • Previous studies on Spanish patients with Primary Biliary Cirrhosis (PBC) have shown extensive, disease-specific cross-reactivity between the 65-kDa heat shock protein (hsp65) of Mycobacterium gordonae and pyruvate dehydrogenase complex-E2 (PDC-E2), the major target of anti-mitochondrial antibody (AMA) [5].
  • Three of 11 patients with MM (27%) and 2 of 6 patients with chronic leukemias (33%) developed anti-PDC-E2 antibodies in association with DLI response; 2 of 12 (17%) patients in the MGUS pretreatment control population also had detectable anti-PDC responses [6].
 

Psychiatry related information on DLAT

  • Primary biliary cirrhosis (PBC) is one of the few nonalcohol-induced liver pathologies that causes false positives in assays of carbohydrate-deficient transferrin (CDT) for diagnosing alcohol abuse [7].
  • Our aim was to determine its importance and its impact on the quality of life and mental health status of patients with PBC [8].
  • E1/E2 dimers and the HCV-LPs of 1b did not bind CD81-LEL, consistent with the notion that CD81 recognition by E2 is strain-specific and does not correlate with permissiveness of infection [9].
  • The increased serum level of Ab with the 16/6 idiotype (16/6 Id) in PBC patients (median 50 ng/ml) was not found in 6/7 of the patients' spouses nor among 27/28 healthy controls or most patients with other types of cirrhosis [10].
  • Of 64 patients with nonalcoholic liver diseases, one individual with chronic active hepatitis (CAH) with an alcohol consumption of 20 g/day, and 10 of 26 subjects with primary biliary cirrhoses (PBC), who claimed to consume either no or only occasional moderate amounts of alcohol, had CDT levels ranging from 81 to 144 mg/liter [11].
 

High impact information on DLAT

  • The 74-kd mitochondrial protein is the E2 component--dihydrolipoamide acetyltransferase--of the pyruvate dehydrogenase complex, and the 52-kd protein is the equivalent E2 component--dihydrolipoamide acyltransferase--of the branched-chain alpha-keto acid dehydrogenase complex [12].
  • A plasmid containing the adenovirus E2 gene, a gene normally requiring E1A-mediated induction during viral infection, is expressed very poorly upon transfection into mouse L cells [13].
  • In addition, efficient E2 expression in the absence of trans induction was obtained by inserting E1A upstream promoter sequences at the 5' or 3' end of the E2 gene, indicating that these E1A sequences possess enhancer properties [13].
  • Cotransfection of the E2 plasmid with a plasmid containing the pseudorabies virus (a herpesvirus) immediate early gene results in an even higher increase in the level of E2 expression [13].
  • All the binding sites contain a related sequence of nucleotides; a 23 base pair (bp) fragment containing this sequence can specifically prevent binding of the E2 protein to the BPV URR [14].
 

Chemical compound and disease context of DLAT

 

Biological context of DLAT

  • Attempts to resolve E3BP from E2 have been unsuccessful, restricting study of the nature and significance of antibody responses to the individual proteins [1].
  • ATP and ADP decreased the affinity of PDK2 for E2 by 3-5-fold and adenosine 5'-(beta,gamma-imino)triphosphate or phosphorylation of E1 similarly reduced PDK2 binding to E2.E1 [19].
  • The interaction of PDK2 with the lipoyl domains of E2 (L1, L2) and the E3-binding protein (L3) were characterized by AUC [19].
  • To address molecular mimicry and cross-recognition among mitochondrial autoantigens, we analyzed reactivity, including agonism and antagonism assays, to a series of single amino acid-substituted peptides using cloned T-cell lines in PBC and controls [20].
  • We have recently taken advantage of motif prediction analysis of HLA-A*0201 and identified the first major histocompatibility complex (MHC) class I restricted epitope, amino acids 159 to 167 on E2 components of pyruvate dehydrogenase complexes (PDC-E2), the major mitochondrial antigens in PBC [21].
 

