Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지
DOI QR코드

DOI QR Code

Alpha-Ketoglutarate: Physiological Functions and Applications

  • Wu, Nan (Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University) ;
  • Yang, Mingyao (Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University) ;
  • Gaur, Uma (Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University) ;
  • Xu, Huailiang (Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University) ;
  • Yao, Yongfang (Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University) ;
  • Li, Diyan (Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University)
  • Received : 2015.06.11
  • Accepted : 2015.08.28
  • Published : 2016.01.01
Download PDF
⟨ Previous Next ⟩

Abstract

Alpha-ketoglutarate (AKG) is a key molecule in the Krebs cycle determining the overall rate of the citric acid cycle of the organism. It is a nitrogen scavenger and a source of glutamate and glutamine that stimulates protein synthesis and inhibits protein degradation in muscles. AKG as a precursor of glutamate and glutamine is a central metabolic fuel for cells of the gastrointestinal tract as well. AKG can decrease protein catabolism and increase protein synthesis to enhance bone tissue formation in the skeletal muscles and can be used in clinical applications. In addition to these health benefits, a recent study has shown that AKG can extend the lifespan of adult Caenorhabditis elegans by inhibiting ATP synthase and TOR. AKG not only extends lifespan, but also delays age-related disease. In this review, we will summarize the advances in AKG research field, in the content of its physiological functions and applications.

Keywords

References

  1. Abcouwer, S. F. (2000) Effects of glutamine on immune cells. Nutrition 16, 67-69.
  2. Abrahams, J. P., Leslie, A. G., Lutter, R. and Walker, J. E. (1994) Structure at 2.8 A resolution of F1-ATPase from bovine heart mitochondria. Nature 370, 621-628. https://doi.org/10.1038/370621a0
  3. Alpers, D. H. (2006) Glutamine: do the data support the cause for glutamine supplementation in humans? Gastroenterology 130, S106- S116. https://doi.org/10.1053/j.gastro.2005.11.049
  4. Andersen, N. K., Tatara, M. R., Krupski, W., Majcher, P. and Harrison, A. P. (2008) The long-term effect of alpha-ketoglutarate, given early in postnatal life, on both growth and various bone parameters in pigs. J. Anim. Physiol. Anim. Nutr. 92, 519-528. https://doi.org/10.1111/j.1439-0396.2007.00742.x
  5. Ashkanazi, J., Carpertier, Y. and Michelsen, C. (1980) Muscle and plasma amino acids following injury. Ann. Surg. 192, 78-85. https://doi.org/10.1097/00000658-198007000-00014
  6. Barthel, A., Schmoll, D. and Unterman, T. G. (2005) FoxO proteins in insulin action and metabolism. Trends Endocrinol. Metab. 16, 183-189. https://doi.org/10.1016/j.tem.2005.03.010
  7. Bellon, G., Chaqour, B., Wegrowski, Y., Monboisse, J. C. and Borel, J. P. (1995) Glutamine increases collagen gene transcription in cultured human fibroblasts. Biochim. Biophys. Acta 1268, 311-323.javascript:checkRefBr('', 'next'); https://doi.org/10.1016/0167-4889(95)00093-8
  8. Bienko, M., Radzki, R., Puzio, I., Filip, R., Pierzynowski, S. and Studzinski, T. (2002) The influence of alpha-ketoglutarate (AKG) on mineralization of femur in rats with established osteopenia. Acta Orthop. Scand. 73, 52.
  9. Bissonnette, R., Friedmann, D., Giroux, J. M., Dolenga, M., Hechtman, P., Der Kaloustian, V. M. and Dubuc, R. (1993) Prolidase deficiency: a multisystemic hereditary disorder. J. Am. Acad. Dermatol. 29, 818-821. https://doi.org/10.1016/0190-9622(93)70245-O
  10. Blagosklonny, M. V. (2006) Aging and immortality: quasi-programmed senescence and its pharmacologic inhibition. Cell Cycle 5, 2087- 2102. https://doi.org/10.4161/cc.5.18.3288
  11. Boyer, P. D. (1997) The ATP synthase-a splendid molecular machine. Annu. Rev. Biochem. 66, 717-749. https://doi.org/10.1146/annurev.biochem.66.1.717
  12. Brauer, M. J., Yuan, J., Bennett, B. D., Lu, W., Kimball, E., Botstein, D. and Rabinowitz, J. D. (2006) Conservation of the metabolomic response to starvation across two divergent microbes. Proc. Natl. Acad. Sci. U.S.A. 103, 19302-19307. https://doi.org/10.1073/pnas.0609508103
  13. Brugnara, L., Vinaixa, M., Murillo, S., Samino, S., Rodriguez, M. A., Beltran, A., Lerin, C., Davison, G., Correig, X. and Novials, A. (2012) Metabolomics approach for analyzing the effects of exercise in subjects with type 1 diabetes mellitus. PloS one 7, e40600. https://doi.org/10.1371/journal.pone.0040600
  14. Brunet, A. (2004) [The multiple roles of FOXO transcription factors]. Med. Sci. 20, 856-859.
  15. Chenu, C. (2002a) Glutamatergic innervation in bone. Microsc. Res. Tech. 58, 70-76. https://doi.org/10.1002/jemt.10120
  16. Chenu, C. (2002b) Glutamatergic regulation of bone remodeling. J. Musculoskelet Neuronal Interact. 2, 282-284.
  17. Chin, R. M., Fu, X., Pai, M. Y., Vergnes, L., Hwang, H., Deng, G., Diep, S., Lomenick, B., Meli, V. S. and Monsalve, G. C. (2014) The metabolite a-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. Nature 510, 397-401. https://doi.org/10.1038/nature13264
  18. Colomb, V., Dabbas, M., Goulet, O., Talbotec, C., Corriol, O. and Ricour, C. (2004) Prepubertal growth in children with long-term parenteral nutrition. Horm. Res. Paediatr. 58, 2-6.
