FBP

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Introductions

Fructose 1,6-bisphosphatase (FBPase) is a key enzyme in gluconeogenesis. It is a potential drug target for the treatment of type II diabetes. The protein is also associated with a rare inherited metabolic disease in which some cancer cells lack the activity of FBPase, which promotes glycolysis and facilitates the Warburg effect. Therefore, there is interest in both inhibiting the enzyme (for the treatment of diabetes) and restoring its activity (for related cancers). The mammalian enzyme is tetrameric, competitively inhibited by fructose 2,6-diphosphate and negatively allosterically regulated by AMP. This allosteric regulation requires information transfer between the AMP binding site and the active site of the enzyme.

Structure

The fold of fructose-1,6-bisphosphatase from pigs was noted to be identical to that of inositol-1-phosphatase (IMPase). Inositol polyphosphate 1-phosphatase (IPPase), IMPase and FBPase share a sequence motif (Asp-Pro-Ile/Leu-Asp-Gly/Ser-Thr/Ser) which has been shown to bind metal ions and participate in catalysis. This motif is also found in the distantly-related fungal, bacterial and yeast IMPase homologues. It has been suggested that these proteins define an ancient structurally conserved family involved in diverse metabolic pathways, including inositol signalling, gluconeogenesis, sulphate assimilation and possibly quinone metabolism.

FBPase and Diabetes

FBPase inhibition has been suggested as a potential therapy for type II diabetes. In this disease, gluconeogenesis is an important factor contributing to glucose overload. Reducing this excess would alleviate the pathology associated with high glucose concentrations in blood and tissues.FBPase is an attractive target because its inhibition would only affect gluconeogenesis and not glycolysis. In addition, the presence of natural metabolic regulation of the enzyme suggests that it is possible to mimic the action of AMP by significantly reducing its activity. Thus, drug discovery efforts have focused on identifying molecules that recognize AMP binding sites and induce metamorphic inhibition of FBPase but do not interact with other adenosine nucleotide-binding enzymes. Some of these have been shown to have antidiabetic properties in cellular and animal models. Recently, the widely used type II diabetes drug metformin has been shown to act (at least in part) through inhibition of FBPase, most likely through AMP-binding site interactions.

FBPase and Tumors

The widespread downregulation of FBP1 promotes tumor progression Metabolic reprogramming has been defined as one of the hallmark features of tumors. FBP1 has been discovered and purified for more than 60 years, and many studies have reported that the gluconeogenic rate-limiting enzyme FBP1 plays an important role in the formation and progression of several tumors. FBP1 is also considered as a potential marker and prognostic marker for cancer. In addition, several studies have shown that low levels of FBP1 are associated with low cancer survival and high recurrence rates. In a few specific tumors, such as breast cancer brain metastases, FBP1 is upregulated, but the mechanism is not clear. Studies have shown that FBP2 expression is generally reduced in gliomas and that low expression of FBP2 is associated with low glioma survival. Ectopic expression of FBP2 activates the AMPK signaling pathway, inhibits the Akt-mTOR pathway and glucose metabolism, promotes apoptosis and inhibits cell proliferation.