Role of fructose 2,6-bisphosphate in the control of glycolysis in mammalian tissues.

Glycolysis is an ubiquitous metabolic pathway. In addition to its catabolic role, glycolysis also serves an anabolic function by providing C3 precursors for the synthesis of fatty acids, cholesterol and amino acids. It is therefore an amphibolic pathway. The difference in metabolic orientation is tissue-specific and depends on the hormonal and nutritional state. Therefore, it is not surprising that different and specific regulatory mechanisms exist to control glycolysis under these various conditions. Cancer cells are a special case in which glycolysis is abnormally high. Qualitative and quantitative approaches have been developed to elucidate the control mechanisms of glycolysis. On the one hand, so-called 'rate-limiting' steps in the pathway have been identified by qualitative analysis. Reactions displaced far from equilibrium, particularly when catalysed by an allosterically regulated enzyme, have been assumed to qualify for control [1]. One such reaction is catalysed by phosphofructokinase (PFK-1). The experimental evidence supporting the key role of PFK-1 stems from the changes in the concentration of PFK-1 effectors observed when glycolysis is stimulated, e.g. following anoxia [2,3]. However, this information remains qualitative and may lead to an oversimplified view. On the other hand, the quantitative analysis of control, developed by Kacser & Burns [4] and Heinrich & Rapoport [5], allows the distribution of control among all steps in a pathway to be calculated. Such an approach has been applied to glycolysis in erythrocytes [6] and yeast [7], and it indicates that control is mainly distributed between hexokinase and PFK1. The study of the mechanism of action of glucagon on liver gluconeogenesis led to the discovery of fructose 2,6-bisphosphate (Fru-2,6-P2) [8,9]. This sugar phosphate is a potent stimulator of PFK-1 [10-12] and is also an inhibitor of fructose 1,6-bisphosphatase (FBPase-l) [13,14]. Fru-2,6-P2 has been detected in all mammalian tissues studied so far, as well as in fungi and plants, but not in prokaryotes [15]. Earlier reviews have dealt with the effect of Fru-2,6-P2 on its two main targets, PFK-1 and FBPase-1, together with the regulation of its synthesis and breakdown in relation to the control of glycolysis/gluconeogenesis in liver [15-22]. Since Fru-2,6-P2 is present in all mammalian tissues, it is tempting to suppose that it plays the major role in the control of glycolysis. The purpose of this article is to specify the conditions under which Fru-2,6-P2 plays a role in the control of glycolysis, and to review recent studies dealing with Fru-2,6-P2 metabolism in mammalian tissues other than liver.