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J. Biol. Chem., Vol. 276, Issue 30, 28554-28561, July 27, 2001

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Regulation of Energy Metabolism in Macrophages during Hypoxia
ROLES OF FRUCTOSE 2,6-BISPHOSPHATE AND RIBOSE 1,5-BISPHOSPHATE^*

Takumi Kawaguchi, Richard L. Veech^§, and Kosaku Uyeda^¶

From the  Department of Biochemistry, Dallas Veterans Affairs Medical Center, Dallas, Texas 75216, the Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75223, and the ^§ National Institute on Alcohol Abuse and Alcoholism, Rockville, Maryland 20852

Macrophages can adapt to the absence of oxygen by switching to anaerobic glycolysis. In this study, we investigated (a) the roles of fructose 2,6-bisphosphate (Fru-2,6-P₂) and ribose 1,5-bisphosphate (Rib-1,5-P₂), potent activators of phosphofructokinase, (b) the enzymes responsible for the synthesis of Rib-1,5-P₂, and (c) the mechanisms of regulation of these enzymes in H36.12j macrophages during the initial phase of hypoxia. Within 1 min after initiating hypoxia, glycolysis was activated through activation of phosphofructokinase. Over the same period, Fru-2,6-P₂ decreased 50% and recovered completely upon reoxygenation. Similar changes in cAMP levels were observed. In contrast, the Rib-1,5-P₂ concentration rapidly increased to a maximum level of 8.0 ± 0.9 nmol/g cell 30 s after hypoxia. Thus, Rib-1,5-P₂ was the major factor increasing the rate of glycolysis during the initial phase of hypoxia. Moreover, we found that Rib-1,5-P₂ was synthesized by two steps: the ribose-phosphate pyrophosphokinase (5-phosphoribosyl-1-pyrophosphate synthetase; PRPP synthetase) reaction (EC 2.7.6.1) catalyzing the reaction, Rib-5-P + ATP  PRPP + AMP and a new enzyme, "PRPP pyrophosphatase" catalyzing the reaction, PRPP  Rib-1,5-P₂ + P_i. Both PRPP synthetase and PRPP pyrophosphatase were significantly activated 30 s after hypoxia. Pretreatment with 1-octadecyl-2-methyl-rac-glycero-3-phosphocholine and calphostin C prevented the activation of ribose PRPP synthetase and PRPP pyrophosphatase as well as increase in Rib-1,5-P₂ and activation of phosphofructokinase 30 s after hypoxia. These data suggest that the activation of the above enzymes was mediated by protein kinase C acting via activation of phosphatidylinositol specific phospholipase C in the macrophages during hypoxia.

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