  19. Curran, S. P. and Ruvkun, G. (2007) Lifespan regulation by evolutionarily conserved genes essential for viability. PLoS Genet. 3, e56. https://doi.org/10.1371/journal.pgen.0030056
  20. Cynober, L. (2004) Ornithine ${\alpha}$-ketoglutarate as a potent precursor of arginine and nitric oxide: a new job for an old friend. J. Nutr. 134, 2858S-2862S. https://doi.org/10.1093/jn/134.10.2858S
  21. Dabek, M., Kruszewska, D., Filip, R., Hotowy, A., Pierzynowski, L., Wojtasz-Pajak, A., Szymanczyk, S., Valverde Piedra, J., Werpachowska, E. and Pierzynowski, S. (2005) ${\alpha}$-Ketoglutarate (AKG) absorption from pig intestine and plasma pharmacokinetics. J. Anim. Physiol. Anim. Nutr. 89, 419-426. https://doi.org/10.1111/j.1439-0396.2005.00566.x
  22. Dakshayani, K. and Subramanian, P. (2006) ${\alpha}$-ketoglutarate modulates the circadian patterns of lipid peroxidation and antioxidant status during N-nitrosodiethylamine-induced hepatocarcinogenesis in rats. J. Med. Food 9, 90-97. https://doi.org/10.1089/jmf.2006.9.90
  23. Danbolt, N. C. (2001) Glutamate uptake. Prog. Neurobiol. 65, 1-105. https://doi.org/10.1016/S0301-0082(00)00067-8
  24. Dillin, A., Hsu, A. L., Arantes-Oliveira, N., Lehrer-Graiwer, J., Hsin, H., Fraser, A. G., Kamath, R. S., Ahringer, J. and Kenyon, C. (2002) Rates of behavior and aging specified by mitochondrial function during development. Science 298, 2398-2401. https://doi.org/10.1126/science.1077780
  25. Dobrowolski, P. J., Piersiak, T., Surve, V. V., Kruszewska, D., Gawron, A., Pacuska, P., Hakanson, R. and Pierzynowski, S. G. (2008) Dietary ${\alpha}$-ketoglutarate reduces gastrectomy-evoked loss of calvaria and trabecular bone in female rats. Scand J. Gastroenterol. 43, 551-558. https://doi.org/10.1080/00365520701824951
  26. Espat, N. J., Watkins, K. T., Lind, D. S., Weis, J. K., Copeland, E. M. and Souba, W. W. (1996) Dietary modulation of amino acid transport in rat and human liver. J. Surg. Res. 63, 263-268. https://doi.org/10.1006/jsre.1996.0258
  27. Fayh, A. P., Friedman, R., Sapata, K. B. and Oliveira, A. R. (2007) [Effect of L-arginine supplementation on secretion of human growth hormone and insulin-like growth factor in adults]. Arq. Bras. Endocrinol. Metabol. 51, 587-592. https://doi.org/10.1590/S0004-27302007000400013
  28. Furukawa, S., Saito, H., Inoue, T., Matsuda, T., Fukatsu, K., Han, I., Ikeda, S. and Hidemura, A. (2000) Supplemental glutamine augments phagocytosis and reactive oxygen intermediate production by neutrophils and monocytes from postoperative patients in vitro. Nutrition 16, 323-329. https://doi.org/10.1016/S0899-9007(00)00228-8
  29. Gianotti, L., Alexander, J. W., Gennari, R., Pyles, T. and Babcock, G. F. (1995) Oral glutamine decreases bacterial translocation and improves survival in experimental gut-origin sepsis. J. Parenter. Enteral Nutr. 19, 69-74. https://doi.org/10.1177/014860719501900169
  30. Giustina, A., Mazziotti, G. and Canalis, E. (2008) Growth hormone, insulin-like growth factors, and the skeleton. Endocr. Rev. 29, 535- 559. https://doi.org/10.1210/er.2007-0036
  31. Gross, D. N., van den Heuvel, A. P. and Birnbaum, M. J. (2008) The role of FoxO in the regulation of metabolism. Oncogene 27, 2320- 2336. https://doi.org/10.1038/onc.2008.25
  32. Gu, Y., Genever, P., Skerry, T. and Publicover, S. (2002) The NMDA type glutamate receptors expressed by primary rat osteoblasts have the same electrophysiological characteristics as neuronal receptors. Calcif. Tissue Int. 70, 194-203. https://doi.org/10.1007/s00223-001-2004-z
  33. Hammarqvist, F., Wernerman, J., Ali, R., von der Decken, A. and Vinnars, E. (1989) Addition of glutamine to total parenteral nutrition after elective abdominal surgery spares free glutamine in muscle, counteracts the fall in muscle protein synthesis, and improves nitrogen balance. Ann. Surg. 209, 455-461. https://doi.org/10.1097/00000658-198904000-00011
  34. Hansen, M., Taubert, S., Crawford, D., Libina, N., Lee, S. J. and Kenyon, C. (2007) Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans. Aging Cell 6, 95-110. https://doi.org/10.1111/j.1474-9726.2006.00267.x
  35. Hardie, D. G., Ross, F. A. and Hawley, S. A. (2012) AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat. Rev. Mol. Cell Biol. 13, 251-262.
