Hormonal Control of Pyruvate Kinase Activity and of Gluconeogenesis in Isolated Hepatocytes

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 1976 Aug 1

PMID 183209

Citations 56

Authors

J E Feliu

L Hue

H G HERS

Affiliations

Soon will be listed here.

Abstract

Treatment of isolated rat hepatocytes with saturating concentrations of glucagon caused several modifications properties of pyruvate kinase (ATP:pyruvate 2-O-phosphotransferase, EC 2.7.1.40): S0.5 (substrate concentration at half maximum velocity) for phosphoenolpyruvate was about doubled, whereas Vmax was not changed; the activity measured at 0.15 mM phosphoenolpyruvate (physiological concentration) was reduced 65-80%; and there was also an increase in the Hill coefficient and in the affinity of the enzyme for the inhibitors Mg-ATP and alanine. Glucagon, 3':5'-cyclic AMP, and epinephrine caused an inactivation of pyruvate kinase together with a sitmulation of gluconeogenesis. Insulin (10 nM) antagonized the effect of suboptimal doses of glucagon or cyclic AMP and of even maximal doses of epinephrine, on both pyruvate kinase activity and on gluconeogenesis. These observations can be explained by a phosphorylation of pyruvate kinase by cyclic-AMP-dependent protein kinase, as described by Ljungström et al. [(1974) Biochim. Biophys. Acta 358, 289-298] in a reconstructed system. They offer a molecular explanation for the hormonal control of gluconeogenesis. Glucose caused an inhibition of gluconeogenesis with no corresponding change in pyruvate kinase activity.

Citing Articles

Exploring glycolytic enzymes in disease: potential biomarkers and therapeutic targets in neurodegeneration, cancer and parasitic infections.

Rojas-Pirela M, Andrade-Alviarez D, Rojas V, Marcos M, Salete-Granado D, Chacon-Arnaude M Open Biol. 2025; 15(2):240239.

PMID: 39904372 PMC: 11793985. DOI: 10.1098/rsob.240239.

Glucagon, cyclic AMP, and hepatic glucose mobilization: A half-century of uncertainty.

Rodgers R Physiol Rep. 2022; 10(9):e15263.

PMID: 35569125 PMC: 9107925. DOI: 10.14814/phy2.15263.

The Role of Catecholamines in Pathophysiological Liver Processes.

Lelou E, Corlu A, Nesseler N, Rauch C, Malledant Y, Seguin P Cells. 2022; 11(6).

PMID: 35326472 PMC: 8947265. DOI: 10.3390/cells11061021.

New Insights to Regulation of Fructose-1,6-bisphosphatase during Anoxia in Red-Eared Slider, .

Gupta A, Varma A, Storey K Biomolecules. 2021; 11(10).

PMID: 34680181 PMC: 8534150. DOI: 10.3390/biom11101548.

Distinct Hepatic PKA and CDK Signaling Pathways Control Activity-Independent Pyruvate Kinase Phosphorylation and Hepatic Glucose Production.

Gassaway B, Cardone R, Padyana A, Petersen M, Judd E, Hayes S Cell Rep. 2019; 29(11):3394-3404.e9.

PMID: 31825824 PMC: 6951436. DOI: 10.1016/j.celrep.2019.11.009.

References

Claus T, Pilkis S, Park C . Stimulation by glucagon of the incorporation of U-14C-labeled substrates into glucose by isolated hepatocytes from fed rats. Biochim Biophys Acta. 1975; 404(1):110-23. DOI: 10.1016/0304-4165(75)90152-x. View

MCDANIEL H . Acute suppression of hepatic gluconeogenesis by glucose in the intact animal. Am J Physiol. 1975; 229(6):1569-75. DOI: 10.1152/ajplegacy.1975.229.6.1569. View

Patterson M, GREENE R . MEASUREMENT OF LOW ENERGY BETA-EMITTERS IN AQUEOUS SOLUTION BY LIQUID SCINTILLATION COUNTING OF EMULSIONS. Anal Chem. 1965; 37:854-7. DOI: 10.1021/ac60226a017. View

LOWRY O, ROSEBROUGH N, FARR A, RANDALL R . Protein measurement with the Folin phenol reagent. J Biol Chem. 1951; 193(1):265-75. View

Titanji V, ZETTERQVIST O, Engstroom L . Regulation in vitro of rat liver pyruvate kinase by phosphorylation-dephosphorylation reactions, catalyzed by cyclic-AMP dependent protein kinases and a histone phosphatase. Biochim Biophys Acta. 1976; 422(1):98-108. DOI: 10.1016/0005-2744(76)90011-5. View

