Abstract
Total 6-phosphofructo-1-kinase (PFK) activity, amounts of each type of PFK subunit, and levels of fructose-2,6-P2 in the cerebral cortex, midbrain, pons-medulla, and cerebellum of 3, 12, and 25 month rats were measured. Further, the role of fructose-2,6-P2 in the regulation of brain PFK activity was examined. A positive correlation was found to exist between the reported losses of glucose utilization as measured by 2-deoxy-D-glucose uptake and PFK activity in each region. That is, both parameters decreased to their lowest level by 12 months of age and remained decreased and fairly constant thereafter. Fructose-2,6-P2 levels did not appear to directly correlate with regional changes in glucose utilization. Also, region-specific and age-related alterations of the PFK subunits were found although these changes apparently did not correlate with decreased glucose utilization. Brain PFK is apparently saturated with fructose-2,6-P2 due to the high endogenous levels, and it contains a large proportion of the C-type subunit which dampens catalytic efficiency. Consequently, brain PFK could exist in a conformational state such that it can readily consume fructose-6-P rather than in an inhibited state requiring activation. This may explain, in part, the ability of brain to efficiently but conservatively utilize available glucose in energy production.
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Abbreviations
- fructose-2,6-P2 :
-
D-fructose 2,6-bisphosphate
- fructose-6-P:
-
D-fructose 6-phosphate
- PAGE:
-
Polyacrylamide Gel Electrophoresis
- PFK:
-
6-phosphofructo-1-kinase
- PPi-PFK:
-
Pyrophosphate-dependent Phosphofructokinase, ribose-1,5-P2, ribose-1,5-bisphosphate
- SDS:
-
Sodium Dodecyl Sulfate
References
Dunaway GA: A review of animal phosphofructokinase isozymes with an emphasis on their physiological role. Mol Cell Biochem 52: 75–91, 1983
Claus TH, El-Maghrabi MR, Regen DM, Stewart HB, McGrane M, Kountz PD, Nyfeler F, Pilkis J, Pilkis SJ: The role of fructose 2,6-bisphosphate in the regulation of carbohydrate metabolism. Curr Topics Cell Reg 23: 57–86, 1984
Dunaway GA, Kasten TP: Nature of the subunits of the 6-phosphofructo-1-kinase from rat tissues. Biochem J 242: 667–671, 1987
Dunaway GA, Kasten TP, Sebo T, Trapp R: Analysis of the phosphofructokinase subunits and isoenzymes in human tissues. Biochem J 251: 677–683, 1988
Foe LG, Kemp RG: Isozyme composition and phosphorylation of brain phosphofructokinase. Arch Biochem Biophys 228: 503–511, 1984
Dunaway GA, Kasten TP: Nature of the rat brain 6-phosphofructo-1-kinase isozymes. J Biol Chem 260: 4180–4185, 1985
Dunaway GA, Kasten TP: Characterization of the rat heart 6-phosphofructo-1-kinase isozymes. J Mol Cell Cardiol 17: 947–957, 1985
Vora S, Seaman C, Durham S, Piomelli S: Isozymes of human phosphofructokinase: identification and subunit structural characterization of a new system. Proc Natl Acad Sci, USA 77: 62–66, 1980
Kahn A, Meienhofer MC, Cottreau D, LaGrange J-L, Dreyfus J-C: Phosphofructokinase (PFK) isozymes in man I. studies in adult human tissues. Hum Genet 48: 93–108, 1979
Meienhofer MC, LaGrange JL, Cottreau D, Lenoir G, Dreyfus J-C, Kahn A: Phosphofructokinase in human cells. Blood 54: 389–400, 1979
Dunaway GA, Kasten TP: Physiological implications of the alteration of 6-phosphofructo-1-kinase isozyme pools during brain development and aging. Brain Res 456: 310–316, 1988
Dunaway GA, Kasten TP, Crabtree S, Mhaskar Y: Age-related changes in the subunit composition and regulation of hepatic 6-phosphofructo-1-kinase. Biochem J 266: 823–827, 1990