  36. Harrison, A. P. and Pierzynowski, S. (2008) Biological effects of 2-oxoglutarate with particular emphasis on the regulation of protein, mineral and lipid absorption/metabolism, muscle performance, kidney function, bone formation and cancerogenesis, all viewed from a healthy ageing perspective state of the art-review article. J. Physiol. Pharmacol. 59, 91-106.
  37. Harrison, A. P., Tygesen, M. P., Sawa-Wojtanowicz, B., Husted, S. and Tatara, M. (2004) ${\alpha}$-Ketoglutarate treatment early in postnatal life improves bone density in lambs at slaughter. Bone 35, 204-209. https://doi.org/10.1016/j.bone.2004.03.016
  38. Hixt, U. and Muller, H. (1996) L-alanyl-glutamine-a glutamine dipeptide for paraenteral nutrition. Environ. Health Perspect. 2, 72-76.
  39. Huang, X., Liu, J., Withers, B. R., Samide, A. J., Leggas, M. and Dickson, R. C. (2013) Reducing signs of aging and increasing lifespan by drug synergy. Aging Cell 12, 652-660. https://doi.org/10.1111/acel.12090
  40. Inoki, K. and Guan, K.-L. (2006) Complexity of the TOR signaling network. Trends Cell Biol. 16, 206-212. https://doi.org/10.1016/j.tcb.2006.02.002
  41. Isemura, M., Hanyu, T., Gejyo, F., Nakazawa, R., Igarashi, R., Matsuo, S., Ikeda, K. and Sato, Y. (1979) Prolidase deficiency with imidodipeptiduria. A familial case with and without clinical symptoms. Clin. Chim. Acta 93, 401-407. https://doi.org/10.1016/0009-8981(79)90291-2
  42. Jones, C., Allan Palmer, T. and Griffiths, R. (1999) Randomized clinical outcome study of critically ill patients given glutamine-supplemented enteral nutrition. Nutrition 15, 108-115. https://doi.org/10.1016/S0899-9007(98)00172-5
  43. Junghans, P., Derno, M., Pierzynowski, S., Hennig, U., Eberhard Rudolph, P. and Souffrant, W. B. (2006) Intraduodenal infusion of ${\alpha}$-ketoglutarate decreases whole body energy expenditure in growing pigs. Clin. Nutr. 25, 489-496. https://doi.org/10.1016/j.clnu.2005.11.003
  44. Kaeberlein, M., Burtner, C. R. and Kennedy, B. K. (2007) Recent developments in yeast aging. PLoS Genet. 3, e84. https://doi.org/10.1371/journal.pgen.0030084
  45. Kaminsky, Y. G., Kosenko, E. A. and Kondrashova, M. N. (1982) Metabolites of citric acid cycle, carbohydrate and phosphorus metabolism, and related reactions, redox and phosphorylating states of hepatic tissue, liver mitochondria and cytosol of the pigeon, under normal feeding and natural nocturnal fasting conditions. Comp. Biochem. Physiol. B. 73, 957-963. https://doi.org/10.1016/0305-0491(82)90343-1
  46. Kapahi, P. and Zid, B. (2004) TOR pathway: linking nutrient sensing to life span. Sci. Aging Knowledge Environ. 2004, pe34.
  47. Kapahi, P., Zid, B. M., Harper, T., Koslover, D., Sapin, V. and Benzer, S. (2004) Regulation of lifespan in drosophila by modulation of genes in the TOR signaling pathway. Curr. Biol. 14, 885-890. https://doi.org/10.1016/j.cub.2004.03.059
  48. Karna, E., Szoka, L. and Palka, J. A. (2013) The mechanism of hydralazine- induced collagen biosynthesis in cultured fibroblasts. Naunyn Schmiedebergs Arch.Pharmacol. 386, 303-309. https://doi.org/10.1007/s00210-013-0836-5
  49. Katewa, S. D. and Kapahi, P. (2011) Role of TOR signaling in aging and related biological processes in Drosophila melanogaster. Exp Gerontol. 46, 382-390. https://doi.org/10.1016/j.exger.2010.11.036
  50. Korkmaz, A., Yurdakok, M., Yigit, S. and Tekinalp, G. (2007) Long-term enteral glutamine supplementation in very low birth weight infants: effects on growth parameters. Turk J. Pediatr. 49, 37-44.
  51. Kowalik, S., Sliwa, E., Tatara, M. R., Krupski, W., Majcher, P. and Studzinski, T. (2005) Influence of alpha-ketoglutarate on mineral density and geometrical and mechanical parameters of femora during postnatal life in piglets. Bull. Vet. Inst. Pulawy 49, 107-111.
