Skip to main content
SpringerLink
Log in

Directed regulation of multienzyme complexes of 2-oxo acid dehydrogenases using phosphonate and phosphinate analogs of 2-oxo acids

  • Regular Papers
  • Review
  • Published:
Biochemistry (Moscow) Aims and scope Submit manuscript

Abstract

2-Oxo acid dehydrogenase complexes are important metabolic checkpoints functioning at the intercept of sugar and amino acid degradation. This review presents a short summary of architectural, catalytic, and regulatory principles of the complexes structure and function, based on recent advances in studies of well-characterized family members. Special attention is given to use of synthetic phosphonate and phosphinate analogs of 2-oxo acids as selective and efficient inhibitors of the cognate complexes in biological systems of bacterial, plant, and animal origin. We summarize our own results concerning the application of synthetic analogs of 2-oxo acids in situ and in vivo to reveal functional interactions between 2-oxo acid dehydrogenase complexes and other components of metabolic networks specific to different cells and tissues. Based on our study of glutamate excitotoxicity in cultured neurons, we show how a modulation of metabolism by specific inhibition of its key reaction may be employed to correct pathologies. This approach is further developed in our study on the action of the phosphonate analog of 2-oxoglutarate in animals. The study revealed that upregulation of 2-oxoglutarate dehydrogenase complex is involved in animal stress response and may provide increased resistance to damaging effects, underlying so-called preconditioning. The presented analysis of published data suggests synthetic inhibitors of metabolic checkpoints as promising tools to solve modern challenges of systems biology, metabolic engineering, and medicine.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

AcP:

acetyl phosphonate

AcPH:

acetyl phosphinate

AcPMe:

methyl ester of acetyl phosphonate

AcPMe2 :

dimethyl ester of acetyl phosphonate

BCDHC:

branched-chain 2-oxo acid dehydrogenase complex

BDK:

branched-chain 2-oxo acid dehydrogenase kinase

BDP:

branched-chain 2-oxo acid dehydrogenase phosphatase

DHTKD1:

dehydrogenase and transketolase domain containing protein 1

MeAcPH:

methyl (acetyl) phosphinate

OGDH:

2-oxoglutarate dehydrogenase

OGDHC:

2-oxoglutarate dehydrogenase complex

OGDHL:

2-oxoglutarate dehydrogenase-like protein

PDHC:

pyruvate dehydrogenase complex

PDK:

pyruvate dehydrogenase kinase

PDP:

pyruvate dehydrogenase phosphatase

PESP:

phosphonoethyl ester of succinyl phosphonate

PMSP:

phosphonomethyl ester of succinyl phosphonate

SP:

succinyl phosphonate

ThDP:

thiamine diphosphate

References

  1. Bunik, V. I., Raddatz, G., and Strumilo, S. A. (2013) Translating enzymology into metabolic regulation: the case of the 2-oxoglutarate dehydrogenase multienzyme complex, Curr. Chem. Biol., 7, 74–93.

    Article  CAS  Google Scholar 

  2. Bunik, V. I., Tylicki, A., and Lukashev, N. V. (2013) Thiamin diphosphate-dependent enzymes: from enzymology to metabolic regulation, drug design and disease models, FEBS J., 280, 6412–6442.

    Article  CAS  PubMed  Google Scholar 

  3. Dahl, H. H., Brown, R. M., Hutchison, W. M., Maragos, C., and Brown, G. K. (1990) A testis-specific form of the human pyruvate dehydrogenase E1 alpha subunit is coded for by an intronless gene on chromosome 4, Genomics, 8, 225–232.

    Article  CAS  PubMed  Google Scholar 

  4. Bunik, V. I., and Degtyarev, D. (2008) Structure–function relationships in the 2-oxo acid dehydrogenase family: substrate-specific signatures and functional predictions for the 2-oxoglutarate dehydrogenase-like proteins, Proteins, 71, 874–890.

    Article  CAS  PubMed  Google Scholar 

  5. Bunik, V., Kaehne, T., Degtyarev, D., Shcherbakova, T., and Reiser, G. (2008) Novel isoenzyme of 2-oxoglutarate dehydrogenase is identified in brain, but not in heart, FEBS J., 275, 4990–5006.

    Article  CAS  PubMed  Google Scholar 

  6. Denton, R. M., Pullen, T. J., Armstrong, C. T., Heesom, K. J., and Rutter, G. A. (2016) Calcium-insensitive splice variants of mammalian E1 subunit of 2-oxoglutarate dehydrogenase complex with tissue-specific patterns of expression, Biochem. J., 473, 1165–1178.

    Article  CAS  PubMed  Google Scholar 

  7. Hoque, M. O., Kim, M. S., Ostrow, K. L., Liu, J., Wisman, G. B., Park, H. L., Poeta, M. L., Jeronimo, C., Henrique, R., Lendvai, A., Schuuring, E., Begum, S., Rosenbaum, E., Ongenaert, M., Yamashita, K., Califano, J., Westra, W., Van der Zee, A. G., Van Criekinge, W., and Sidransky, D. (2008) Genome-wide promoter analysis uncovers portions of the cancer methylome, Cancer Res., 68, 2661–2670.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ostrow, K. L., Park, H. L., Hoque, M. O., Kim, M. S., Liu, J., Argani, P., Westra, W., Van Criekinge, W., and Sidransky, D. (2009) Pharmacologic unmasking of epigenetically silenced genes in breast cancer, Clin. Cancer Res., 15, 1184–1191.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Fedorova, M. S., Kudryavtseva, A. V., Lakunina, V. A., Snezhlina, A. V., Volchenko, N. N., Slavnova, E. N., Danilova, T. V., Sadritdinova, A. F., Melnikova, N. V., Belova, A. A., Klimina, K. M., Sidorov, D. V., Alexeev, B. Y., Kaprin, A. D., Dmitriev, A. A., and Krasnov, G. S. (2015) Downregulation of OGDHL expression is associated with promoter hypermethylation in colorectal cancer, Mol. Biol. (Moscow), 49, 678–688.

    Article  CAS  Google Scholar 

  10. Sen, T., Sen, N., Noordhuis, M. G., Ravi, R., Wu, T. C., Ha, P. K., Sidransky, D., and Hoque, M. O. (2012) OGDHL is a modifier of AKT-dependent signaling and NF-kappaB function, PLoS One, 7, e48770.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Danhauser, K., Sauer, S. W., Haack, T. B., Wieland, T., Staufner, C., Graf, E., Zschocke, J., Strom, T. M., Traub, T., Okun, J. G., Meitinger, T., Hoffmann, G. F., Prokisch, H., and Kolker, S. (2012) DHTKD1 mutations cause 2aminoadipic and 2-oxoadipic aciduria, Am. J. Hum. Genet., 91, 1082–1087.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hagen, J., te Brinke, H., Wanders, R. J., Knegt, A. C., Oussoren, E., Hoogeboom, A. J., Ruijter, G. J., Becker, D., Schwab, K. O., Franke, I., Duran, M., Waterham, H. R., Sass, J. O., and Houten, S. M. (2015) Genetic basis of alpha-aminoadipic and alpha-ketoadipic aciduria, J. Inherit. Metab. Dis., 38, 873–879.

    Article  CAS  PubMed  Google Scholar 

  13. Stiles, A. R., Venturoni, L., Mucci, G., Elbalalesy, N., Woontner, M., Goodman, S., and Abdenur, J. E. (2015) New cases of DHTKD1 mutations in patients with 2ketoadipic aciduria, JIMD Rep., 25, 15–19.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Bunik, V., Westphal, A. H., and De Kok, A. (2000) Kinetic properties of the 2-oxoglutarate dehydrogenase complex from Azotobacter vinelandii evidence for the formation of a precatalytic complex with 2-oxoglutarate, Eur. J. Biochem., 267, 3583–3591.

    Article  CAS  PubMed  Google Scholar 

  15. Bunik, V. I., and Pavlova, O. G. (1993) Inactivation of alpha-ketoglutarate dehydrogenase during oxidative decarboxylation of alpha-ketoadipic acid, FEBS Lett., 323, 166–170.