Dunaway GA, Kasten TP: Physiological relevance of the changing subunit composition and regulatory properties of the 6-phosphofructo-1-kinase isozyme pools during heart and muscle development. Mole Cell Biochem 87: 71–77, 1989
Reinhart GD, Lardy HA: Rat liver phosphofructokinase: kinetic and physiological ramifications of aggregation behavior. Biochem 19: 1491–1495, 1980
Claus TH, Schlumpf JR, El-Maghrabi MR, Pilkis J, Pilkis SJ: Mechanism of action of glucagon on hepatocyte phosphofructokinase activity. Proc Natl Acad Sci, USA 77: 6501–6506, 1980
Van Schaftingen E, Hue L, Hers H-G: Study of the fructose 6-phosphate/fructose 1,6-bisphosphate cycle in the liverin vivo. Biochem J 192: 263–271, 1980
Furuya E, Uyeda K: An activation factor of liver phosphofructokinase. Proc Natl Acad Sci, USA 77: 5861–5864, 1980
Hue L, Rider MH: Role of fructose 2,6-bisphosphate in the control of glycolysis in mammalian tissues. Biochem J 245: 313–324, 1987
Narabayashi H, Lawsaon JWR, Uyeda K: Regulation of phosphofructokinase in perfused rat heart. J Biol Chem 260: 9750–9758, 1985
Lawson JWR, Uyeda K: Effects of insulin and work on fructose 2,6-bisphosphate content and phosphofructokinase activity in perfused rat hearts. J Biol Chem 262: 3165–3173, 1987
Uyeda K, Furuya E, Richards CS, Yokoyama M: Fructose-2,6-P2, chemistry and biological function. Mol Cell Biochem 48: 97–120, 1982
Hue L, Blackmore PE, Shikama H, Robinson-Steiner A, Exton JH: Regulation of fructose-2,6-bisphosphate content in rat hepatocytes, perfused hearts and perfused hind limbs. J Biol Chem 257: 4308–4313, 1982
Pilkis SJ, El-Maghrabi MR, Pilkis J, Claus TH: Inhibition of Fructose-1,6-Bisdphosphatase by Fructose 2,6-Bisphosphate. J Biol Chem 256: 3619–3622, 1981
Ogushi S, Lawson JWR, Dobson GP, Veech RL, Uyeda K: A new transient activator of phosphofructokinase during initiation of rapid glycolysis in brain. J Biol Chem 265: 10943–10949, 1990
Ishikawa E, Ogushi S, Ishikawa T, Uyeda K: Activation of mammalian phosphofructokinases by ribose 1,5-bisphosphate. J Biol Chem 265: 18875–18878, 1990
London ED, Nespor SM, Ohata M, Rapport SI: Local cerebral glucose utilization during development and aging of the Fischer-344 rat. J Neurochem 37: 217–221, 1981
Bradford MM: A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72: 248–254, 1976
Williamson DH, Bronson JT: Concentrations of metabolites in animal tissues. In: HU Bergmeyer (ed) Methods of Enzymatic Analysis, 2nd Ed., Vol 4, Verlag Chemie International, Deerfield Beach, Florida, 1974, pp 2280, 2293–2299
Van Schaftingen E, Lederer B, Barons R, Hers H-G: A kinetics study of pyrophosphate: fructose-6-phosphate phosphotransferase from potato tubers. Eur J Biochem 129: 191–195, 1982
Erecinska M, Silver IA: ATP and brain function. J Cereb Blood Flow Metab 9: 2–19, 1989
Sokoloff L, Reivich M, Kennedy C, Des Rosiers MH, Patlak CS, Pettigrew KD, Sakurda O, Shinohara M: The [14C]Deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the consious and anesthetized albino rat. J Neurochem 28: 897–916, 1977
Kasten T, Colliver JA, Montrey RD, Dunaway GA: The effects of various anesthetics on tissue levels of fructose-2,6-bisphosphate in rats. Lab Animal Sci 40: 399–401, 1990
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Kasten, T.P., Mhaskar, Y. & Dunaway, G.A. Regulation of brain 6-phosphofructo-1-kinase: effects of aging, fructose-2,6-bisphosphate, and regional subunit distribution. Mol Cell Biochem 120, 61–68 (1993). https://doi.org/10.1007/BF00925985
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DOI: https://doi.org/10.1007/BF00925985