  52. Kristensen, N. B., Jungvid, H., Fernandez, J. A. and Pierzynowski, S. (2002) Absorption and metabolism of ${\alpha}$-ketoglutarate in growing pigs. J. Anim. Physiol. Anim. Nutr. 86, 239-245. https://doi.org/10.1046/j.1439-0396.2002.00380.x
  53. Lamande, S. R. and Bateman, J. F. (1999) Procollagen folding and assembly: the role of endoplasmic reticulum enzymes and molecular chaperones. Semin. Cell Dev. Biol. 10, 455-464. https://doi.org/10.1006/scdb.1999.0317
  54. Lambert, B. D., Filip, R., Stoll, B., Junghans, P., Derno, M., Hennig, U., Souffrant, W. B., Pierzynowski, S. and Burrin, D. G. (2006) First-pass metabolism limits the intestinal absorption of enteral ${\alpha}$-ketoglutarate in young pigs. J. Nutr. 136, 2779-2784. https://doi.org/10.1093/jn/136.11.2779
  55. Le Boucher, J., Coudray-Lucas, C., Lasnier, E., Jardel, A., Ekindjian, O. G. and Cynober, L. A. (1997) Enteral administration of ornithine alpha-ketoglutarate or arginine alpha-ketoglutarate: a comparative study of their effects on glutamine pools in burn-injured rats. Crit. Care Med. 25, 293-298. https://doi.org/10.1097/00003246-199702000-00017
  56. Le Boucher, J. and Cynober, L. A. (1997) Ornithine alpha-ketoglutarate: the puzzle. Nutrition 14, 870-873.
  57. Lee, S. S., Lee, R. Y., Fraser, A. G., Kamath, R. S., Ahringer, J. and Ruvkun, G. (2003) A systematic RNAi screen identifies a critical role for mitochondria in C. elegans longevity. Nat. Genet. 33, 40-48.
  58. Lomenick, B., Hao, R., Jonai, N., Chin, R. M., Aghajan, M., Warburton, S., Wang, J., Wu, R. P., Gomez, F. and Loo, J. A. (2009) Target identification using drug affinity responsive target stability (DARTS) Proc. Natl. Acad. Sci. U.S.A. 106, 21984-21989. https://doi.org/10.1073/pnas.0910040106
  59. Luong, N., Davies, C. R., Wessells, R. J., Graham, S. M., King, M. T., Veech, R., Bodmer, R. and Oldham, S. M. (2006) Activated FOXOmediated insulin resistance is blocked by reduction of TOR activity. Cell Metab. 4, 133-142. https://doi.org/10.1016/j.cmet.2006.05.013
  60. MacFie, J. and McNaught, C. (2002) Glutamine and gut barrier function. Nutrition 18, 433-434. https://doi.org/10.1016/S0899-9007(02)00766-9
  61. Melendez, A., Talloczy, Z., Seaman, M., Eskelinen, E. L., Hall, D. H. and Levine, B. (2003) Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science 301, 1387-1391. https://doi.org/10.1126/science.1087782
  62. Mentaverri, R., Kamel, S., Wattel, A., Prouillet, C., Sevenet, N., Petit, J., Tordjmann, T. and Brazier, M. (2003) Regulation of bone resorption and osteoclast survival by nitric oxide: Possible involvement of NMDA-receptor. J. Cell. Biochem. 88, 1145-1156. https://doi.org/10.1002/jcb.10463
  63. Myara, I., Charpentier, C. and Lemonnier, A. (1984) Prolidase and prolidase deficiency. Life Sci. 34, 1985-1998. https://doi.org/10.1016/0024-3205(84)90363-1
  64. Myllyharju, J. (2003) Prolyl 4-hydroxylases, the key enzymes of collagen biosynthesis. Matrix Biol. 22, 15-24. https://doi.org/10.1016/S0945-053X(03)00006-4
  65. Neu, J., Shenoy, V. and Chakrabarti, R. (1996) Glutamine nutrition and metabolism: where do we go from here? FASEB J. 10, 829-837. https://doi.org/10.1096/fasebj.10.8.8666159
  66. Ogle, C. K., Ogle, J. D., Mao, J. X., Simon, J., Noel, J. G., Li, B.-G. and Alexander, J. W. (1994) Effect of glutamine on phagocytosis and bacterial killing by normal and pediatric burn patient neutrophils. J. Parenter. Enteral Nutr. 18, 128-133. https://doi.org/10.1177/0148607194018002128
  67. Palka, J. A. and Phang, J. M. (1997) Prolidase activity in fibroblasts is regulated by interaction of extracellular matrix with cell surface integrin receptors. J. Cell. Biochem. 67, 166-175. https://doi.org/10.1002/(SICI)1097-4644(1997)28/29+<166::AID-JCB20>3.0.CO;2-E
  68. Panosyan, E. H., Grigoryan, R. S., Avramis, I. A., Seibel, N. L., Gaynon, P. S., Siegel, S. E., Fingert, H. J. and AVRAMIS, V. I. (2004) Deamination of glutamine is a prerequisite for optimal asparagine deamination by asparaginases in vivo (CCG-1961) Anticancer Res. 24, 1121-1126.
  69. Parry-Billings, M., Calder, P., Newsholme, E. and Evans, J. (1990) Does glutamine contribute to immunosuppression after major burns? Lancet 336, 523-525. https://doi.org/10.1016/0140-6736(90)92083-T
  70. Pesty, F. H., Sultan, F. and Braun, B. (1997) Glutamine homologues and derivatives: A limiting factor in current artificial nutrition? Nutrition 13, 575-577. https://doi.org/10.1016/S0899-9007(97)00025-7
  71. Pierzynowski, S. and Sjodin, A. (1998) Perspectives of glutamine and its derivatives as feed additives for farm animals. J. Anim. Feed Sci. 7, 79-91. https://doi.org/10.22358/jafs/69957/1998
  72. Pierzynowski, S. G., Filip, R. and Harrison, A. (2007) Effect of feed supplementation with alpha-ketoglutarate, combined with vitamin B-6 or C, on the performance and haemoglobin and amino acid levels in growing rats. Bull. Vet. Inst. Pulawy 51, 289-296.