    Article  CAS  PubMed  Google Scholar 

  16. Goncalves, R. L., Bunik, V. I., and Brand, M. D. (2016) Production of superoxide/hydrogen peroxide by the mitochondrial 2-oxoadipate dehydrogenase complex, Free Radic. Biol. Med., 91, 247–255.

    Article  CAS  PubMed  Google Scholar 

  17. Xu, W., Zhu, H., Gu, M., Luo, Q., Ding, J., Yao, Y., Chen, F., and Wang, Z. (2013) DHTKD1 is essential for mitochondrial biogenesis and function maintenance, FEBS Lett., 587, 3587–3592.

    Article  CAS  PubMed  Google Scholar 

  18. Jia, X., Miao, Z., Li, W., Zhang, L., Feng, C., He, Y., Bi, X., Wang, L., Du, Y., Hou, M., Hao, D., Xiao, Y., Chen, L., and Li, K. (2014) Cancer-risk module identification and module-based disease risk evaluation: a case study on lung cancer, PLoS One, 9, e92395.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Wu, C., Orozco, C., Boyer, J., Leglise, M., Goodale, J., Batalov, S., Hodge, C. L., Haase, J., Janes, J., Huss, J. W., 3rd, and Su, A. I. (2009) BioGPS: an extensible and customizable portal for querying and organizing gene annotation resources, Genome Biol., 10, R130.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. GTEx Consortium (2013) The Genotype-Tissue Expression (GTEx) project, Nat. Genet., 45, 580–585.

    Article  CAS  Google Scholar 

  21. Xu, W. Y., Gu, M. M., Sun, L. H., Guo, W. T., Zhu, H. B., Ma, J. F., Yuan, W. T., Kuang, Y., Ji, B. J., Wu, X. L., Chen, Y., Zhang, H. X., Sun, F. T., Huang, W., Huang, L., Chen, S. D., and Wang, Z. G. (2012) A nonsense mutation in DHTKD1 causes Charcot–Marie–Tooth disease type 2 in a large Chinese pedigree, Am. J. Hum. Genet., 91, 1088–1094.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kumaran, S., Patel, M. S., and Jordan, F. (2013) Nuclear magnetic resonance approaches in the study of 2-oxo acid dehydrogenase multienzyme complexes–a literature review, Molecules, 18, 11873–11903.

    Article  CAS  PubMed  Google Scholar 

  23. Danson, M. J., Hooper, E. A., and Perham, R. N. (1978) Intramolecular coupling of active sites in the pyruvate dehydrogenase multienzyme complex of Escherichia coli, Biochem. J., 175, 193–198.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Cate, R. L., Roche, T. E., and Davis, L. C. (1980) Rapid intersite transfer of acetyl groups and movement of pyruvate dehydrogenase component in the kidney pyruvate dehydrogenase complex, J. Biol. Chem., 255, 7556–7562.

    CAS  PubMed  Google Scholar 

  25. Perham, R. N. (1991) Domains, motifs, and linkers in 2oxo acid dehydrogenase multienzyme complexes: a paradigm in the design of a multifunctional protein, Biochemistry, 30, 8501–8512.

    Article  CAS  PubMed  Google Scholar 

  26. Patel, M. S., and Korotchkina, L. G. (2001) Regulation of mammalian pyruvate dehydrogenase complex by phosphorylation: complexity of multiple phosphorylation sites and kinases, Exp. Mol. Med., 33, 191–197.

    Article  CAS  PubMed  Google Scholar 

  27. Mattevi, A., Schierbeek, A. J., and Hol, W. G. (1991) Refined crystal structure of lipoamide dehydrogenase from Azotobacter vinelandii at 2.2 Å resolution. A comparison with the structure of glutathione reductase, J. Mol. Biol., 220, 975–994.

    Article  CAS  PubMed  Google Scholar 

  28. Mattevi, A., Obmolova, G., Kalk, K. H., Van Berkel, W. J., and Hol, W. G. (1993) Three-dimensional structure of lipoamide dehydrogenase from Pseudomonas fluorescens at 2.8 Å resolution. Analysis of redox and thermostability properties, J. Mol. Biol., 230, 1200–1215.

    Article  CAS  PubMed  Google Scholar 

  29. Brautigam, C. A., Chuang, J. L., Tomchick, D. R., Machius, M., and Chuang, D. T. (2005) Crystal structure of human dihydrolipoamide dehydrogenase: NAD+/NADH binding and the structural basis of disease-causing mutations, J. Mol. Biol., 350, 543–552.

    Article  CAS  PubMed  Google Scholar 

  30. Aevarsson, A., Chuang, J. L., Wynn, R. M., Turley, S., Chuang, D. T., and Hol, W. G. (2000) Crystal structure of human branched-chain alpha-ketoacid dehydrogenase and the molecular basis of multienzyme complex deficiency in maple syrup urine disease, Structure, 8, 277–291.

    Article  CAS  PubMed  Google Scholar 

  31. Arjunan, P., Nemeria, N., Brunskill, A., Chandrasekhar, K., Sax, M., Yan, Y., Jordan, F., Guest, J. R., and Furey, W. (2002) Structure of the pyruvate dehydrogenase multienzyme complex E1 component from Escherichia coli at 1.85 Å resolution, Biochemistry, 41, 5213–5221.

    Article  CAS  PubMed  Google Scholar 

  32. Ciszak, E. M., Korotchkina, L. G., Dominiak, P. M., Sidhu, S., and Patel, M. S. (2003) Structural basis for flipflop action of thiamin pyrophosphate-dependent enzymes revealed by human pyruvate dehydrogenase, J. Biol. Chem., 278, 21240–21246.

    Article  CAS  PubMed  Google Scholar 

  33. Frank, R. A., Price, A. J., Northrop, F. D., Perham, R. N., and Luisi, B. F. (2007) Crystal structure of the E1 component of the Escherichia coli 2-oxoglutarate dehydrogenase multienzyme complex, J. Mol. Biol., 368, 639–651.

    Article  CAS  PubMed  Google Scholar 

  34. Kato, M., Wynn, R. M., Chuang, J. L., Tso, S. C., Machius, M., Li, J., and Chuang, D. T. (2008) Structural basis for inactivation of the human pyruvate dehydrogenase complex by phosphorylation: role of disordered phosphorylation loops, Structure, 16, 1849–1859.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Milne, J. L., Shi, D., Rosenthal, P. B., Sunshine, J. S., Domingo, G. J., Wu, X., Brooks, B. R., Perham, R. N., Henderson, R., and Subramaniam, S. (2002) Molecular architecture and mechanism of an icosahedral pyruvate dehydrogenase complex: a multifunctional catalytic machine, EMBO J., 21, 5587–5598.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Gu, Y., Zhou, Z. H., McCarthy, D. B., Reed, L. J., and Stoops, J. K. (2003) 3D electron microscopy reveals the variable deposition and protein dynamics of the peripheral pyruvate dehydrogenase component about the core, Proc. Natl. Acad. Sci. USA, 100, 7015–7020.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Murphy, G. E., and Jensen, G. J. (2005) Electron cryotomography of the E. coli pyruvate and 2-oxoglutarate dehydrogenase complexes, Structure, 13, 1765–1773.

    Article  CAS  PubMed  Google Scholar 

  38. Robien, M. A., Clore, G. M., Omichinski, J. G., Perham, R. N., Appella, E., Sakaguchi, K., and Gronenborn, A. M. (1992) Three-dimensional solution structure of the E3binding domain of the dihydrolipoamide succinyltransferase core from the 2-oxoglutarate dehydrogenase multienzyme complex of Escherichia coli, Biochemistry, 31, 3463–3471.

    Article  CAS  PubMed  Google Scholar 

  39. Mattevi, A., Obmolova, G., Kalk, K. H., Teplyakov, A., and Hol, W. G. (1993) Crystallographic analysis of substrate binding and catalysis in dihydrolipoyl transacetylase (E2p), Biochemistry, 32, 3887–3901.

    Article  CAS  PubMed  Google Scholar 

  40. Mattevi, A., Obmolova, G., Kalk, K. H., Westphal, A. H., De Kok, A., and Hol, W. G. (1993) Refined crystal structure of the catalytic domain of dihydrolipoyl transacetylase (E2p) from Azotobacter vinelandii at 2.6 Å resolution, J. Mol. Biol., 230, 1183–1199.

    Article  CAS  PubMed  Google Scholar 

  41. Kalia, Y. N., Brocklehurst, S. M., Hipps, D. S., Appella, E., Sakaguchi, K., and Perham, R. N. (1993) The high-resolution structure of the peripheral subunit-binding domain of dihydrolipoamide acetyltransferase from the pyruvate dehydrogenase multienzyme complex of Bacillus stearothermophilus, J. Mol. Biol., 230, 323–341.

    Article  CAS  PubMed  Google Scholar 

  42. Dardel, F., Davis, A. L., Laue, E. D., and Perham, R. N. (1993) Three-dimensional structure of the lipoyl domain from Bacillus stearothermophilus pyruvate dehydrogenase multienzyme complex, J. Mol. Biol., 229, 1037–1048.

    Article  CAS  PubMed  Google Scholar 

  43. Green, J. D., Laue, E. D., Perham, R. N., Ali, S. T., and Guest, J. R. (1995) Three-dimensional structure of a lipoyl domain from the dihydrolipoyl acetyltransferase component of the pyruvate dehydrogenase multienzyme complex of Escherichia coli, J. Mol. Biol., 248, 328–343.

    CAS  PubMed  Google Scholar 

  44. Ricaud, P. M., Howard, M. J., Roberts, E. L., Broadhurst, R. W., and Perham, R. N. (1996) Three-dimensional structure of the lipoyl domain from the dihydrolipoyl succinyltransferase component of the 2-oxoglutarate dehydrogenase multienzyme complex of Escherichia coli, J. Mol. Biol., 264, 179–190.

    Article  CAS  PubMed  Google Scholar 

  45. Chang, C. F., Chou, H. T., Chuang, J. L., Chuang, D. T., and Huang, T. H. (2002) Solution structure and dynamics of the lipoic acid-bearing domain of human mitochondrial branched-chain alpha-keto acid dehydrogenase complex, J. Biol. Chem., 277, 15865–15873.

    Article  CAS  PubMed  Google Scholar 

  46. Chang, C. F., Chou, H. T., Lin, Y. J., Lee, S. J., Chuang, J. L., Chuang, D. T., and Huang, T. H. (2006) Structure of the subunit binding domain and dynamics of the di-domain region from the core of human branched chain alphaketoacid dehydrogenase complex, J. Biol. Chem., 281, 28345–28353.

    Article  CAS  PubMed  Google Scholar 

  47. Wang, J., Nemeria, N. S., Chandrasekhar, K., Kumaran, S., Arjunan, P., Reynolds, S., Calero, G., Brukh, R., Kakalis, L., Furey, W., and Jordan, F. (2014) Structure and function of the catalytic domain of the dihydrolipoyl acetyltransferase component in Escherichia coli pyruvate dehydrogenase complex, J. Biol. Chem., 289, 15215–15230.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Jilka, J. M., Rahmatullah, M., Kazemi, M., and Roche, T. E. (1986) Properties of a newly characterized protein of the bovine kidney pyruvate dehydrogenase complex, J. Biol. Chem., 261, 1858–1867.

    CAS  PubMed  Google Scholar 

  49. Smolle, M., Prior, A. E., Brown, A. E., Cooper, A., Byron, O., and Lindsay, J. G. (2006) A new level of architectural complexity in the human pyruvate dehydrogenase complex, J. Biol. Chem., 281, 19772–19780.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Harris, R. A., Bowker-Kinley, M. M., Wu, P., Jeng, J., and Popov, K. M. (1997) Dihydrolipoamide dehydrogenasebinding protein of the human pyruvate dehydrogenase complex. DNA-derived amino acid sequence, expression, and reconstitution of the pyruvate dehydrogenase complex, J. Biol. Chem., 272, 19746–19751.

    Article  CAS  PubMed  Google Scholar 

  51. Behal, R. H., Browning, K. S., Hall, T. B., and Reed, L. J. (1989) Cloning and nucleotide sequence of the gene for protein X from Saccharomyces cerevisiae, Proc. Natl. Acad. Sci. USA, 86, 8732–8736.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Klingbeil, M. M., Walker, D. J., Arnette, R., Sidawy, E., Hayton, K., Komuniecki, P. R., and Komuniecki, R. (1996) Identification of a novel dihydrolipoyl dehydrogenase-binding protein in the pyruvate dehydrogenase complex of the anaerobic parasitic nematode, Ascaris suum, J. Biol. Chem., 271, 5451–5457.

    Article  CAS  PubMed  Google Scholar 

  53. Taylor, A. E., Cogdell, R. J., and Lindsay, J. G. (1992) Immunological comparison of the pyruvate dehydrogenase complexes from pea mitochondria and chloroplasts, Planta, 188, 225–231.

    Article  CAS  PubMed  Google Scholar 

  54. Broz, A. K., Tovar-Mendez, A., Mooney, B. P., Johnston, M. L., Miernyk, J. A., and Randall, D. D. (2014) A novel regulatory mechanism based upon a dynamic core structure for the mitochondrial pyruvate dehydrogenase complex? Mitochondrion, 19, Pt. B, 144–153.

    Article  CAS  PubMed  Google Scholar 

  55. Rice, J. E., Dunbar, B., and Lindsay, J. G. (1992) Sequences directing dihydrolipoamide dehydrogenase (E3) binding are located on the 2-oxoglutarate dehydrogenase (E1) component of the mammalian 2-oxoglutarate dehydrogenase multienzyme complex, EMBO J., 11, 3229–3235.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. McCartney, R. G., Rice, J. E., Sanderson, S. J., Bunik, V., Lindsay, H., and Lindsay, J. G. (1998) Subunit interactions in the mammalian alpha-ketoglutarate dehydrogenase complex. Evidence for direct association of the alphaketoglutarate dehydrogenase and dihydrolipoamide dehydrogenase components, J. Biol. Chem., 273, 24158–24164.

    Article  CAS  PubMed  Google Scholar 

  57. Hanemaaijer, R., Westphal, A. H., Van Der Heiden, T., De Kok, A., and Veeger, C. (1989) The quaternary structure of the dihydrolipoyl transacetylase component of the pyruvate dehydrogenase complex from Azotobacter vinelandii. A reconsideration, Eur. J. Biochem., 179, 287–292.

    Article  CAS  PubMed  Google Scholar 

  58. Izard, T., Sarfaty, S., Westphal, A., De Kok, A., and Hol, W. G. (1997) Improvement of diffraction quality upon rehydration of dehydrated icosahedral Enterococcus faecalis pyruvate dehydrogenase core crystals, Protein Sci., 6, 913–915.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. De Kok, A., Hengeveld, A. F., Martin, A., and Westphal, A. H. (1998) The pyruvate dehydrogenase multi-enzyme complex from Gram-negative bacteria, Biochim. Biophys. Acta, 1385, 353–366.

    Article  PubMed  Google Scholar 

  60. Randall, D. D., Miernyk, J. A., Fang, T. K., Budde, R. J., and Schuller, K. A. (1989) Regulation of the pyruvate dehydrogenase complexes in plants, Ann. N. Y. Acad. Sci., 573, 192–205.

    Article  CAS  PubMed  Google Scholar 

  61. Tovar-Mendez, A., Miernyk, J. A., and Randall, D. D. (2003) Regulation of pyruvate dehydrogenase complex activity in plant cells, Eur. J. Biochem., 270, 1043–1049.

    Article  CAS  PubMed  Google Scholar 

  62. Grande, H. J., Bresters, T. W., De Abreu, R. A., De Kok, A., and Veeger, C. (1975) The pyruvate-dehydrogenase complex from Azotobacter vinelandii. 3. Stoichiometry and function of the individual components, Eur. J. Biochem., 59, 355–363.

    Article  CAS  PubMed  Google Scholar 

  63. Bosma, H. J., De Kok, A., Westphal, A. H., and Veeger, C. (1984) The composition of the pyruvate dehydrogenase complex from Azotobacter vinelandii. Does a unifying model exist for the complexes from gram-negative bacteria? Eur. J. Biochem., 142, 541–549.