Anatomical context of DLAT

  • The patients had neuroradiological evidence of discrete lesions restricted to the globus pallidus, and both are homozygous for different mutations in the DLAT gene [22].
  • Previous work has postulated that either E3BP, or a molecule cross-reactive with the PDC-E2 molecule, is uniquely expressed on the surface of biliary epithelial cells in PBC [2].
  • In both PBC and controls, the expression of all 2-OADC component mRNA studied herein were found in hepatocytes and infiltrating mononuclear cells, without significant differences [2].
  • Autoreactive CD4+ T cells specific for human PDC-E2 are also present in both the peripheral blood and liver mononuclear cell infiltrates of PBC patients [23].
  • We used the T2 cell line to screen 79 overlapping 15mer peptides, spanning the entire PDC-E2 molecule [21].
 

Associations of DLAT with chemical compounds

  • Mutations in DLAT, the gene encoding dihydrolipoamide acetyltransferase, the E2 core component of the complex, have not been described previously [22].
  • The dihydrolipoyl acetyltransferase (E2) has an enormous impact on pyruvate dehydrogenase kinase (PDK) phosphorylation of the pyruvate dehydrogenase (E1) component by acting as a mobile binding framework and in facilitating and mediating regulation of PDK activity [19].
  • Lipoate reduction fostered somewhat tighter binding at more sites by E2 and severalfold tighter binding at the majority of sites on E2.E1 [19].
  • One study has suggested the presence of T cell epitopes throughout PDC-E2, whilst another has identified a single dominant 14 amino acid T cell epitope (p163) spanning the lipoic acid binding lysine residue in the inner lipoyl domain (ILD) of PDC-E2 [24].
  • E2 activation of PDK2 resulted in a greatly enhanced sensitivity to inhibition by pyruvate or DCA; pyruvate was effective at significantly lower levels than DCA [25].
 

Physical interactions of DLAT

  • The E2 60-mer bound approximately 18 PDK2 dimers with a Kd similar to GST-L2 [19].
  • The dihydrolipoyl acetyltransferase (E2) and the dihydrolipoyl dehydrogenase-binding protein (E3BP) are multidomain proteins that form the oligomeric core of the complex [26].
  • In contrast, the sizes of the E3-binding site and the catalytic domain of PDC-E2 from several species are essentially similar and show considerable conservation of specific amino acid residues [27].
 

Enzymatic interactions of DLAT

  • Conversion of all of the lipoyl groups in the E2 60mer to the oxidized form (E2(ox)) greatly reduced k(cat) and the K(m) of PDK2 for ATP [28].
 

Regulatory relationships of DLAT

  • PDK2 was activated only by assembled E2, and this activated state beget high responsiveness to those effectors [25].
  • PDK3 was activated 17-fold by E2; the majority of this activation was facilitated by the free L2 domain (half-maximal activation at 3.3 microm L2) [25].
  • Anti-E3 antibody-positive sera of PBC patients or normal controls and their IgG fraction did not inhibit the enzyme activity of E3 [29].
  • Anti-PDC-E2 antibodies cross-react specifically with mycobacterial hsp65, and we have demonstrated that the motif SxGDL[ILV]AE shared by PDC-E2(212-226) and hsp's is a cross-reactive target [30].
  • Transcytosis experiments performed using human polymeric immunoglobulin receptor (pIgR) expressing Madine-Darby canine kidney (MDCK) cells showed that one of the recombinants showed a high degree of colocalization with PDC-E2 [31].
 