  73. Radzki, R., Bienko, M., Puzio, I., Filip, R., Pierzynowski, S. and Studzinski, T. (2002) The effect of alpha-ketoglutarate (AKG) on mineralization of femur in ovariectomized rats. Acta Orthop. Scand. 73, 52.
  74. Rani, R. S., Leela, A. C. and Rao, G. N. (2012) Effect of dielectric constant on protonation equilibria of l-aspartic acid and ethylenediamine in 1, 2-propanediol-water mixtures. P. Natl A Sci. India A. 82, 313-316. https://doi.org/10.1007/s40010-012-0047-3
  75. Riedel, E., Nundel, M. and Hampl, H. (1996) alpha-Ketoglutarate application in hemodialysis patients improves amino acid metabolism. Nephron 74, 261-265. https://doi.org/10.1159/000189319
  76. Roth, E., Funovics, J., Mühlbacher, F., Schemper, M., Mauritz, W., Sporn, P. and Fritsch, A. (1982) Metabolic disorders in severe abdominal sepsis: glutamine deficiency in skeletal muscle. Clin. Nutr. 1, 25-41. https://doi.org/10.1016/0261-5614(82)90004-8
  77. Salvalaggio, P. R. and Campos, A. C. (2002) Bacterial translocation and glutamine. Nutrition 18, 435-437. https://doi.org/10.1016/S0899-9007(02)00770-0
  78. Sawyer, D. W., Donowitz, G. R. and Mandell, G. L. (1989) Polymorphonuclear neutrophils: an effective antimicrobial force. 11, S1532- S1544. https://doi.org/10.1093/clinids/11.Supplement_7.S1532
  79. Schlegel, L., Coudray-Lucas, C., Barbut, F., Le Boucher, J., Jardel, A., Zarrabian, S. and Cynober, L. (2000) Bacterial dissemination and metabolic changes in rats induced by endotoxemia following intestinal E. coli overgrowth are reduced by ornithine ${\alpha}$-ketoglutarate administration. J. Nutr. 130, 2897-2902. https://doi.org/10.1093/jn/130.12.2897
  80. Selman, C., Tullet, J. M., Wieser, D., Irvine, E., Lingard, S. J., Choudhury, A. I., Claret, M., Al-Qassab, H., Carmignac, D. and Ramadani, F. (2009) Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science 326, 140-144. https://doi.org/10.1126/science.1177221
  81. Sheaffer, K. L., Updike, D. L. and Mango, S. E. (2008) The target of rapamycin pathway antagonizes pha-4/FoxA to control development and aging. Curr. Biol. 18, 1355-1364. https://doi.org/10.1016/j.cub.2008.07.097
  82. Sliwa, E. (2010) 2-Oxoglutaric acid administration diminishes fundectomy- induced osteopenia in pigs. J. Anim. Physiol. Anim. Nutr. 94, e86-e95. https://doi.org/10.1111/j.1439-0396.2009.00985.x
  83. Sliwa, E., Dobrowolski, P., Tatara, M., Piersiak, T., Siwicki, A., Rokita, E. and Pierzynowski, S. (2009) Alpha-ketoglutarate protects the liver of piglets exposed during prenatal life to chronic excess of dexamethasone from metabolic and structural changes. J. Anim. Physiol. Anim. Nutr. 93, 192-202. https://doi.org/10.1111/j.1439-0396.2007.00805.x
  84. Son, E. D., Choi, G. H., Kim, H., Lee, B., Chang, I. S. and Hwang, J. S. (2007) Alpha-ketoglutarate stimulates procollagen production in cultured human dermal fibroblasts, and decreases UVB-induced wrinkle formation following topical application on the dorsal skin of hairless mice. Biol. Pharm. Bull. 30, 1395-1399. https://doi.org/10.1248/bpb.30.1395
  85. Spencer, G. J., McGrath, C. J. and Genever, P. G. (2007) Current perspectives on NMDA-type glutamate signalling in bone. Int. J. Biochem. Cell Biol. 39, 1089-1104. https://doi.org/10.1016/j.biocel.2006.11.002
  86. Stanfel, M. N., Shamieh, L. S., Kaeberlein, M. and Kennedy, B. K. (2009) The TOR pathway comes of age. Biochim. Biophys. Acta 1790, 1067-1074. https://doi.org/10.1016/j.bbagen.2009.06.007
  87. Stoll, B., McNelly, S., Buscher, H. P. and Häussinger, D. (1991) Functional hepatocyte heterogeneity in glutamate, aspartate and ${\alpha}$-ketoglutarate uptake: A histoautoradiographical study. Hepatology 13, 247-253. https://doi.org/10.1002/hep.1840130208
  88. Tapiero, H., Mathe, G., Couvreur, P. and Tew, K. (2002) II. Glutamine and glutamate. Biomed. Pharmacother. 56, 446-457. https://doi.org/10.1016/S0753-3322(02)00285-8
  89. Tatara, M., Brodzki, A., Krupski, W., Silmanowicz, P., Majcher, P., Pierzynowski, S. and Studziński, T. (2005a) Effects of alpha-ketoglutarate on bone homeostasis and plasma amino acids in turkeys. Poult Sci. 84, 1604-1609. https://doi.org/10.1093/ps/84.10.1604
  90. Tatara, M., Tygesen, M. P., Sawa-Wojtanowicz, B., Krupski, W., Majcher, P. and Harrison, A. P. (2007) Bone development: The effect of short-term alpha-ketoglutarate administration on long-term mechanical properties of ribs in ram lambs. Small Ruminant Res. 67, 179-183. https://doi.org/10.1016/j.smallrumres.2005.09.031
  91. Tatara, M. R., Silmanowicz, P., Majcher, P., Krupski, W. and Studziński, T. (2005b) Influence of alpha-ketoglutarate on cortical bone atrophy after denervation of the humerus in turkey. Bull. Vet. Inst. Pulawy 49, 113-116.
