The role of high rates of glycolysis and glutamine utilization in rapidly dividing cells

Abstract

The rates of utilization of both glucose and glutamine are high in rapidly dividing cells such as enterocytes, lymphocytes, thymocytes, tumour cells; the oxidation of both glucose and glutamine is only partial, glucose to lactate and glutamine to glutamate, alanine or aspartate; and these partial processes are termed glycolysis and glutaminolysis respectively. Both processes generate energy and also provide precursors for important biosynthetic processes in such cells. However, the rates of utilization of precursors for macromolecular biosynthesis are very low in comparison to the rates of partial oxidation, and energy generation per se may not be the correct explanation for high rates of glycolysis and glutaminolysis in these cells since oxidation is only partial and other fuels can be used to generate energy. Both the high fluxes and the metabolic characteristics of these two processes can be explained by application of quantitative principles of control as applied to branched metabolic pathways (Crabtree & Newsholme, 1985). If the flux through one branch is greatly in excess of the other, then the sensitivity of the flux of the low-flux pathway to regulators is very high. Hence, it is suggested that, in rapidly dividing cells, high rates of glycolysis and glutaminolysis are required not for energy or precursor provision per se but for high sensitivity of the pathways involved in the use of precursors for macromolecular synthesis to specific regulators to permit high rates of proliferation when required - for example, in lymphocytes in response to a massive infection.

Fasting vs dietary restriction in cellular protection and cancer treatment: from model organisms to patients

“…The Warburg effect does not only apply to cancer cells, but also to rapidly dividing normal cells such as lymphocytes, thymocytes and enterocytes (Newsholme et al, 1985). Although oxidative phosphorylation is far superior to glycolysis in terms of ATP production, glycolysis provides biosynthetic precursors that are essential to rapidly dividing cells.…”

Heat shock response and autophagy—cooperation and control

“…75,76 Glutamine is the most abundant free amino acid in the body and it is critical for the proper functioning of the immune cells that utilize it at high rates for antigen presentation and cytokines production. 77,78 In addition, macrophage-derived cytokine stimulates glutamine synthesis in muscle cells. 79 This loop of interaction between cytokines and glutamine represents cooperation and codependence between muscle and the immune system.…”

Quantifying Reductive Carboxylation Flux of Glutamine to Lipid in a Brown Adipocyte Cell Line

“…The pathway for glutamine utilization in rapidly dividing cell is generally described as "glutaminolysis" where glutamine enters the citric acid cycle (CAC) as ␣-ketoglutarate traversing the cycle to oxaloacetate and exits as pyruvate or aspartate (1,4). Pyruvate then could be converted to acetyl-CoA and citrate in the lipogenic pathway.…”

“…Glutamine is utilized at a high rate by rapidly growing cells, including almost all cultured cell lines, where it is required at super-physiological concentrations of 2-4 mM for optimal growth (1). Recently, we evaluated the role of glutamine as a substrate for lipogenesis in a transformed wild type (WT) 5 and IRS-1 knock-out brown adipose cell lines developed by Kahn and co-workers (2).…”