Skip to main content
NCBI home page
Biochemical Journal logoLink to Biochemical Journal
. 1992 Jan 1;281(Pt 1):267–272. doi: 10.1042/bj2810267

Inhibition of glycolysis by 5-amino-4-imidazolecarboxamide riboside in isolated rat hepatocytes.

M F Vincent 1, F Bontemps 1, G Van den Berghe 1
PMCID: PMC1130672  PMID: 1531010

Abstract

5-Amino-4-imidazolecarboxamide riboside (AICAriboside; Z-riboside), the nucleotide corresponding to AICAribotide (AICAR or ZMP), an intermediate of the 'de novo' pathway of purine nucleotide biosynthesis, has been shown to inhibit gluconeogenesis in isolated rat hepatocytes [Vincent, Marangos, Gruber & Van den Berghe (1991) Diabetes 40, 1259-1266]. We now report that glycosis is also inhibited and even more sensitive to AICAriboside in these cells. In hepatocyte suspensions from fasted rats, production of lactate from 15 mM-glucose was half-maximally inhibited by 25-50 microM-AICAriboside. AICAriboside influenced two regulatory steps of glycolysis: (1) it decreased the release of 3H2O from [2-3H]glucose and the concentrations of both glucose 6-phosphate and fructose 6-phosphate, indicating that it diminished the phosphorylation of glucose by glucokinase; (2) it decreased the concentration of fructose 2,6-bisphosphate (Fru-2,6-P2), the main physiological stimulator of liver 6-phosphofructo-1-kinase. Further studies showed that AICAriboside induced an inactivation of 6-phosphofructo-2-kinase, the enzyme that produces Fru-2,6-P2, without affecting the concentration of cyclic AMP. Similarly to the inhibiton of gluconeogenesis by AICAriboside, the inhibition of glycolysis became apparent after an approx. 10 min latency and persisted when the cells were washed after addition of AICAriboside, strongly suggesting that the effects were also exerted by the Z-nucleotides, which accumulate after addition of AICAriboside to hepatocytes. An increased uptake of lactate was evident when 50-200 microM-AICAriboside was added 15 min after addition of glucose. This can be explained by the higher sensitivity of glycolysis, as compared with gluconeogenesis, to inhibition by AICAriboside, and reveals the simultaneous operation of both processes.