  92. Taylor, A. (2002) Osteoblastic glutamate receptor function regulates bone formation and resorption. J. Musculoskelet. Neuronal Interact. 2, 285-290.
  93. Tocaj, A., Filip, R., Lindergard, B., Wernerman, J., Studzinski, T., Ohman, K. and Pierzynowski, S. (2003) Alpha-ketoglutarate (AKG) inhibit osteoporosis development in postmenopausal women. In Journal of Bone and Mineral Research, Vol. 18, pp. S267-S267. Amer Soc Bone & Mineral Res 2025 M St, Nw, Ste 800, Washington, Dc 20036-3309 USA.
  94. Toivonen, J. M., Walker, G. A., Martinez-Diaz, P., Bjedov, I., Driege, Y., Jacobs, H. T., Gems, D. and Partridge, L. (2007) No influence of Indy on lifespan in Drosophila after correction for genetic and cytoplasmic background effects. PLoS Genet. 3, e95. https://doi.org/10.1371/journal.pgen.0030095
  95. Tritos, N. A. and Biller, B. M. (2009) Growth hormone and bone. Curr. Opin. Endocrinol. Diabetes Obes. 16, 415-422. https://doi.org/10.1097/MED.0b013e3283319e6d
  96. Tsang, W. Y., Sayles, L. C., Grad, L. I., Pilgrim, D. B. and Lemire, B. D. (2001) Mitochondrial respiratory chain deficiency in Caenorhabditis elegans results in developmental arrest and increased life span. J. Biol. Chem. 276, 32240-32246. https://doi.org/10.1074/jbc.M103999200
  97. Urban, J., Soulard, A., Huber, A., Lippman, S., Mukhopadhyay, D., Deloche, O., Wanke, V., Anrather, D., Ammerer, G. and Riezman, H. (2007) Sch9 Is a Major Target of TORC1 in Saccharomyces cerevisiae. Mol. Cell 26, 663-674. https://doi.org/10.1016/j.molcel.2007.04.020
  98. Vellai, T., Takacs-Vellai, K., Zhang, Y., Kovacs, A. L., Orosz, L. and Müller, F. (2003) Influence of TOR kinase on lifespan in C. elegans. Nature 426, 620.
  99. Velvizhi, S., Dakshayani, K. B. and Subramanian, P. (2002) Effects of ${\alpha}$-ketoglutarate on antioxidants and lipid peroxidation products in rats treated with ammonium acetate. Nutrition 18, 747-750. https://doi.org/10.1016/S0899-9007(02)00825-0
  100. Wang, Y., Zhou, Y. and Graves, D. T. (2014) FOXO transcription factors: their clinical significance and regulation. Biomed. Res. Int. 2014, 925350.
  101. Webb, A. E. and Brunet, A. (2014) FOXO transcription factors: key regulators of cellular quality control. Trends Biochem. Sci. 39, 159-169. https://doi.org/10.1016/j.tibs.2014.02.003
  102. Welborn, J. R., Shpun, S., Dantzler, W. H. and Wright, S. H. (1998) Effect of ${\alpha}$-ketoglutarate on organic anion transport in single rabbit renal proximal tubules. Am. J. Physiol. Renal Physiol. 274, F165- F174. https://doi.org/10.1152/ajprenal.1998.274.1.F165
  103. Wernerman, J., Hammarqvist, F. and Vinnars, E. (1990) ${\alpha}$-Ketoglutarate and postoperative muscle catabolism. Lancet 335, 701-703. https://doi.org/10.1016/0140-6736(90)90811-I
  104. Wiren, M. and Permert, J. (2002) ${\alpha}$-ketoglutarate-supplemented enteral nutrition: effects on postoperative nitrogen balance and muscle catabolism. Nutrition 18, 725-728. https://doi.org/10.1016/S0899-9007(02)00844-4
  105. Wu, G., Fang, Y. Z., Yang, S., Lupton, J. R. and Turner, N. D. (2004) Glutathione metabolism and its implications for health. J. Nutr. 134, 489-492. https://doi.org/10.1093/jn/134.3.489
  106. Wullschleger, S., Loewith, R. and Hall, M. N. (2006) TOR signaling in growth and metabolism. Cell 124, 471-484. https://doi.org/10.1016/j.cell.2006.01.016
  107. Yeh, S. L., Lai, Y. N., Shang, H. F., Lin, M. T. and Chen, W. J. (2004) Effects of glutamine supplementation on innate immune response in rats with gut-derived sepsis. Br. J. Nutr. 91, 423-430. https://doi.org/10.1079/BJN20031069
  108. Ziegler, T. R. and Daignault, N. M. (2000) Glutamine regulation of human immune cell function. Nutrition 16, 458-459. https://doi.org/10.1016/S0899-9007(00)00359-2
  109. Zimmerman, J. J. and Ringer, T. V. (1992) Inflammatory host responses in sepsis. Crit. Care Clin. 8, 163-189. https://doi.org/10.1016/S0749-0704(18)30273-2

Cited by

  1. Dietary 2-oxoglutarate prevents bone loss caused by neonatal treatment with maximal dexamethasone dose vol.242, pp.7, 2017, https://doi.org/10.1177/1535370217693322
  2. Applying pathway engineering to enhance production of alpha-ketoglutarate in Yarrowia lipolytica vol.100, pp.23, 2016, https://doi.org/10.1007/s00253-016-7913-x