Other interactions of DLAT

 

Analytical, diagnostic and therapeutic context of DLAT

  • Sera from 47 PBC patients were studied by immunoblotting and enzyme-linked immunosorbent assay (ELISA) against rE2, rE3BP, rE3BPCore, and both unlipoylated (U) and lipoylated (L) rLip [1].
  • The apparent importance of autoreactive responses to these self-antigens does, however, raise the possibility that antigen-specific immunotherapy may offer a novel route to therapy in PBC [23].
  • We examined the immunoreactivity of AMA by immunofluorescense, immunoblotting, and enzyme inhibition assay in serum samples from 59 patients with liver diseases other than PBC and 71 healthy subjects [3].
  • Although the ELISA based approaches have advantages in terms of laboratory practicality, they are slightly less sensitive for the diagnosis of PBC than immunofluorescence (occasional patients with PBC show reactivity with PDC related antigens not present in the antigen preparations available for use with ELISA) [35].
  • The serum reaction to anti-2-oxo-acid dehydrogenase complex (2-OADC) enzymes, the antigens recognized by antimitochondrial antibodies (AMA), can be detected by immunoblotting in patients with liver diseases other than primary biliary cirrhosis (PBC), who are negative for AMA by conventional indirect immunofluorescence [3].

References

  1. Characterization of the autoantibody responses to recombinant E3 binding protein (protein X) of pyruvate dehydrogenase in primary biliary cirrhosis. Palmer, J.M., Jones, D.E., Quinn, J., McHugh, A., Yeaman, S.J. Hepatology (1999) [Pubmed]
  2. In situ nucleic acid detection of PDC-E2, BCOADC-E2, OGDC-E2, PDC-E1alpha, BCOADC-E1alpha, OGDC-E1, and the E3 binding protein (protein X) in primary biliary cirrhosis. Harada, K., Sudo, Y., Kono, N., Ozaki, S., Tsuneyama, K., Gershwin, M.E., Nakanuma, Y. Hepatology (1999) [Pubmed]
  3. Clinical significance of positive immunoblotting but negative immunofluorescence for antimitochondrial antibodies in patients with liver diseases other than primary biliary cirrhosis. Masuda, J., Omagar, K., Miyakawa, H., Hazama, H., Ohba, K., Kinoshita, H., Matsuo, I., Isomoto, H., Murata, I., Kohno, S. Autoimmunity (2002) [Pubmed]
  4. Autoreactive responses to pyruvate dehydrogenase complex in the pathogenesis of primary biliary cirrhosis. Yeaman, S.J., Kirby, J.A., Jones, D.E. Immunol. Rev. (2000) [Pubmed]
  5. Disease-specific cross-reactivity between mimicking peptides of heat shock protein of Mycobacterium gordonae and dominant epitope of E2 subunit of pyruvate dehydrogenase is common in Spanish but not British patients with primary biliary cirrhosis. Bogdanos, D.P., Pares, A., Baum, H., Caballeria, L., Rigopoulou, E.I., Ma, Y., Burroughs, A.K., Rodes, J., Vergani, D. J. Autoimmun. (2004) [Pubmed]
  6. Differential epitope mapping of antibodies to PDC-E2 in patients with hematologic malignancies after allogeneic hematopoietic stem cell transplantation and primary biliary cirrhosis. Bellucci, R., Oertelt, S., Gallagher, M., Li, S., Zorn, E., Weller, E., Porcheray, F., Alyea, E.P., Soiffer, R.J., Munshi, N.C., Gershwin, M.E., Ritz, J. Blood (2007) [Pubmed]
  7. Carbohydrate-deficient transferrin and false-positive results for alcohol abuse in primary biliary cirrhosis: differential diagnosis by detection of mitochondrial autoantibodies. Bean, P., Sutphin, M.S., Liu, Y., Anton, R., Reynolds, T.B., Shoenfeld, Y., Peter, J.B. Clin. Chem. (1995) [Pubmed]