    Article  CAS  PubMed  Google Scholar 

  64. Schulze, E., Westphal, A. H., Boumans, H., and De Kok, A. (1991) Site-directed mutagenesis of the dihydrolipoyl transacetylase component (E2p) of the pyruvate dehydrogenase complex from Azotobacter vinelandii. Binding of the peripheral components E1p and E3, Eur. J. Biochem., 202, 841–848.

    Article  CAS  PubMed  Google Scholar 

  65. Lessard, I. A., and Perham, R. N. (1995) Interaction of component enzymes with the peripheral subunit-binding domain of the pyruvate dehydrogenase multienzyme complex of Bacillus stearothermophilus: stoichiometry and specificity in self-assembly, Biochem. J., 306 (Pt. 3), 727–733.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Domingo, G. J., Chauhan, H. J., Lessard, I. A., Fuller, C., and Perham, R. N. (1999) Self-assembly and catalytic activity of the pyruvate dehydrogenase multienzyme complex from Bacillus stearothermophilus, Eur. J. Biochem., 266, 1136–1146.

    Article  CAS  PubMed  Google Scholar 

  67. Reed, L. J., Pettit, F. H., Eley, M. H., Hamilton, L., Collins, J. H., and Oliver, R. M. (1975) Reconstitution of the Escherichia coli pyruvate dehydrogenase complex, Proc. Natl. Acad. Sci. USA, 72, 3068–3072.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Jung, H. I., Bowden, S. J., Cooper, A., and Perham, R. N. (2002) Thermodynamic analysis of the binding of component enzymes in the assembly of the pyruvate dehydrogenase multienzyme complex of Bacillus stearothermophilus, Protein Sci., 11, 1091–1100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Jung, H. I., Cooper, A., and Perham, R. N. (2003) Interactions of the peripheral subunit-binding domain of the dihydrolipoyl acetyltransferase component in the assembly of the pyruvate dehydrogenase multienzyme complex of Bacillus stearothermophilus, Eur. J. Biochem., 270, 4488–4496.

    Article  CAS  PubMed  Google Scholar 

  70. Strumilo, S. (2005) Short-term regulation of the alphaketoglutarate dehydrogenase complex by energy-linked and some other effectors, Biochemistry (Moscow), 70, 726–729.

    Article  CAS  Google Scholar 

  71. Strumilo, S. (2005) Short-term regulation of the mammalian pyruvate dehydrogenase complex, Acta Biochim. Pol., 52, 759–764.

    CAS  PubMed  Google Scholar 

  72. Tylicki, A., Bunik, V. I., and Strumilo, S. (2011) 2-Oxoglutarate dehydrogenase complex and its multipoint control, Postepy Biochem., 57, 304–313.

    PubMed  Google Scholar 

  73. Harris, R. A., Bowker-Kinley, M. M., Huang, B., and Wu, P. (2002) Regulation of the activity of the pyruvate dehydrogenase complex, Adv. Enzyme Regul., 42, 249–259.

    Article  CAS  PubMed  Google Scholar 

  74. Saunier, E., Benelli, C., and Bortoli, S. (2016) The pyruvate dehydrogenase complex in cancer: An old metabolic gatekeeper regulated by new pathways and pharmacological agents, Int. J. Cancer, 138, 809–817.

    Article  CAS  PubMed  Google Scholar 

  75. Obayashi, M., Sato, Y., Harris, R. A., and Shimomura, Y. (2001) Regulation of the activity of branched-chain 2-oxo acid dehydrogenase (BCODH) complex by binding BCODH kinase, FEBS Lett., 491, 50–54.

    Article  CAS  PubMed  Google Scholar 

  76. Armstrong, C. T., Anderson, J. L., and Denton, R. M. (2014) Studies on the regulation of the human E1 subunit of the 2-oxoglutarate dehydrogenase complex, including the identification of a novel calcium-binding site, Biochem. J., 459, 369–381.

    Article  CAS  PubMed  Google Scholar 

  77. Vassylyev, D. G., and Symersky, J. (2007) Crystal structure of pyruvate dehydrogenase phosphatase 1 and its functional implications, J. Mol. Biol., 370, 417–426.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Turkan, A., Hiromasa, Y., and Roche, T. E. (2004) Formation of a complex of the catalytic subunit of pyruvate dehydrogenase phosphatase isoform 1 (PDP1c) and the L2 domain forms a Ca2+ binding site and captures PDP1c as a monomer, Biochemistry, 43, 15073–15085.

    Article  CAS  PubMed  Google Scholar 

  79. Olson, M. S. (1989) Regulation of the mitochondrial multienzyme complexes in complex metabolic systems, Ann. N. Y. Acad. Sci., 573, 218–229.

    Article  CAS  PubMed  Google Scholar 

  80. Bunik, V. I., Raddatz, G., Wanders, R. J., and Reiser, G. (2006) Brain pyruvate and 2-oxoglutarate dehydrogenase complexes are mitochondrial targets of the CoA ester of the Refsum disease marker phytanic acid, FEBS Lett., 580, 3551–3557.

    Article  CAS  PubMed  Google Scholar 

  81. Strumilo, S. A., and Vinogradov, V. V. (1988) Vitamin-Dependent Enzymes of Adrenal Gland (2-Oxo Acid Dehydrogenases) [in Russian], Institute for Biochemistry of the Academy of Sciences of BSSR, Minsk.

    Google Scholar 

  82. Patel, M. S. (1974) Inhibition by the branched-chain 2-oxo acids of the 2-oxoglutarate dehydrogenase complex in developing rat and human brain, Biochem. J., 144, 91–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Gudi, R., Bowker-Kinley, M. M., Kedishvili, N. Y., Zhao, Y., and Popov, K. M. (1995) Diversity of the pyruvate dehydrogenase kinase gene family in humans, J. Biol. Chem., 270, 28989–28994.

    Article  CAS  PubMed  Google Scholar 

  84. Huang, B., Gudi, R., Wu, P., Harris, R. A., Hamilton, J., and Popov, K. M. (1998) Isoenzymes of pyruvate dehydrogenase phosphatase. DNA-derived amino acid sequences, expression, and regulation, J. Biol. Chem., 273, 17680–17688.

    Article  CAS  PubMed  Google Scholar 

  85. Roche, T. E., Baker, J. C., Yan, X., Hiromasa, Y., Gong, X., Peng, T., Dong, J., Turkan, A., and Kasten, S. A. (2001) Distinct regulatory properties of pyruvate dehydrogenase kinase and phosphatase isoforms, Prog. Nucleic Acid Res. Mol. Biol., 70, 33–75.

    Article  CAS  PubMed  Google Scholar 

  86. Damuni, Z., Merryfield, M. L., Humphreys, J. S., and Reed, L. J. (1984) Purification and properties of branchedchain alpha-keto acid dehydrogenase phosphatase from bovine kidney, Proc. Natl. Acad. Sci. USA, 81, 4335–4338.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Huang, Y., and Chuang, D. T. (1996) Structural organization of the rat branched-chain 2-oxo-acid dehydrogenase kinase gene and partial characterization of the promoterregulatory region, Biochem. J., 313 (Pt. 2), 603–609.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Harris, R. A., Joshi, M., Jeoung, N. H., and Obayashi, M. (2005) Overview of the molecular and biochemical basis of branched-chain amino acid catabolism, J. Nutr., 135, 1527S–1530S.

    CAS  PubMed  Google Scholar 

  89. Shimomura, Y., Honda, T., Shiraki, M., Murakami, T., Sato, J., Kobayashi, H., Mawatari, K., Obayashi, M., and Harris, R. A. (2006) Branched-chain amino acid catabolism in exercise and liver disease, J. Nutr., 136, 250S–253S.

    CAS  PubMed  Google Scholar 

  90. Zhou, M., Lu, G., Gao, C., Wang, Y., and Sun, H. (2012) Tissue-specific and nutrient regulation of the branchedchain alpha-keto acid dehydrogenase phosphatase, protein phosphatase 2Cm (PP2Cm), J. Biol. Chem., 287, 23397–23406.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Oyarzabal, A., Martinez-Pardo, M., Merinero, B., Navarrete, R., Desviat, L. R., Ugarte, M., and Rodriguez-Pombo, P. (2013) A novel regulatory defect in the branched-chain alpha-keto acid dehydrogenase complex due to a mutation in the PPM1K gene causes a mild variant phenotype of maple syrup urine disease, Hum. Mutat., 34, 355–362.

