Rapid increase of phosphoribosyl pyrophosphate concentration after mitogenic stimulation of lymphocytes

Hovi, Tapani; Allison, A. C.; Allsop, Jennifer

doi:10.1016/0014-5793(75)81014-3

Cited by 39 publications

(8 citation statements)

References 17 publications

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“…We found a rapid and sustained increase in PRPP concentrations in human lymphocytes following mitogenic stimulation [48], as well as markedly increased de novo purine synthesis, as shown by incorporation of [14C]glycine into purine nucleotides [50]. In stimulated cells the label was about equally distributed into pools of adenosine nucleotides on the one hand and inosine and guanosine nucleotides on the other, whereas in resting cells synthesis of adenosine nucleotides predominates.…”

Section: Purine Metabolism In Lymphocytes and Genetic Defectsmentioning

confidence: 78%

The design and development of an immunosuppressive drug, mycophenolate mofetil

Allison¹,

Eugui²

1993

Springer Semin Immunopathol

137

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Section: Purine Metabolism In Lymphocytes and Genetic Defectsmentioning

confidence: 78%

The design and development of an immunosuppressive drug, mycophenolate mofetil

Allison¹,

Eugui²

1993

Springer Semin Immunopathol

137

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“…Inhibitors of the synthesis de novo of purine bases inhibit lymphocyte proliferation, suggesting that the activity of the salvage pathway of purine synthesis is insufficient to support DNA synthesis. Hovi et al (1975) have reported a transient increase in the concentration of phosphoribosyl pyrophosphate in phytohaemagglutinin-treated human peripheral blood lymphocytes, which reaches a peak after 30min and then slowly returns to basal values. The concentration of phosphoribosyl pyrophosphate may be an important factor in the regulation of purine biosynthesis (Green & Martin, 1974).…”

Section: Discussionmentioning

confidence: 99%

“…The concentration of phosphoribosyl pyrophosphate may be an important factor in the regulation of purine biosynthesis (Green & Martin, 1974). Additionally, increased intracellular concentrations of glucose 6-phosphate (Culvenor & Weidemann, 1976;Keig, 1973) may be necessary for maximal purine biosynthesis from glucose in mitogen-treated lymphocytes, and may be the direct cause of the increase in phosphoribosyl pyrophosphate observed by Hovi et al (1975). Since the maximum catalytic activity of phosphofructokinase in lymphoid tissue is much higher than that of the glucose carrier (Yasmeen et al, 1977), an elevation of the steady state concentration of intracellular glucose 6-phosphate would require a very large stimulation of glucose transport and/or inhibition of phosphofructokinase.…”

Section: Discussionmentioning

confidence: 99%

Aerobic glycolysis and lymphocyte transformation

Hume

Radik

Ferber

et al. 1978

Biochemical Journal

151

109

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1. The role of enhanced aerobic glycolysis in the transformation of rat thymocytes by concanavalin A has been investigated. Concanavalin A addition doubled [U-(14)C]glucose uptake by rat thymocytes over 3h and caused an equivalent increased incorporation into protein, lipids and RNA. A disproportionately large percentage of the extra glucose taken up was converted into lactate, but concanavalin A also caused a specific increase in pyruvate oxidation, leading to an increase in the percentage contribution of glucose to the respiratory fuel. 2. Acetoacetate metabolism, which was not affected by concanavalin A, strongly suppressed pyruvate oxidation in the presence of [U-(14)C]glucose, but did not prevent the concanavalin A-induced stimulation of this process. Glucose uptake was not affected by acetoacetate in the presence or absence of concanavalin A, but in each case acetoacetate increased the percentage of glucose uptake accounted for by lactate production. 3. [(3)H]Thymidine incorporation into DNA in concanavalin A-treated thymocyte cultures was sensitive to the glucose concentration in the medium in a biphasic manner. Very low concentrations of glucose (25mum) stimulated DNA synthesis half-maximally, but maximum [(3)H]thymidine incorporation was observed only when the glucose concentration was raised to 1mm. Lactate addition did not alter the sensitivity of [(3)H]-thymidine uptake to glucose, but inosine blocked the effect of added glucose and strongly inhibited DNA synthesis. 4. It is suggested that the major function of enhanced aerobic glycolysis in transforming lymphocytes is to maintain higher steady-state amounts of glycolytic intermediates to act as precursors for macromolecule synthesis.

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“…Indeed, glycolytic intermediates are maintained at high levels in the G 1 phase of the cell cycle and at especially high levels in tumor cells (Eigenbrodt et al 1992), and this is supported by increased glycolytic flux with a high rate of lactate production. Additionally, a rapid accumulation of PRPP is observed in thymocytes after mitogenic stimulation (Hovi et al 1975), and this may be directly caused by increased intracellular concentrations of glucose-6-phosphate (Culvenor & Weidemann 1976) to support nucleotide biosynthesis. Thus, during cell growth, glycolytic flux may be enhanced to allow for fast cell growth by maintaining the pool sizes of glycolytic intermediates as they are depleted for anabolic reactions.…”

Section: Why Do Proliferating Cells Excrete So Much Lactate?mentioning

confidence: 99%

Aerobic Glycolysis: Meeting the Metabolic Requirements of Cell Proliferation

Lunt

Heiden

2011

Annu. Rev. Cell Dev. Biol.

2,499

2,296

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Warburg's observation that cancer cells exhibit a high rate of glycolysis even in the presence of oxygen (aerobic glycolysis) sparked debate over the role of glycolysis in normal and cancer cells. Although it has been established that defects in mitochondrial respiration are not the cause of cancer or aerobic glycolysis, the advantages of enhanced glycolysis in cancer remain controversial. Many cells ranging from microbes to lymphocytes use aerobic glycolysis during rapid proliferation, which suggests it may play a fundamental role in supporting cell growth. Here, we review how glycolysis contributes to the metabolic processes of dividing cells. We provide a detailed accounting of the biosynthetic requirements to construct a new cell and illustrate the importance of glycolysis in providing carbons to generate biomass. We argue that the major function of aerobic glycolysis is to maintain high levels of glycolytic intermediates to support anabolic reactions in cells, thus providing an explanation for why increased glucose metabolism is selected for in proliferating cells throughout nature.

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Rapid increase of phosphoribosyl pyrophosphate concentration after mitogenic stimulation of lymphocytes

Cited by 39 publications

References 17 publications

The design and development of an immunosuppressive drug, mycophenolate mofetil

The design and development of an immunosuppressive drug, mycophenolate mofetil

Aerobic glycolysis and lymphocyte transformation

Aerobic Glycolysis: Meeting the Metabolic Requirements of Cell Proliferation

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