  8. Impact of fatigue on the quality of life of patients with primary biliary cirrhosis. Huet, P.M., Deslauriers, J., Tran, A., Faucher, C., Charbonneau, J. Am. J. Gastroenterol. (2000) [Pubmed]
  9. Structural features of envelope proteins on hepatitis C virus-like particles as determined by anti-envelope monoclonal antibodies and CD81 binding. Triyatni, M., Vergalla, J., Davis, A.R., Hadlock, K.G., Foung, S.K., Liang, T.J. Virology (2002) [Pubmed]
  10. Anti-DNA antibody idiotypes in primary biliary cirrhosis. Schattner, A., Kaburaki, Y., Kaplan, M.M., Miller, K.B. Cell. Immunol. (1987) [Pubmed]
  11. Carbohydrate-deficient transferrin, a marker for chronic alcohol consumption in different ethnic populations. Behrens, U.J., Worner, T.M., Braly, L.F., Schaffner, F., Lieber, C.S. Alcohol. Clin. Exp. Res. (1988) [Pubmed]
  12. Detection of autoantibodies to recombinant mitochondrial proteins in patients with primary biliary cirrhosis. Van de Water, J., Cooper, A., Surh, C.D., Coppel, R., Danner, D., Ansari, A., Dickson, R., Gershwin, M.E. N. Engl. J. Med. (1989) [Pubmed]
  13. Activation of gene expression by adenovirus and herpesvirus regulatory genes acting in trans and by a cis-acting adenovirus enhancer element. Imperiale, M.J., Feldman, L.T., Nevins, J.R. Cell (1983) [Pubmed]
  14. Bovine papillomavirus E2 trans-activating gene product binds to specific sites in papillomavirus DNA. Androphy, E.J., Lowy, D.R., Schiller, J.T. Nature (1987) [Pubmed]
  15. Chromosome localization and RFLP analysis of PDC-E2: the major autoantigen of primary biliary cirrhosis. Leung, P.S., Watanabe, Y., Munoz, S., Teuber, S.S., Patel, M.S., Korenberg, J.R., Hara, P., Coppel, R., Gershwin, M.E. Autoimmunity (1993) [Pubmed]
  16. Mobile sequences in the pyruvate dehydrogenase complex, the E2 component, the catalytic domain and the 2-oxoglutarate dehydrogenase complex of Azotobacter vinelandii, as detected by 600 MHz 1H-NMR spectroscopy. Hanemaaijer, R., Vervoort, J., Westphal, A.H., de Kok, A., Veeger, C. FEBS Lett. (1988) [Pubmed]
  17. Autoantibodies from patients with primary biliary cirrhosis recognize a restricted region within the cytoplasmic tail of nuclear pore membrane glycoprotein Gp210. Nickowitz, R.E., Worman, H.J. J. Exp. Med. (1993) [Pubmed]
  18. The effect of ursodeoxycholic acid therapy on the natural course of primary biliary cirrhosis. Corpechot, C., Carrat, F., Bahr, A., Chrétien, Y., Poupon, R.E., Poupon, R. Gastroenterology (2005) [Pubmed]
  19. Facilitated interaction between the pyruvate dehydrogenase kinase isoform 2 and the dihydrolipoyl acetyltransferase. Hiromasa, Y., Roche, T.E. J. Biol. Chem. (2003) [Pubmed]
  20. Fine specificity of T cells reactive to human PDC-E2 163-176 peptide, the immunodominant autoantigen in primary biliary cirrhosis: implications for molecular mimicry and cross-recognition among mitochondrial autoantigens. Shigematsu, H., Shimoda, S., Nakamura, M., Matsushita, S., Nishimura, Y., Sakamoto, N., Ichiki, Y., Niho, Y., Gershwin, M.E., Ishibashi, H. Hepatology (2000) [Pubmed]
  21. Comprehensive mapping of HLA-A0201-restricted CD8 T-cell epitopes on PDC-E2 in primary biliary cirrhosis. Matsumura, S., Kita, H., He, X.S., Ansari, A.A., Lian, Z.X., Van De Water, J., Yamamoto, K., Tsuji, T., Coppel, R.L., Kaplan, M., Gershwin, M.E. Hepatology (2002) [Pubmed]