    Article  CAS  PubMed  Google Scholar 

  92. Oyarzabal, A., Bravo-Alonso, I., Sanchez-Arago, M., Rejas, M. T., Merinero, B., Garcia-Cazorla, A., Artuch, R., Ugarte, M., and Rodriguez-Pombo, P. (2016) Mitochondrial response to the BCKDK-deficiency: some clues to understand the positive dietary response in this form of autism, Biochim. Biophys. Acta, 1862, 592–600.

    Article  CAS  PubMed  Google Scholar 

  93. Yan, J., Lawson, J. E., and Reed, L. J. (1996) Role of the regulatory subunit of bovine pyruvate dehydrogenase phosphatase, Proc. Natl. Acad. Sci. USA, 93, 4953–4956.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Lawson, J. E., Park, S. H., Mattison, A. R., Yan, J., and Reed, L. J. (1997) Cloning, expression, and properties of the regulatory subunit of bovine pyruvate dehydrogenase phosphatase, J. Biol. Chem., 272, 31625–31629.

    Article  CAS  PubMed  Google Scholar 

  95. Damuni, Z., Humphreys, J. S., and Reed, L. J. (1984) Stimulation of pyruvate dehydrogenase phosphatase activity by polyamines, Biochem. Biophys. Res. Commun., 124, 95–99.

    Article  CAS  PubMed  Google Scholar 

  96. Damuni, Z., Lim Tung, H. Y., and Reed, L. J. (1985) Specificity of the heat-stable protein inhibitor of the branched-chain alpha-keto acid dehydrogenase phosphatase, Biochem. Biophys. Res. Commun., 133, 878–883.

    Article  CAS  PubMed  Google Scholar 

  97. Damuni, Z., Humphreys, J. S., and Reed, L. J. (1986) A potent, heat-stable protein inhibitor of [branched-chain alpha-keto acid dehydrogenase]-phosphatase from bovine kidney mitochondria, Proc. Natl. Acad. Sci. USA, 83, 285–289.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Damuni, Z., and Reed, L. J. (1988) Branched-chain alpha-keto acid dehydrogenase phosphatase and its inhibitor protein from bovine kidney, Methods Enzymol., 166, 321–329.

    Article  CAS  PubMed  Google Scholar 

  99. Fan, J., Kang, H. B., Shan, C., Elf, S., Lin, R., Xie, J., Gu, T. L., Aguiar, M., Lonning, S., Chung, T. W., Arellano, M., Khoury, H. J., Shin, D. M., Khuri, F. R., Boggon, T. J., Kang, S., and Chen, J. (2014) Tyr-301 phosphorylation inhibits pyruvate dehydrogenase by blocking substrate binding and promotes the Warburg effect, J. Biol. Chem., 289, 26533–26541.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Hitosugi, T., Fan, J., Chung, T. W., Lythgoe, K., Wang, X., Xie, J., Ge, Q., Gu, T. L., Polakiewicz, R. D., Roesel, J. L., Chen, G. Z., Boggon, T. J., Lonial, S., Fu, H., Khuri, F. R., Kang, S., and Chen, J. (2011) Tyrosine phosphorylation of mitochondrial pyruvate dehydrogenase kinase 1 is important for cancer metabolism, Mol. Cell, 44, 864–877.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Fan, J., Shan, C., Kang, H. B., Elf, S., Xie, J., Tucker, M., Gu, T. L., Aguiar, M., Lonning, S., Chen, H., Mohammadi, M., Britton, L. M., Garcia, B. A., Aleckovic, M., Kang, Y., Kaluz, S., Devi, N., Van Meir, E. G., Hitosugi, T., Seo, J. H., Lonial, S., Gaddh, M., Arellano, M., Khoury, H. J., Khuri, F. R., Boggon, T. J., Kang, S., and Chen, J. (2014) Tyr phosphorylation of PDP1 toggles recruitment between ACAT1 and SIRT3 to regulate the pyruvate dehydrogenase complex, Mol. Cell, 53, 534–548.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Shan, C., Kang, H. B., Elf, S., Xie, J., Gu, T. L., Aguiar, M., Lonning, S., Hitosugi, T., Chung, T. W., Arellano, M., Khoury, H. J., Shin, D. M., Khuri, F. R., Boggon, T. J., and Fan, J. (2014) Tyr-94 phosphorylation inhibits pyruvate dehydrogenase phosphatase 1 and promotes tumor growth, J. Biol. Chem., 289, 21413–21422.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Cairns, R. A., Harris, I. S., and Mak, T. W. (2011) Regulation of cancer cell metabolism, Nat. Rev. Cancer, 11, 85–95.

    Article  CAS  PubMed  Google Scholar 

  104. Jha, M. K., and Suk, K. (2013) Pyruvate dehydrogenase kinase as a potential therapeutic target for malignant gliomas, Brain Tumor Res. Treat., 1, 57–63.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Bingham, P. M., Stuart, S. D., and Zachar, Z. (2014) Lipoic acid and lipoic acid analogs in cancer metabolism and chemotherapy, Expert Rev. Clin. Pharmacol., 7, 837–846.

    Article  CAS  PubMed  Google Scholar 

  106. Ozden, O., Park, S. H., Wagner, B. A., Yong Song, H., Zhu, Y., Vassilopoulos, A., Jung, B., Buettner, G. R., and Gius, D. (2014) SIRT3 deacetylates and increases pyruvate dehydrogenase activity in cancer cells, Free Radic. Biol. Med., 76, 163–172.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Park, J., Chen, Y., Tishkoff, D. X., Peng, C., Tan, M., Dai, L., Xie, Z., Zhang, Y., Zwaans, B. M., Skinner, M. E., Lombard, D. B., and Zhao, Y. (2013) SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways, Mol. Cell, 50, 919–930.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Gibson, G. E., Xu, H., Chen, H. L., Chen, W., Denton, T. T., and Zhang, S. (2015) Alpha-ketoglutarate dehydrogenase complex-dependent succinylation of proteins in neurons and neuronal cell lines, J. Neurochem., 134, 86–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Barry, G. F. (2000) Phosphonate metabolizing plants, in Google Patents, US Patent No. WO/2000/029596.

    Google Scholar 

  110. Zhang, G., Allen, K. N., and Dunaway-Mariano, D. (2003) Enzymatic synthesis of radiolabeled phosphonoacetaldehyde, Anal. Biochem., 322, 233–237.

    Article  CAS  PubMed  Google Scholar 

  111. Olsen, D. B., Hepburn, T. W., Moos, M., Mariano, P. S., and Dunaway-Mariano, D. (1988) Investigation of the Bacillus cereus phosphonoacetaldehyde hydrolase. Evidence for a Schiff base mechanism and sequence analysis of an active-site peptide containing the catalytic lysine residue, Biochemistry, 27, 2229–2234.

    Article  CAS  PubMed  Google Scholar 

  112. Zhang, G., Dai, J., Lu, Z., and Dunaway-Mariano, D. (2003) The phosphonopyruvate decarboxylase from Bacteroides fragilis, J. Biol. Chem., 278, 41302–41308.

    Article  CAS  PubMed  Google Scholar 

  113. Nakashita, H., Kozuka, K., Hidaka, T., Hara, O., and Seto, H. (2000) Identification and expression of the gene encoding phosphonopyruvate decarboxylase of Streptomyces hygroscopicus, Biochim. Biophys. Acta, 1490, 159–162.

    Article  CAS  PubMed  Google Scholar 

  114. Chang, W. C., Dey, M., Liu, P., Mansoorabadi, S. O., Moon, S. J., Zhao, Z. K., Drennan, C. L., and Liu, H. W. (2013) Mechanistic studies of an unprecedented enzymecatalyzed 1,2-phosphono-migration reaction, Nature, 496, 114–118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Kamat, S. S., Williams, H. J., and Raushel, F. M. (2011) Intermediates in the transformation of phosphonates to phosphate by bacteria, Nature, 480, 570–573.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Kononova, S. V., and Nesmeyanova, M. A. (2002) Phosphonates and their degradation by microorganisms, Biochemistry (Moscow), 67, 184–195.