  3. Enasidenib, a targeted inhibitor of mutant IDH2 proteins, for treatment of relapsed or refractory acute myeloid leukemia 2018, https://doi.org/10.2217/fon-2017-0392
  4. Alpha-ketoglutarate enhances milk protein synthesis by porcine mammary epithelial cells vol.48, pp.9, 2016, https://doi.org/10.1007/s00726-016-2249-5
  5. Review of the Amphibian Immune Response to Chytridiomycosis, and Future Directions vol.9, pp.1664-3224, 2018, https://doi.org/10.3389/fimmu.2018.02536
  6. The pleiotropic effects of the glutamate dehydrogenase (GDH) pathway in Saccharomyces cerevisiae vol.17, pp.1, 2018, https://doi.org/10.1186/s12934-018-1018-4
  7. 5-Hydroxymethylfurfural and Alpha-Ketoglutaric Acid as an Ergogenic Aid During Intensified Soccer Training: A Placebo Controlled Randomized Study pp.1939-022X, 2018, https://doi.org/10.1080/19390211.2018.1494662
  8. Metabolic responses and pathway changes of mammalian cells under different culture conditions with media supplementations vol.34, pp.3, 2018, https://doi.org/10.1002/btpr.2623
  9. The Cardio- and Neuroprotective Effects of Corvitin and 2-Oxoglutarate in Rats with Pituitrin-Isoproterenol-Induced Myocardial Damage vol.2018, pp.2090-2255, 2018, https://doi.org/10.1155/2018/9302414
  10. Metabolic alterations in triptolide-induced acute hepatotoxicity vol.32, pp.10, 2018, https://doi.org/10.1002/bmc.4299
  11. Chytridiomycosis causes catastrophic organism-wide metabolic dysregulation including profound failure of cellular energy pathways vol.8, pp.1, 2018, https://doi.org/10.1038/s41598-018-26427-z
  12. Interorgan Metabolic Crosstalk in Human Insulin Resistance vol.98, pp.3, 2018, https://doi.org/10.1152/physrev.00015.2017
  13. Stimuli and sensors that initiate skeletal muscle hypertrophy following resistance exercise vol.126, pp.1, 2019, https://doi.org/10.1152/japplphysiol.00685.2018
  14. Automated network generation and analysis of biochemical reaction pathways using RING vol.49, pp.None, 2016, https://doi.org/10.1016/j.ymben.2018.07.009
  15. Influence of Liver Condition and Copper on Selective Parameters of Post-Mortem Dog Tissue Samples vol.8, pp.12, 2018, https://doi.org/10.3390/ani8120237
  16. The influence of progesterone on bovine uterine fluid energy, nucleotide, vitamin, cofactor, peptide, and xenobiotic composition during the conceptus elongation-initiation window vol.9, pp.None, 2016, https://doi.org/10.1038/s41598-019-44040-6
  17. Hepatic Mitochondrial Oxidative Metabolism and Lipogenesis Synergistically Adapt to Mediate Healthy Embryonic-to-Neonatal Transition in Chicken vol.9, pp.None, 2016, https://doi.org/10.1038/s41598-019-56715-1
  18. Isocitrate Lyase and Succinate Semialdehyde Dehydrogenase Mediate the Synthesis of α-Ketoglutarate in Pseudomonas fluorescens vol.10, pp.None, 2019, https://doi.org/10.3389/fmicb.2019.01929
  19. Regulation Is in the Air: The Relationship between Hypoxia and Epigenetics in Cancer vol.8, pp.4, 2016, https://doi.org/10.3390/cells8040300
  20. Metabolic Profiling of Tumors, Sera, and Skeletal Muscles from an Orthotopic Murine Model of Gastric Cancer Associated-Cachexia vol.18, pp.4, 2016, https://doi.org/10.1021/acs.jproteome.9b00088
  21. Metabolic profiling of zebrafish embryo development from blastula period to early larval stages vol.14, pp.5, 2019, https://doi.org/10.1371/journal.pone.0213661
  22. Metabolomics Analyses in High-Low Feed Efficient Dairy Cows Reveal Novel Biochemical Mechanisms and Predictive Biomarkers vol.9, pp.7, 2019, https://doi.org/10.3390/metabo9070151
  23. Novel approaches for glioblastoma treatment: Focus on tumor heterogeneity, treatment resistance, and computational tools vol.2, pp.6, 2016, https://doi.org/10.1002/cnr2.1220
  24. Urinary Organic Acids Increase After Clinical Stabilization of Hospitalized Children With Severe Acute Malnutrition vol.40, pp.4, 2016, https://doi.org/10.1177/0379572119853930
  25. Biocompatible photoinitiators based on poly‐α‐ketoesters vol.58, pp.2, 2020, https://doi.org/10.1002/pol.20199929
  26. Is Dietary 2-Oxoglutaric Acid Effective in Accelerating Bone Growth and Development in Experimentally-Induced Intrauterine Growth Retarded Gilts? vol.10, pp.4, 2016, https://doi.org/10.3390/ani10040728
  27. Multimodal Role of Amino Acids in Microbial Control and Drug Development vol.9, pp.6, 2016, https://doi.org/10.3390/antibiotics9060330