Claus T, Pilkis S . Regulation by insulin of gluconeogenesis in isolated rat hepatocytes. Biochim Biophys Acta. 1976; 421(2):246-62. DOI: 10.1016/0304-4165(76)90291-9. View

Ekman P, Dahlqvist U, Humble E, Engstrom L . Comparative kinetic studies on the L-type pyruvate kinase from rat liver and the enzyme phosphorylated by cyclic 3', 5'-AMP-stimulated protein kinase. Biochim Biophys Acta. 1976; 429(2):374-82. DOI: 10.1016/0005-2744(76)90285-0. View

Desbuquois B, Krug F, Cuatrecasas P . Inhibitors of glucagon inactivation. Effect on glucagon--receptor interactions and glucagon-stimulated adenylate cyclase activity in liver cell membranes. Biochim Biophys Acta. 1974; 343(1):101-20. DOI: 10.1016/0304-4165(74)90242-6. View

Clark M, Kneer N, Bosch A, LARDY H . The fructose 1,6-diphosphatase-phosphofructokinase substrate cycle. A site of regulation of hepatic gluconeogenesis by glucagon. J Biol Chem. 1974; 249(18):5695-703. View

10.

TAUNTON O, Stifel F, Greene H, HERMAN R . Rapid reciprocal changes in rat hepatic glycolytic enzyme and fructose diphosphatase activities following insulin and glucagon injection. J Biol Chem. 1974; 249(22):7228-39. View

11.

FLORY W, Peczon B, Koeppe R, Spivey H . Kinetic properties of rat liver pyruvate kinase at cellular concentrations of enzyme, substrates and modifiers. Biochem J. 1974; 141(1):127-31. PMC: 1168057. DOI: 10.1042/bj1410127. View

12.

Carbonell J, Feliu J, Marco R, SOLS A . Pyruvate kinase. Classes of regulatory isoenzymes in mammalian tissues. Eur J Biochem. 1973; 37(1):148-56. DOI: 10.1111/j.1432-1033.1973.tb02969.x. View

13.

Faupel R, Seitz H, Tarnowski W, Thiemann V, Weiss C . The problem of tissue sampling from experimental animals with respect to freezing technique, anoxia, stress and narcosis. A new method for sampling rat liver tissue and the physiological values of glycolytic intermediates and related compounds. Arch Biochem Biophys. 1972; 148(2):509-22. DOI: 10.1016/0003-9861(72)90170-1. View

14.

VENEZIALE C . Gluconeogenesis from fructose in isolated rat liver. Stimulation by glucagon. Biochemistry. 1971; 10(18):3443-7. DOI: 10.1021/bi00794a020. View

15.

Freidmann B, GOODMAN Jr E, Saunders H, Kostos V, WEINHOUSE S . An estimation of pyruvate recycling during gluconeogenesis in the perfused rat liver. Arch Biochem Biophys. 1971; 143(2):566-78. DOI: 10.1016/0003-9861(71)90241-4. View

16.

Ruderman N, Herrera M . Glucose regulation of hepatic gluconeogenesis. Am J Physiol. 1968; 214(6):1346-51. DOI: 10.1152/ajplegacy.1968.214.6.1346. View

17.

Thomas J, Schlender K, Larner J . A rapid filter paper assay for UDPglucose-glycogen glucosyltransferase, including an improved biosynthesis of UDP-14C-glucose. Anal Biochem. 1968; 25(1):486-99. DOI: 10.1016/0003-2697(68)90127-9. View

18.

KREBS H, HEMS R, Weidemann M, SPEAKE R . The fate of isotopic carbon in kidney cortex synthesizing glucose from lactate. Biochem J. 1966; 101(1):242-9. PMC: 1270089. DOI: 10.1042/bj1010242. View

19.

Tanaka T, Sue F, Morimura H . Feed-forward activation and feed-back inhibition of pyruvate kinase type L of rat liver. Biochem Biophys Res Commun. 1967; 29(3):444-9. DOI: 10.1016/0006-291x(67)90477-9. View

20.

Hue L, Bontemps F, Hers H . The effects of glucose and of potassium ions on the interconversion of the two forms of glycogen phosphorylase and of glycogen synthetase in isolated rat liver preparations. Biochem J. 1975; 152(1):105-14. PMC: 1172445. DOI: 10.1042/bj1520105. View