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Gene Review

PDHX  -  pyruvate dehydrogenase complex, component X

Homo sapiens

Synonyms: DLDBP, Dihydrolipoamide dehydrogenase-binding protein of pyruvate dehydrogenase complex, E3-binding protein, E3BP, Lipoyl-containing pyruvate dehydrogenase complex component X, ...
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Disease relevance of PDHX


High impact information on PDHX

  • Transcription factors such as Pdx1, p48 and Nkx2.2 have been shown to be essential for the proper differentiation of exocrine and endocrine tissue; however, pancreas development also involves intricate interactions between the pancreatic epithelium and its surrounding mesenchyme [6].
  • Here we report the 3D structure of the PLP synthase complex with substrate glutamine bound as well as those of the individual synthase and glutaminase subunits Pdx1 and Pdx2, respectively [7].
  • Insulin protects islets from apoptosis via Pdx1 and specific changes in the human islet proteome [8].
  • PDX-1-treated human liver cells express insulin, store it in defined granules, and secrete the hormone in a glucose-regulated manner [9].
  • The results suggests that cyclopamine expands the endodermal region where Shh signaling does not occur, resulting in pancreatic differentiation in a larger region of PDX1-expressing foregut endoderm [10].

Chemical compound and disease context of PDHX


Biological context of PDHX

  • The 9.5 MDa human pyruvate dehydrogenase complex (PDC) utilizes the specific dihydrolipoamide dehydrogenase (E3) binding protein (E3BP) to tether the essential E3 component to the 60-meric core of the complex [15].
  • Attempts to resolve E3BP from E2 have been unsuccessful, restricting study of the nature and significance of antibody responses to the individual proteins [1].
  • Furthermore, adenovirus-mediated Foxo1 overexpression reduced the nuclear expression of PDX-1, whereas repression of Foxo1 by Foxo1-specific small interfering RNA retained the nuclear expression of PDX-1 under oxidative stress conditions [16].
  • The sequence of exons 1-9 and exon 11 of the PDHX gene were normal, but exon 10 was impossible to amplify with standard PCR [17].
  • Since the L1 element inserted in the PDHX gene is full-length, we favor the model of the template jumping as opposed to that of the microhomology-mediated end-joining for linking the 5' end of the nascent L1 copy to its genomic target [18].

Anatomical context of PDHX

  • 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 [19].
  • It has been shown that oxidative stress and activation of the c-Jun N-terminal kinase (JNK) pathway induce the nucleocytoplasmic translocation of the pancreatic transcription factor PDX-1, which leads to pancreatic beta-cell dysfunction [16].
  • These complexes, which are larger than ribosomes and which consist of multiple copies of E1, E2, and E3 subunits together with regulatory kinases and phosphatases and, in the case of PDC, an E3-binding protein (protein X), each play an important role in oxidative metabolism in mitochondria [20].
  • We previously reported that exogenous PDX-1 protein can permeate cells and induce insulin gene expression in progenitor cells [21].
  • To gain further insight into the nature and function of the domains of the human protein X (a pyruvate dehydrogenase complex component also known as the E3-binding protein), we expressed the wild-type as well as two artificially created variants, K37E and S422H, in SV40-immortalized protein X-deficient and E2-deficient human skin fibroblasts [22].

Associations of PDHX with chemical compounds


Physical interactions of PDHX

  • Here, we report crystal structures of the binding domain (E3BD) of human E3BP alone and in complex with human E3 at 1.6 angstroms and 2.2 angstroms, respectively [15].
  • The dihydrolipoyl acetyltransferase (E2) and the dihydrolipoyl dehydrogenase-binding protein (E3BP) are multidomain proteins that form the oligomeric core of the complex [26].

Other interactions of PDHX

  • Structural insight into interactions between dihydrolipoamide dehydrogenase (E3) and E3 binding protein of human pyruvate dehydrogenase complex [15].
  • The forkhead transcription factor Foxo1 bridges the JNK pathway and the transcription factor PDX-1 through its intracellular translocation [16].
  • In this study, we have shown that the forkhead transcription factor Foxo1/FKHR plays a role as a mediator between the JNK pathway and PDX-1 [16].
  • Firstly, the sequence corresponding to the lipoic domain of E3BP (E3BP-LD) was amplified by polymerase chain reaction and recombinant protein and then purified [11].
  • Gel shift assays demonstrated the physical association between a homeodomain protein, pancreatic-duodenal homeobox factor-1 (PDX1) and the 45-bp cytomegalovirus (CMV) region [4].

Analytical, diagnostic and therapeutic context of PDHX

  • In this study, we characterized binding of human E3 to the E3-binding domain of E3BP by x-ray crystallography at 2.6-angstroms resolution, and we used this structural information to interpret the specificity for selective binding [27].
  • Sequence analysis of the PDHc E1 alpha gene and the PDHX genes revealed no mutations [28].
  • The suppression of oxidative stress by a potent antioxidant, N-acetyl-l-cysteine or probucol, led to the recovery of insulin biosynthesis and PDX-1 expression in nuclei and improved glucose tolerance in animal models for type 2 diabetes [29].
  • Important regulators of beta-cell formation and function, PDX-1, FoxA2, and Nkx2.2, were shown to specifically bind to region 3 in vivo using the chromatin immunoprecipitation assay [30].
  • We used DNA binding (gel shift) assays and Western immunoblots to demonstrate that cellular levels of the transcription factor PDX-1, normally decreased by glucotoxicity, were preserved with CDK5 inhibition, as was the binding of PDX-1 to the insulin promoter [31].


  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. 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]
  3. Leigh's disease due to a new mutation in the PDHX gene. Schiff, M., Miné, M., Brivet, M., Marsac, C., Elmaleh-Bergés, M., Evrard, P., Ogier de Baulny, H. Ann. Neurol. (2006) [Pubmed]
  4. PDX1, a cellular homeoprotein, binds to and regulates the activity of human cytomegalovirus immediate early promoter. Chao, S.H., Harada, J.N., Hyndman, F., Gao, X., Nelson, C.G., Chanda, S.K., Caldwell, J.S. J. Biol. Chem. (2004) [Pubmed]
  5. Endocrine pancreatic tissue plasticity in obese humans is associated with cytoplasmic expression of PBX-1 in pancreatic ductal cells. Muharram, G., Beucher, A., Moerman, E., Belaïch, S., Gmyr, V., Vandewalle, B., Pattou, F., Kerr-Conte, J. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  6. Pancreas development and diabetes. St-Onge, L., Wehr, R., Gruss, P. Curr. Opin. Genet. Dev. (1999) [Pubmed]
  7. Structure of a bacterial pyridoxal 5'-phosphate synthase complex. Strohmeier, M., Raschle, T., Mazurkiewicz, J., Rippe, K., Sinning, I., Fitzpatrick, T.B., Tews, I. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  8. Insulin protects islets from apoptosis via Pdx1 and specific changes in the human islet proteome. Johnson, J.D., Bernal-Mizrachi, E., Alejandro, E.U., Han, Z., Kalynyak, T.B., Li, H., Beith, J.L., Gross, J., Warnock, G.L., Townsend, R.R., Permutt, M.A., Polonsky, K.S. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  9. Cell-replacement therapy for diabetes: Generating functional insulin-producing tissue from adult human liver cells. Sapir, T., Shternhall, K., Meivar-Levy, I., Blumenfeld, T., Cohen, H., Skutelsky, E., Eventov-Friedman, S., Barshack, I., Goldberg, I., Pri-Chen, S., Ben-Dor, L., Polak-Charcon, S., Karasik, A., Shimon, I., Mor, E., Ferber, S. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  10. Pancreas development is promoted by cyclopamine, a hedgehog signaling inhibitor. Kim, S.K., Melton, D.A. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  11. Autoepitope mapping and reactivity of autoantibodies to the dihydrolipoamide dehydrogenase-binding protein (E3BP) and the glycine cleavage proteins in primary biliary cirrhosis. Dubel, L., Tanaka, A., Leung, P.S., Van de Water, J., Coppel, R., Roche, T., Johanet, C., Motokawa, Y., Ansari, A., Gershwin, M.E. Hepatology (1999) [Pubmed]
  12. Lactic acidosis and developmental delay due to deficiency of E3 binding protein (protein X) of the pyruvate dehydrogenase complex. Ramadan, D.G., Head, R.A., Al-Tawari, A., Habeeb, Y., Zaki, M., Al-Ruqum, F., Besley, G.T., Wraith, J.E., Brown, R.M., Brown, G.K. J. Inherit. Metab. Dis. (2004) [Pubmed]
  13. Pancreatic Duodenal Homeobox (PDX-1) in health and disease. Melloul, D., Tsur, A., Zangen, D. Journal of pediatric endocrinology & metabolism : JPEM. (2002) [Pubmed]
  14. In vitro transdifferentiation of mature hepatocytes into insulin-producing cells. Yamada, S., Yamamoto, Y., Nagasawa, M., Hara, A., Kodera, T., Kojima, I. Endocr. J. (2006) [Pubmed]
  15. Structural insight into interactions between dihydrolipoamide dehydrogenase (E3) and E3 binding protein of human pyruvate dehydrogenase complex. Brautigam, C.A., Wynn, R.M., Chuang, J.L., Machius, M., Tomchick, D.R., Chuang, D.T. Structure (2006) [Pubmed]
  16. The forkhead transcription factor Foxo1 bridges the JNK pathway and the transcription factor PDX-1 through its intracellular translocation. Kawamori, D., Kaneto, H., Nakatani, Y., Matsuoka, T.A., Matsuhisa, M., Hori, M., Yamasaki, Y. J. Biol. Chem. (2006) [Pubmed]
  17. A novel gross deletion caused by non-homologous recombination of the PDHX gene in a patient with pyruvate dehydrogenase deficiency. Miné, M., Brivet, M., Schiff, M., de Baulny, H.O., Chuzhanova, N., Marsac, C. Mol. Genet. Metab. (2006) [Pubmed]
  18. A large genomic deletion in the PDHX gene caused by the retrotranspositional insertion of a full-length LINE-1 element. Miné, M., Chen, J.M., Brivet, M., Desguerre, I., Marchant, D., de Lonlay, P., Bernard, A., Férec, C., Abitbol, M., Ricquier, D., Marsac, C. Hum. Mutat. (2007) [Pubmed]
  19. 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]
  20. 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]
  21. Mechanism of PDX-1 protein transduction. Noguchi, H., Matsushita, M., Matsumoto, S., Lu, Y.F., Matsui, H., Bonner-Weir, S. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  22. Expression and functional characterization of human protein X variants in SV40-immortalized protein X-deficient and E2-deficient human skin fibroblasts. Seyda, A., Robinson, B.H. Arch. Biochem. Biophys. (2000) [Pubmed]
  23. Organization of the cores of the mammalian pyruvate dehydrogenase complex formed by E2 and E2 plus the E3-binding protein and their capacities to bind the E1 and E3 components. Hiromasa, Y., Fujisawa, T., Aso, Y., Roche, T.E. J. Biol. Chem. (2004) [Pubmed]
  24. Does the aspartic acid to asparagine substitution at position 76 in the pancreas duodenum homeobox gene (PDX1) cause late-onset type 2 diabetes? Elbein, S.C., Karim, M.A. Diabetes Care (2004) [Pubmed]
  25. Pyruvate dehydrogenase E3 binding protein deficiency. Brown, R.M., Head, R.A., Brown, G.K. Hum. Genet. (2002) [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. How dihydrolipoamide dehydrogenase-binding protein binds dihydrolipoamide dehydrogenase in the human pyruvate dehydrogenase complex. Ciszak, E.M., Makal, A., Hong, Y.S., Vettaikkorumakankauv, A.K., Korotchkina, L.G., Patel, M.S. J. Biol. Chem. (2006) [Pubmed]
  28. Mitochondrial dysfunction in a patient with Joubert syndrome. Morava, E., Dinopoulos, A., Kroes, H.Y., Rodenburg, R.J., van Bokhoven, H., van den Heuvel, L.P., Smeitink, J.A. Neuropediatrics. (2005) [Pubmed]
  29. Oxidative stress and pancreatic beta-cell dysfunction. Kaneto, H., Kawamori, D., Matsuoka, T.A., Kajimoto, Y., Yamasaki, Y. American journal of therapeutics. (2005) [Pubmed]
  30. FoxA2, Nkx2.2, and PDX-1 regulate islet beta-cell-specific mafA expression through conserved sequences located between base pairs -8118 and -7750 upstream from the transcription start site. Raum, J.C., Gerrish, K., Artner, I., Henderson, E., Guo, M., Sussel, L., Schisler, J.C., Newgard, C.B., Stein, R. Mol. Cell. Biol. (2006) [Pubmed]
  31. Inhibition of Cyclin-dependent Kinase 5 Activity Protects Pancreatic Beta Cells from Glucotoxicity. Ubeda, M., Rukstalis, J.M., Habener, J.F. J. Biol. Chem. (2006) [Pubmed]
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