  28. The interplay between oxidative stress and bioenergetic failure in neuropsychiatric illnesses: can we explain it and can we treat it? vol.47, pp.7, 2016, https://doi.org/10.1007/s11033-020-05590-5
  29. Characterization of highly active 2-keto-3-deoxy-L-arabinonate and 2-keto-3-deoxy-D-xylonate dehydratases in terms of the biotransformation of hemicellulose sugars to chemicals vol.104, pp.16, 2016, https://doi.org/10.1007/s00253-020-10742-5
  30. Cryopreservation and the Freeze–Thaw Stress Response in Yeast vol.11, pp.8, 2016, https://doi.org/10.3390/genes11080835
  31. Alpha-Ketoglutaric Acid Production from a Mixture of Glycerol and Rapeseed Oil by Yarrowia lipolytica Using Different Substrate Feeding Strategies vol.12, pp.15, 2020, https://doi.org/10.3390/su12156109
  32. NCX1 and EAAC1 transporters are involved in the protective action of glutamate in an in vitro Alzheimer's disease-like model vol.91, pp.None, 2016, https://doi.org/10.1016/j.ceca.2020.102268
  33. Polyinosinic:polycytidylic acid in vivo enhances Chinook salmon (Oncorhynchus tshawytscha) immunity and alters the fish metabolome vol.28, pp.6, 2020, https://doi.org/10.1007/s10499-020-00599-w
  34. The Protective Role of Alpha-Ketoglutaric Acid on the Growth and Bone Development of Experimentally Induced Perinatal Growth-Retarded Piglets vol.11, pp.1, 2016, https://doi.org/10.3390/ani11010137
  35. Integrative Network Analysis Revealed Genetic Impact of Pyruvate Kinase L/R on Hepatocyte Proliferation and Graft Survival after Liver Transplantation vol.2021, pp.None, 2016, https://doi.org/10.1155/2021/7182914
  36. Nontargeted Metabolomic Analysis of Plasma Metabolite Changes in Patients with Adolescent Idiopathic Scoliosis vol.2021, pp.None, 2016, https://doi.org/10.1155/2021/5537811
  37. Cholesterol Content, Fatty Acid Profile and Health Lipid Indices in the Egg Yolk of Eggs from Hens at the End of the Laying Cycle, Following Alpha-Ketoglutarate Supplementation vol.10, pp.3, 2016, https://doi.org/10.3390/foods10030596
  38. Succinate Anaplerosis Has an Onco-Driving Potential in Prostate Cancer Cells vol.13, pp.7, 2016, https://doi.org/10.3390/cancers13071727
  39. Divergent trajectories of cellular bioenergetics, intermediary metabolism and systemic redox status in survivors and non-survivors of critical illness vol.41, pp.None, 2016, https://doi.org/10.1016/j.redox.2021.101907
  40. Engineering Posttranslational Regulation of Glutamine Synthetase for Controllable Ammonia Production in the Plant Symbiont Azospirillum brasilense vol.87, pp.14, 2016, https://doi.org/10.1128/aem.00582-21
  41. Enteromorpha prolifera polysaccharide prevents high‐ fat diet‐induced obesity in hamsters: A NMR‐based metabolomic evaluation vol.86, pp.8, 2016, https://doi.org/10.1111/1750-3841.15818
  42. Metabolomic signature of the Dravet syndrome: A genetic mouse model study vol.62, pp.8, 2016, https://doi.org/10.1111/epi.16976
  43. Regulation of Eukaryote Metabolism: An Abstract Model Explaining the Warburg/Crabtree Effect vol.9, pp.9, 2021, https://doi.org/10.3390/pr9091496
  44. Overview of Metabolomic Analysis and the Integration with Multi-Omics for Economic Traits in Cattle vol.11, pp.11, 2016, https://doi.org/10.3390/metabo11110753
  45. The Reactive Species Interactome in the Brain vol.35, pp.14, 2016, https://doi.org/10.1089/ars.2020.8238
  46. Simple Esterification of [1-13C]-Alpha-Ketoglutarate Enhances Membrane Permeability and Allows for Noninvasive Tracing of Glutamate and Glutamine Production vol.16, pp.11, 2016, https://doi.org/10.1021/acschembio.1c00561
  47. Rejuvant®, a potential life-extending compound formulation with alpha-ketoglutarate and vitamins, conferred an average 8 year reduction in biological aging, after an average of 7 months of use, in vol.13, pp.22, 2016, https://doi.org/10.18632/aging.203736
  48. The Effect of L-Glutamine on Basal Albumen and Yolk Indices, and Albumen Amino Acids Composition vol.11, pp.12, 2016, https://doi.org/10.3390/ani11123556
  49. Alterations in Metabolome and Microbiome Associated with an Early Stress Stage in Male Wistar Rats: A Multi-Omics Approach vol.22, pp.23, 2016, https://doi.org/10.3390/ijms222312931
  50. Investigating the pathogenesis of high‐serum gamma‐glutamyl transferase activity in Thoroughbred racehorses: A series of case‐control studies vol.54, pp.1, 2016, https://doi.org/10.1111/evj.13435