  22. Clinical and genetic spectrum of pyruvate dehydrogenase deficiency: dihydrolipoamide acetyltransferase (E2) deficiency. Head, R.A., Brown, R.M., Zolkipli, Z., Shahdadpuri, R., King, M.D., Clayton, P.T., Brown, G.K. Ann. Neurol. (2005) [Pubmed]
  23. Biochemistry and autoimmune response to the 2-oxoacid dehydrogenase complexes in primary biliary cirrhosis. Bassendine, M.F., Jones, D.E., Yeaman, S.J. Semin. Liver Dis. (1997) [Pubmed]
  24. T cell responses to the putative dominant autoepitope in primary biliary cirrhosis (PBC). Palmer, J.M., Diamond, A.G., Yeaman, S.J., Bassendine, M.F., Jones, D.E. Clin. Exp. Immunol. (1999) [Pubmed]
  25. Marked differences between two isoforms of human pyruvate dehydrogenase kinase. Baker, J.C., Yan, X., Peng, T., Kasten, S., Roche, T.E. J. Biol. Chem. (2000) [Pubmed]
  26. Distinct regulatory properties of pyruvate dehydrogenase kinase and phosphatase isoforms. Roche, T.E., Baker, J.C., Yan, X., Hiromasa, Y., Gong, X., Peng, T., Dong, J., Turkan, A., Kasten, S.A. Prog. Nucleic Acid Res. Mol. Biol. (2001) [Pubmed]
  27. Molecular biology of the human pyruvate dehydrogenase complex: structural aspects of the E2 and E3 components. Thekkumkara, T.J., Pons, G., Mitroo, S., Jentoft, J.E., Patel, M.S. Ann. N. Y. Acad. Sci. (1989) [Pubmed]
  28. Pyruvate dehydrogenase kinase isoform 2 activity stimulated by speeding up the rate of dissociation of ADP. Bao, H., Kasten, S.A., Yan, X., Hiromasa, Y., Roche, T.E. Biochemistry (2004) [Pubmed]
  29. Humoral and cellular immune responses to dihydrolipoamide dehydrogenase (E3): lack of specificity for primary biliary cirrhosis. Tanaka, H., Maeda, T., Onishi, S., Yamamoto, Y. Liver (1995) [Pubmed]
  30. Primary biliary cirrhosis is characterized by IgG3 antibodies cross-reactive with the major mitochondrial autoepitope and its Lactobacillus mimic. Bogdanos, D.P., Baum, H., Okamoto, M., Montalto, P., Sharma, U.C., Rigopoulou, E.I., Vlachogiannakos, J., Ma, Y., Burroughs, A.K., Vergani, D. Hepatology (2005) [Pubmed]
  31. Characterization of recombinant monoclonal IgA anti-PDC-E2 autoantibodies derived from patients with PBC. Fukushima, N., Nalbandian, G., Van De Water, J., White, K., Ansari, A.A., Leung, P., Kenny, T., Kamita, S.G., Hammock, B.D., Coppel, R.L., Stevenson, F., Ishibashi, H., Gershwin, M.E. Hepatology (2002) [Pubmed]
  32. Deficiency of the pyruvate dehydrogenase component in pyruvate dehydrogenase complex-deficient human fibroblasts. Immunological identification. Ho, L., Hu, C.W., Packman, S., Patel, M.S. J. Clin. Invest. (1986) [Pubmed]
  33. Molecular architecture of the pyruvate dehydrogenase complex: bridging the gap. Smolle, M., Lindsay, J.G. Biochem. Soc. Trans. (2006) [Pubmed]
  34. Immunoglobulin gene usage and immunohistochemical characteristics of human monoclonal antibodies to the mitochondrial autoantigens of primary biliary cirrhosis induced in the XenoMouse. Sasaki, M., Van De Water, J., Kenny, T.P., Gallo, M.L., Leung, P.S., Nakanuma, Y., Ansari, A.A., Coppel, R.L., Neuberger, J., Gershwin, M.E. Hepatology (2001) [Pubmed]
  35. Autoantigens in primary biliary cirrhosis. Jones, D.E. J. Clin. Pathol. (2000) [Pubmed]
 
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