    Article  CAS  Google Scholar 

  117. Laber, B., and Amrhein, N. (1987) Metabolism of 1aminoethylphosphinate generates acetylphosphinate, a potent inhibitor of pyruvate dehydrogenase, Biochem. J., 248, 351–358.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Peck, S. C., Gao, J., and Van der Donk, W. A. (2012) Discovery and biosynthesis of phosphonate and phosphinate natural products, Methods Enzymol., 516, 101–123.

    Article  CAS  PubMed  Google Scholar 

  119. He, H. W., Peng, H., and Tan, X. S. (2014) Environmentally Friendly Alkylphosphonate Herbicides, Chemical Industry Press, Beijing.

    Book  Google Scholar 

  120. Eto, M. (1997) Functions of phosphorus moiety in agrochemical molecules, Biosci. Biotech. Biochem., 61, 1–11.

    Article  CAS  Google Scholar 

  121. Engel, R. (1977) Phosphonates as analogues of natural phosphates, Chem. Rev., 77, 349–367.

    Article  CAS  Google Scholar 

  122. Vvedensky, V. (1888) Some data on structure of phosphoric acid, Zh. Russ. Fiz. Khim. Obshch., 20, 29–34.

    Google Scholar 

  123. Kabachnik, M. I., and Rossiyskaya, P. A. (1945) Esters of α-ketophosphinic acids, Izv. Akad. Nauk SSSR Ser. Khim., 4, 364–374.

    Google Scholar 

  124. Kreutzkamp, N., and Mengel, W. (1967) Darstellung einiger γ- und α-dicarbonyl-phosphonsaure-ester. 10. Mitt. uber carbonyl- und cyan-phosphonester, Arch. Pharm., 300, 389–392.

    Article  CAS  Google Scholar 

  125. Kluger, R., and Pike, D. C. (1977) Active site generated analogues of reactive intermediates in enzymic reactions. Potent inhibition of pyruvate dehydrogenase by a phosphonate analogue of pyruvate, J. Am. Chem. Soc., 99, 4504–4506.

    Article  CAS  PubMed  Google Scholar 

  126. Khomutov, R. M., Osipova, T. I., and Zhukov, Y. N. (1978) Synthesis of alpha-ketophosphonic acids, Bull. Acad. Sci. USSR. Div. Chem. Sci., 27, 1210–1213.

    Article  Google Scholar 

  127. Baillie, A. C., Wright, K., Wright, B. J., and Earnshaw, C. G. (1988) Inhibitors of pyruvate dehydrogenase as herbicides, Pestic. Biochem. Physiol., 30, 103–112.

    Article  CAS  Google Scholar 

  128. Kluger, R., and Pike, D. C. (1979) Chemical synthesis of a proposed enzyme-generated “reactive intermediate analogue” derived from thiamin diphosphate. Self-activation of pyruvate dehydrogenase by conversion of the analogue to its components, J. Am. Chem. Soc., 101, 6425–6428.

    Article  CAS  Google Scholar 

  129. Biryukov, A. I., Bunik, V. I., Zhukov, Y. N., Khurs, E. N., and Khomutov, R. M. (1996) Succinyl phosphonate inhibits alpha-ketoglutarate oxidative decarboxylation, catalyzed by alpha-ketoglutarate dehydrogenase complexes from E. coli and pigeon breast muscle, FEBS Lett., 382, 167–170.

    Article  CAS  PubMed  Google Scholar 

  130. Fang, M., Toogood, R. D., Macova, A., Ho, K., Franzblau, S. G., McNeil, M. R., Sanders, D. A., and Palmer, D. R. (2010) Succinylphosphonate esters are competitive inhibitors of MenD that show active-site discrimination between homologous alpha-ketoglutarate-decarboxylating enzymes, Biochemistry, 49, 2672–2679.

    Article  CAS  PubMed  Google Scholar 

  131. Bunik, V. I., and Fernie, A. R. (2009) Metabolic control exerted by the 2-oxoglutarate dehydrogenase reaction: a cross-kingdom comparison of the crossroad between energy production and nitrogen assimilation, Biochem. J., 422, 405–421.

    Article  CAS  PubMed  Google Scholar 

  132. Nemeria, N. S., Korotchkina, L. G., Chakraborty, S., Patel, M. S., and Jordan, F. (2006) Acetylphosphinate is the most potent mechanism-based substrate-like inhibitor of both the human and Escherichia coli pyruvate dehydrogenase components of the pyruvate dehydrogenase complex, Bioorg. Chem., 34, 362–379.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Arjunan, P., Sax, M., Brunskill, A., Chandrasekhar, K., Nemeria, N., Zhang, S., Jordan, F., and Furey, W. (2006) A thiamin-bound, pre-decarboxylation reaction intermediate analogue in the pyruvate dehydrogenase E1 subunit induces large scale disorder-to-order transformations in the enzyme and reveals novel structural features in the covalently bound adduct, J. Biol. Chem., 281, 15296–15303.

    Article  CAS  PubMed  Google Scholar 

  134. Karaman, R., Goldblum, A., Breuer, E., and Leader, H. J. (1989) Acylphosphonic acids and methyl hydrogen acylphosphonates: physical and chemical properties and theoretical calculations, J. Chem. Soc. Perkin Trans., 1, 765–774.

    Article  Google Scholar 

  135. Bunik, V. I., Biryukov, A. I., and Zhukov, Yu. N. (1992) Inhibition of pigeon breast muscle alpha-ketoglutarate dehydrogenase by phosphonate analogues of alpha-ketoglutarate, FEBS Lett., 303, 197–201.

    Article  CAS  PubMed  Google Scholar 

  136. Bunik, V. I., and Pavlova, O. G. (1997) Inhibition of pigeon breast muscle alpha-ketoglutarate dehydrogenase by structural analogs of alpha-ketoglutarate, Biochemistry (Moscow), 62, 1012–1020.

    CAS  Google Scholar 

  137. Nemeria, N., Baykal, A., Joseph, E., Zhang, S., Yan, Y., Furey, W., and Jordan, F. (2004) Tetrahedral intermediates in thiamin diphosphate-dependent decarboxylations exist as a 1′,4′-imino tautomeric form of the coenzyme, unlike the Michaelis complex or the free coenzyme, Biochemistry, 43, 6565–6575.

    Article  CAS  PubMed  Google Scholar 

  138. Kale, S., Ulas, G., Song, J., Brudvig, G. W., Furey, W., and Jordan, F. (2008) Efficient coupling of catalysis and dynamics in the E1 component of Escherichia coli pyruvate dehydrogenase multienzyme complex, Proc. Natl. Acad. Sci. USA, 105, 1158–1163.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Kale, S., and Jordan, F. (2009) Conformational ensemble modulates cooperativity in the rate-determining catalytic step in the E1 component of the Escherichia coli pyruvate dehydrogenase multienzyme complex, J. Biol. Chem., 284, 33122–33129.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Nemeria, N. S., Arjunan, P., Chandrasekhar, K., Mossad, M., Tittmann, K., Furey, W., and Jordan, F. (2010) Communication between thiamin cofactors in the Escherichia coli pyruvate dehydrogenase complex E1 component active centers: evidence for a “direct pathway” between the 4′-aminopyrimidine N1′ atoms, J. Biol. Chem., 285, 11197–11209.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Fang, M., Macova, A., Hanson, K. L., Kos, J., and Palmer, D. R. (2011) Using substrate analogues to probe the kinetic mechanism and active site of Escherichia coli MenD, Biochemistry, 50, 8712–8721.

    Article  CAS  PubMed  Google Scholar 

  142. Bunik, V. I., Denton, T. T., Xu, H., Thompson, C. M., Cooper, A. J., and Gibson, G. E. (2005) Phosphonate analogues of alpha-ketoglutarate inhibit the activity of the alpha-ketoglutarate dehydrogenase complex isolated from brain and in cultured cells, Biochemistry, 44, 10552–10561.