Full text

PDF
267

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bartrons R., Hue L., Van Schaftingen E., Hers H. G. Hormonal control of fructose 2,6-bisphosphate concentration in isolated rat hepatocytes. Biochem J. 1983 Sep 15;214(3):829–837. doi: 10.1042/bj2140829. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bartrons R., Van Schaftingen E., Hers H. G. The ability of adenosine to decrease the concentration of fructose 2,6-bisphosphate in isolated hepatocytes. A cyclic AMP-mediated effect. Biochem J. 1984 Feb 15;218(1):157–163. doi: 10.1042/bj2180157. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bontemps F., Hue L., Hers H. G. Phosphorylation of glucose in isolated rat hepatocytes. Sigmoidal kinetics explained by the activity of glucokinase alone. Biochem J. 1978 Aug 15;174(2):603–611. doi: 10.1042/bj1740603. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Engler R. Consequences of activation and adenosine-mediated inhibition of granulocytes during myocardial ischemia. Fed Proc. 1987 May 15;46(7):2407–2412. [PubMed] [Google Scholar]
  5. Feliú J. E., Hue L., Hers H. G. Hormonal control of pyruvate kinase activity and of gluconeogenesis in isolated hepatocytes. Proc Natl Acad Sci U S A. 1976 Aug;73(8):2762–2766. doi: 10.1073/pnas.73.8.2762. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Gruber H. E., Hoffer M. E., McAllister D. R., Laikind P. K., Lane T. A., Schmid-Schoenbein G. W., Engler R. L. Increased adenosine concentration in blood from ischemic myocardium by AICA riboside. Effects on flow, granulocytes, and injury. Circulation. 1989 Nov;80(5):1400–1411. doi: 10.1161/01.cir.80.5.1400. [DOI] [PubMed] [Google Scholar]
  7. Hers H. G., Hue L. Gluconeogenesis and related aspects of glycolysis. Annu Rev Biochem. 1983;52:617–653. doi: 10.1146/annurev.bi.52.070183.003153. [DOI] [PubMed] [Google Scholar]
  8. Hers H. G., Van Schaftingen E. Fructose 2,6-bisphosphate 2 years after its discovery. Biochem J. 1982 Jul 15;206(1):1–12. doi: 10.1042/bj2060001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hue L., Blackmore P. F., Exton J. H. Fructose 2,6-bisphosphate. Hormonal regulation and mechanism of its formation in liver. J Biol Chem. 1981 Sep 10;256(17):8900–8903. [PubMed] [Google Scholar]
  10. Hue L., Rider M. H. Role of fructose 2,6-bisphosphate in the control of glycolysis in mammalian tissues. Biochem J. 1987 Jul 15;245(2):313–324. doi: 10.1042/bj2450313. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hue L. The role of futile cycles in the regulation of carbohydrate metabolism in the liver. Adv Enzymol Relat Areas Mol Biol. 1981;52:247–331. doi: 10.1002/9780470122976.ch4. [DOI] [PubMed] [Google Scholar]
  12. Katz J., Rognstad R. Futile cycles in the metabolism of glucose. Curr Top Cell Regul. 1976;10:237–289. doi: 10.1016/b978-0-12-152810-2.50013-9. [DOI] [PubMed] [Google Scholar]
  13. Parry M. J., Walker D. G. Purification and properties of adenosine 5'-triphospae-D-glucose 6-phosphotransferase from rat liver. Biochem J. 1966 May;99(2):266–274. doi: 10.1042/bj0990266. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Pilkis S. J., Pilkis J., el-Maghrabi M. R., Claus T. H. The sugar phosphate specificity of rat hepatic 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase. J Biol Chem. 1985 Jun 25;260(12):7551–7556. [PubMed] [Google Scholar]
  15. Riquelme P. T., Kneer N. M., Wernette-Hammond M. E., Lardy H. A. Inhibition by 2,5-anhydromannitol of glycolysis in isolated rat hepatocytes and in Ehrlich ascites cells. Proc Natl Acad Sci U S A. 1985 Jan;82(1):78–82. doi: 10.1073/pnas.82.1.78. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Riquelme P. T., Wernette-Hammond M. E., Kneer N. M., Lardy H. A. Mechanism of action of 2,5-anhydro-D-mannitol in hepatocytes. Effects of phosphorylated metabolites on enzymes of carbohydrate metabolism. J Biol Chem. 1984 Apr 25;259(8):5115–5123. [PubMed] [Google Scholar]
  17. Riquelme P. T., Wernette-Hammond M. E., Kneer N. M., Lardy H. A. Regulation of carbohydrate metabolism by 2,5-anhydro-D-mannitol. Proc Natl Acad Sci U S A. 1983 Jul;80(14):4301–4305. doi: 10.1073/pnas.80.14.4301. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Sabina R. L., Holmes E. W., Becker M. A. The enzymatic synthesis of 5-amino-4-imidazolecarboxamide riboside triphosphate (ZTP). Science. 1984 Mar 16;223(4641):1193–1195. doi: 10.1126/science.6199843. [DOI] [PubMed] [Google Scholar]
  19. Seglen P. O. Protein-catabolic stage of isolated rat hepatocytes. Biochim Biophys Acta. 1977 Jan 24;496(1):182–191. doi: 10.1016/0304-4165(77)90126-x. [DOI] [PubMed] [Google Scholar]
  20. Van Schaftingen E. A protein from rat liver confers to glucokinase the property of being antagonistically regulated by fructose 6-phosphate and fructose 1-phosphate. Eur J Biochem. 1989 Jan 15;179(1):179–184. doi: 10.1111/j.1432-1033.1989.tb14538.x. [DOI] [PubMed] [Google Scholar]
  21. Van den Berghe G., Bontemps F., Hers H. G. Purine catabolism in isolated rat hepatocytes. Influence of coformycin. Biochem J. 1980 Jun 15;188(3):913–920. doi: 10.1042/bj1880913. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Vincent M. F., Marangos P. J., Gruber H. E., Van den Berghe G. Inhibition by AICA riboside of gluconeogenesis in isolated rat hepatocytes. Diabetes. 1991 Oct;40(10):1259–1266. doi: 10.2337/diab.40.10.1259. [DOI] [PubMed] [Google Scholar]
  23. Whelan J. M., Bagnara A. S. Factors affecting the rate of purine ribonucleotide dephosphorylation in human erythrocytes. Biochim Biophys Acta. 1979 Jul 26;563(2):466–478. doi: 10.1016/0005-2787(79)90065-0. [DOI] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES