Fructose 2,6-bisphosphate: the last milestone of the 20th century in metabolic control?

Abstract

ery Hers reported the discovery of fructose 2,6-bisphosphate, a novel, potent allosteric stimulator of liver 6-phosphofructo-1-kinase. The Brussels team were also at the forefront of other advances in hepatic glucose metabolism and many of their findings were published in the Biochemical Journal. Their demonstration that the concentration of fructose 2,6-bisphosphate was greatly increased in hepatocytes incubated in the presence of glucose, and its disappearance on incubation with glucagon, provided an elegant switching mechanism between the two opposing pathways of glycolysis and gluconeogenesis. The discovery was a landmark in the understanding of the control of liver carbohydrate metabolism and fructose 2,6-bisphosphate was subsequently shown to play a major role in controlling glycolysis in other tissues and in transformed cells. This article looks at the run-up to the discovery of fructose 2,6-bisphosphate and the years thereafter, with the background threat of transatlantic competition from the groups of Simon Pilkis and Kosaku Uyeda. We also review new developments on the bifunctional enzymes responsible for its synthesis and degradation (6-phosphofructo2-kinase/fructose-2,6-bisphosphatase) and the encoding genes since, in the cancer field, therapeutic targeting of fructose 2,6bisphosphate synthesis could be effective in halting tumour cell proliferation.