    Article  CAS  PubMed  Google Scholar 

  143. Bera, A. K., Polovnikova, L. S., Roestamadji, J., Widlanski, T. S., Kenyon, G. L., McLeish, M. J., and Hasson, M. S. (2007) Mechanism-based inactivation of benzoylformate decarboxylase, a thiamin diphosphatedependent enzyme, J. Am. Chem. Soc., 129, 4120–4121.

    Article  CAS  PubMed  Google Scholar 

  144. Schonbrunn-Hanebeck, E., Laber, B., and Amrhein, N. (1990) Slow-binding inhibition of the Escherichia coli pyruvate dehydrogenase multienzyme complex by acetylphosphinate, Biochemistry, 29, 4880–4885.

    Article  CAS  PubMed  Google Scholar 

  145. Bunik, V. I., Artiukhov, A., Kazantsev, A., Goncalves, R., Daloso, D., Oppermann, H., Kulakovskaya, E., Lukashev, N., Fernie, A., Brand, M., and Gaunitz, F. (2015) Specific inhibition by synthetic analogs of pyruvate reveals that the pyruvate dehydrogenase reaction is essential for metabolism and viability of glioblastoma cells, Oncotarget, 6, 40036–40052.

    PubMed  PubMed Central  Google Scholar 

  146. Da Shim, J., Nemeria, N. S., Balakrishnan, A., Patel, H., Song, J., Wang, J., Jordan, F., and Farinas, E. T. (2011) Assignment of function to histidines 260 and 298 by engineering the E1 component of the Escherichia coli 2-oxoglutarate dehydrogenase complex; substitutions that lead to acceptance of substrates lacking the 5-carboxyl group, Biochemistry, 50, 7705–7709.

    Article  CAS  PubMed Central  Google Scholar 

  147. Araujo, W. L., Nunes-Nesi, A., Trenkamp, S., Bunik, V. I., and Fernie, A. R. (2008) Inhibition of 2-oxoglutarate dehydrogenase in potato tuber suggests the enzyme is limiting for respiration and confirms its importance in nitrogen assimilation, Plant Physiol., 148, 1782–1796.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. O’Brien, T. A., Kluger, R., Pike, D. C., and Gennis, R. B. (1980) Phosphonate analogues of pyruvate. Probes of substrate binding to pyruvate oxidase and other thiamin pyrophosphate-dependent decarboxylases, Biochim. Biophys. Acta, 613, 10–17.

    Article  PubMed  Google Scholar 

  149. Dixon, H. B., Giddens, R. A., Harrison, R. A., Henderson, C. E., Norris, W. E., Parker, D. M., Perham, R. N., Slater, P., and Sparkes, M. J. (1991) A synthesis of acylphosphonic acids and of 1-aminoalkylphosphonic acids: the action of pyruvate dehydrogenase and lactate dehydrogenase on acetylphosphonic acid, J. Enzyme Inhib., 5, 111–117.

    Article  CAS  PubMed  Google Scholar 

  150. Araujo, W. L., Tohge, T., Nunes-Nesi, A., Daloso, D. M., Nimick, M., Krahnert, I., Bunik, V. I., Moorhead, G. B., and Fernie, A. R. (2012) Phosphonate analogs of 2-oxoglutarate perturb metabolism and gene expression in illuminated Arabidopsis leaves, Front. Plant Sci., 3, 114.

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Van der Merwe, M. J., Osorio, S., Araujo, W. L., Balbo, I., Nunes-Nesi, A., Maximova, E., Carrari, F., Bunik, V. I., Persson, S., and Fernie, A. R. (2010) Tricarboxylic acid cycle activity regulates tomato root growth via effects on secondary cell wall production, Plant Physiol., 153, 611–621.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  152. Bunik, V. I., Kabysheva, M. S., Klimuk, E. I., Storozhevykh, T. P., and Pinelis, V. G. (2009) Phosphono analogues of 2-oxoglutarate protect cerebellar granule neurons upon glutamate excitotoxicity, Ann. N. Y. Acad. Sci., 1171, 521–529.

    Article  CAS  PubMed  Google Scholar 

  153. Araujo, W. L., Trofimova, L., Mkrtchyan, G., Steinhauser, D., Krall, L., Graf, A., Fernie, A. R., and Bunik, V. I. (2013) On the role of the mitochondrial 2-oxoglutarate dehydrogenase complex in amino acid metabolism, Amino Acids, 44, 683–700.

    Article  CAS  PubMed  Google Scholar 

  154. Aleshin, V. A., Artiukhov, A. V., Oppermann, H., Kazantsev, A. V., Lukashev, N. V., and Bunik, V. I. (2015) Mitochondrial impairment may increase cellular NAD(P)H: resazurin oxidoreductase activity, perturbing the NAD(P)H-based viability assays, Cells, 4, 427–451.

    Article  PubMed  PubMed Central  Google Scholar 

  155. Zundorf, G., Kahlert, S., Bunik, V. I., and Reiser, G. (2009) Alpha-ketoglutarate dehydrogenase contributes to production of reactive oxygen species in glutamate-stimulated hippocampal neurons in situ, Neuroscience, 158, 610–616.

    Article  CAS  PubMed  Google Scholar 

  156. Santos, S. S., Gibson, G. E., Cooper, A. J., Denton, T. T., Thompson, C. M., Bunik, V. I., Alves, P. M., and Sonnewald, U. (2006) Inhibitors of the alpha-ketoglutarate dehydrogenase complex alter [1-13C]glucose and [U-13C]glutamate metabolism in cerebellar granule neurons, J. Neurosci. Res., 83, 450–458.

    Article  CAS  PubMed  Google Scholar 

  157. Diaz-Munoz, M. D., Bell, S. E., Fairfax, K., Monzon-Casanova, E., Cunningham, A. F., Gonzalez-Porta, M., Andrews, S. R., Bunik, V. I., Zarnack, K., Curk, T., Heggermont, W. A., Heymans, S., Gibson, G. E., Kontoyiannis, D. L., Ule, J., and Turner, M. (2015) The RNA-binding protein HuR is essential for the B cell antibody response, Nat. Immunol., 16, 415–425.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Kabysheva, M. S., Storozhevykh, T. P., Pinelis, V. G., and Bunik, V. I. (2009) Synthetic regulators of the 2-oxoglutarate oxidative decarboxylation alleviate the glutamate excitotoxicity in cerebellar granule neurons, Biochem. Pharmacol., 77, 1531–1540.

    Article  CAS  PubMed  Google Scholar 

  159. Circello, B. T., Miller, C. G., Lee, J. H., Van der Donk, W. A., and Metcalf, W. W. (2011) The antibiotic dehydrophos is converted to a toxic pyruvate analog by peptide bond cleavage in Salmonella enterica, Antimicrob. Agents Chemother., 55, 3357–3362.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Trofimova, L. K., Araujo, W. L., Strokina, A. A., Fernie, A. R., Bettendorff, L., and Bunik, V. I. (2012) Consequences of the alpha-ketoglutarate dehydrogenase inhibition for neuronal metabolism and survival: implications for neurodegenerative diseases, Curr. Med. Chem., 19, 5895–5906.

    Article  CAS  PubMed  Google Scholar 

  161. Bunik, V., Mkrtchyan, G., Grabarska, A., Oppermann, H., Daloso, D., Araujo, W. L., Juszczak, M., Rzeski, W., Bettendorff, L., Fernie, A. R., Meixensberger, J., Stepulak, A., and Gaunitz, F. (2016) Inhibition of mitochondrial 2-oxoglutarate dehydrogenase impairs viability of cancer cells in a cell-specific metabolism-dependent manner, Oncotarget, 7, 26400–26421.

    PubMed  PubMed Central  Google Scholar 

  162. Graf, A., Trofimova, L., Loshinskaja, A., Mkrtchyan, G., Strokina, A., Lovat, M., Tylicky, A., Strumilo, S., Bettendorff, L., and Bunik, V. I. (2013) Up-regulation of 2-oxoglutarate dehydrogenase as a stress response, Int. J. Biochem. Cell Biol., 45, 175–189.

