FBP Inhibitors

Chemical inhibitors of fructose 1,6-bisphosphate (FBP) interact with various enzymes in the glycolytic pathway to reduce the cellular levels of FBP. 3-Phosphoglycerate directly competes with FBP for binding to phosphoglycerate mutase 1 (PGAM1), which is responsible for the conversion of 3-phosphoglycerate to 2-phosphoglycerate. By inhibiting PGAM1, the glycolytic flux is curtailed, leading to a decrease in FBP levels. Oxamate acts as an inhibitor of lactate dehydrogenase (LDH), causing an accumulation of pyruvate and an increased conversion of pyruvate to oxaloacetate, which in turn reduces the production of phosphoenolpyruvate and decreases the levels of FBP due to diminished gluconeogenesis. Similarly, 2-Deoxy-D-glucose is phosphorylated within cells to a molecule that inhibits hexokinase, thus preventing the conversion of glucose to glucose-6-phosphate and ultimately decreasing FBP levels. Lonidamine and 3-Bromopyruvic acid both inhibit hexokinase, which also results in reduced formation of glucose-6-phosphate and subsequent FBP.

Iodoacetate targets glyceraldehyde 3-phosphate dehydrogenase (GAPDH), an enzyme that facilitates the conversion of glyceraldehyde 3-phosphate to 1,3-bisphosphoglycerate, and its inhibition leads to a reduction in FBP levels. Sodium fluoride inhibits enolase, which catalyzes the conversion of 2-phosphoglycerate to phosphoenolpyruvate, thereby decreasing the production of FBP. N-bromosuccinimide inactivates aldolase, an enzyme required for cleaving FBP into dihydroxyacetone phosphate and glyceraldehyde 3-phosphate; this action directly diminishes FBP levels. Arsenate disrupts the normal glycolytic process by forming unstable intermediates with enzymes like GAPDH, causing a decrease in the production of 1,3-bisphosphoglycerate and thus reducing FBP levels. Phloretin impairs the uptake of glucose by inhibiting glucose transporters, leading to a reduced substrate for glycolytic enzymes and a subsequent decrease in FBP levels. Lastly, quercetin inhibits phosphofructokinase, the enzyme that phosphorylates fructose 6-phosphate to FBP, resulting in lowered levels of FBP, while alpha-cyano-4-hydroxycinnamic acid inhibits monocarboxylate transporters (MCTs), reducing lactate efflux and consequently the production of FBP via gluconeogenesis.