    Article  CAS  PubMed  Google Scholar 

  163. Araujo, W. L., Tohge, T., Osorio, S., Lohse, M., Balbo, I., Krahnert, I., Sienkiewicz-Porzucek, A., Usadel, B., Nunes-Nesi, A., and Fernie, A. R. (2012) Antisense inhibition of the 2-oxoglutarate dehydrogenase complex in tomato demonstrates its importance for plant respiration and during leaf senescence and fruit maturation, Plant Cell, 24, 2328–2351.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Shi, Q., Risa, O., Sonnewald, U., and Gibson, G. E. (2009) Mild reduction in the activity of the alpha-ketoglutarate dehydrogenase complex elevates GABA shunt and glycolysis, J. Neurochem., 109 (Suppl. 1), 214–221.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Cheshchevik, V., Janssen, A. J. M., Dremza, I. K., Zavodnik, I. B., and Bunik, V. I. (2010) The OGDHCexerted control of mitochondrial respiration is increased under energy demand, in Proc. the MiP 2010 and FEBS Workshop Mitochondrial Physiology (Renner-Sattler, K., and Gnaiger, E., eds.) Obergurgl, Tyrol, Austria, pp. 76–77.

    Google Scholar 

  166. Quinlan, C. L., Goncalves, R. L., Hey-Mogensen, M., Yadava, N., Bunik, V. I., and Brand, M. D. (2014) The 2oxoacid dehydrogenase complexes in mitochondria can produce superoxide/hydrogen peroxide at much higher rates than complex I, J. Biol. Chem., 289, 8312–8325.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Bunik, V. I., and Sievers, C. (2002) Inactivation of the 2oxo acid dehydrogenase complexes upon generation of intrinsic radical species, Eur. J. Biochem., 269, 5004–5015.

    Article  CAS  PubMed  Google Scholar 

  168. Negovsky, V. A., Gurvich, A. M., and Zolotokrylina, E. S. (1987) Post-resuscitation Disease [in Russian], Meditsina, Moscow.

    Google Scholar 

  169. Korge, P., Calmettes, G., and Weiss, J. N. (2016) Reactive oxygen species production in cardiac mitochondria after complex I inhibition: modulation by substrate-dependent regulation of the NADH/NAD(+) ratio, Free Radic. Biol. Med., 96, 22–33.

    Article  CAS  PubMed  Google Scholar 

  170. Mathieu, L., Costa, A. L., Le Bachelier, C., Slama, A., Lebre, A. S., Taylor, R. W., Bastin, J., and Djouadi, F. (2016) Resveratrol attenuates oxidative stress in mitochondrial complex I deficiency: involvement of SIRT3, Free Radic. Biol. Med., 96, 190–198.

    Article  CAS  PubMed  Google Scholar 

  171. Fujikawa, D. G. (2015) The role of excitotoxic programmed necrosis in acute brain injury, Comput. Struct. Biotechnol. J., 13, 212–221.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Pardo, B., Contreras, L., Serrano, A., Ramos, M., Kobayashi, K., Iijima, M., Saheki, T., and Satrustegui, J. (2006) Essential role of aralar in the transduction of small Ca2+ signals to neuronal mitochondria, J. Biol. Chem., 281, 1039–1047.

    Article  CAS  PubMed  Google Scholar 

  173. Bunik, V. I. (2003) 2-Oxo acid dehydrogenase complexes in redox regulation, Eur. J. Biochem., 270, 1036–1042.

    Article  CAS  PubMed  Google Scholar 

  174. Graff, C. L., and Pollack, G. M. (2004) Drug transport at the blood–brain barrier and the choroid plexus, Curr. Drug Metab., 5, 95–108.

    Article  CAS  PubMed  Google Scholar 

  175. Badhan, R. K., Kaur, M., Lungare, S., and Obuobi, S. (2014) Improving brain drug targeting through exploitation of the nose-to-brain route: a physiological and pharmacokinetic perspective, Curr. Drug Deliv., 11, 458–471.

    Article  CAS  PubMed  Google Scholar 

  176. Djupesland, P. G., Messina, J. C., and Mahmoud, R. A. (2014) The nasal approach to delivering treatment for brain diseases: an anatomic, physiologic, and delivery technology overview, Ther. Deliv., 5, 709–733.

    Article  CAS  PubMed  Google Scholar 

  177. Trofimova, L., Lovat, M., Groznaya, A., Efimova, E., Dunaeva, T., Maslova, M., Graf, A., and Bunik, V. (2010) Behavioral impact of the regulation of the brain 2-oxoglutarate dehydrogenase complex by synthetic phosphonate analog of 2-oxoglutarate: implications into the role of the complex in neurodegenerative diseases, Int. J. Alzheimer’s Dis., 749061.

    Google Scholar 

  178. Kulakovskaya, E. A., Loshinskaya, A. A., Graf, A. V., Trofimova, L. K., Maslova, M. V., Bunik, V. I., and Sokolova, N. A. (2012) Effects of acute hypoxia and 2oxoglutarate dehydrogenase complex (OGDHC) inhibitor on cardiac performance in male and female rats, in: IV Congr. of Russian Pharmacologists “Innovations in Modern Pharmacology”, Content of the Congress (Kharkevich, D. A., and Seredenin, S. B., eds.) Kazan, Russia.

    Google Scholar 

  179. Graf, A., Kabysheva, M., Klimuk, E., Trofimova, L., Dunaeva, T., Zundorf, G., Kahlert, S., Reiser, G., Storozhevykh, T., Pinelis, V., Sokolova, N., and Bunik, V. (2009) Role of 2-oxoglutarate dehydrogenase in brain pathologies involving glutamate neurotoxicity, J. Mol. Catal. B Enzym., 61, 80–87.

    Article  CAS  Google Scholar 

  180. Mkrtchyan, G., Graf, A., Trofimova, L., and Bunik, V. (2014) Strong positive correlation between the activity of the 2-oxoglutarate dehydrogenase complex and glutamate level in rat cortex disappears after metabolic stress, in Parkinson’s Disease: Genetics, Mechanisms and Therapeutics and the Joint Meeting on Alzheimer’s Disease–From Fundamental Insights to Light at the End of Translational Tunnel (Trojanowsky, J. Q., Albright, C. F., and Zheng, H., eds.) Keystone, Colorado, USA, p. 104.

    Google Scholar 

  181. Bunik, V. I., Schloss, J. V., Pinto, J. T., Dudareva, N., and Cooper, A. J. (2011) A survey of oxidative paracatalytic reactions catalyzed by enzymes that generate carbanionic intermediates: implications for ROS production, cancer etiology, and neurodegenerative diseases, Adv. Enzymol. Relat. Areas Mol. Biol., 77, 307–360.

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Gibson, G. E., Blass, J. P., Beal, M. F., and Bunik, V. (2005) The alpha-ketoglutarate–dehydrogenase complex: a mediator between mitochondria and oxidative stress in neurodegeneration, Mol. Neurobiol., 31, 43–63.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Lomonosov Moscow State University, Faculty of Bioengineering and Bioinformatics, 119991, Moscow, Russia

    A. V. Artiukhov & V. I. Bunik

  2. Lomonosov Moscow State University, Faculty of Biology, 119991, Moscow, Russia

    A. V. Graf

  3. Moscow Institute of Physics and Technology, Faculty of Nano-, Bio-, Informational and Cognitive Technologies, 123098, Moscow, Russia

    A. V. Graf

  4. Lomonosov Moscow State University, Belozersky Institute of Physico-Chemical Biology, 119991, Moscow, Russia

    V. I. Bunik

Authors
  1. A. V. Artiukhov
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. V. Graf
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. V. I. Bunik
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to V. I. Bunik.

Additional information

Published in Russian in Biokhimiya, 2016, Vol. 81, No. 12, pp. 1793–1818.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Artiukhov, A.V., Graf, A.V. & Bunik, V.I. Directed regulation of multienzyme complexes of 2-oxo acid dehydrogenases using phosphonate and phosphinate analogs of 2-oxo acids. Biochemistry Moscow 81, 1498–1521 (2016). https://doi.org/10.1134/S0006297916120129

Download citation

  • Received:

  • Revised:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S0006297916120129

Key words

Search

Navigation