Fructose bisphosphatase

Fructose bisphosphatase (FBPase) is an enzyme that plays a critical role in the process of gluconeogenesis, the metabolic pathway that results in the generation of glucose from certain non-carbohydrate carbon substrates. It catalyzes the hydrolysis of fructose 1,6-bisphosphate to fructose 6-phosphate and inorganic phosphate, which is a key step in the regulation of glucose levels in the blood.

Function

FBPase is predominantly found in the liver, where it facilitates the last step but one in gluconeogenesis. By converting fructose 1,6-bisphosphate into fructose 6-phosphate, it helps in maintaining glucose homeostasis, especially during fasting or in conditions like diabetes mellitus. This enzyme is allosterically inhibited by AMP and fructose 2,6-bisphosphate, and activated by citrate, thus integrating signals from the energy status of the cell and the availability of substrates for gluconeogenesis.

Structure

The enzyme exists in two isoforms in mammals: FBPase-1, which is found in the liver and kidneys, and FBPase-2, which is located in muscle tissues. Each isoform has a distinct role and regulation mechanism, reflecting the different metabolic needs of these tissues. The structure of FBPase includes a homotetramer in most species, with each subunit consisting of a domain that binds the substrate and a domain responsible for the allosteric regulation of the enzyme.

Clinical Significance

Mutations in the gene encoding FBPase can lead to Fructose bisphosphatase deficiency, a rare inherited metabolic disorder characterized by impaired gluconeogenesis. This condition can result in hypoglycemia, lactic acidosis, and an increased risk of ketosis. Early diagnosis and management are crucial for preventing severe metabolic crises.

Regulation

The activity of FBPase is tightly regulated by a balance between allosteric effectors and hormonal signals. Insulin, for example, indirectly inhibits FBPase by increasing the levels of fructose 2,6-bisphosphate, an allosteric inhibitor of the enzyme, during the fed state. In contrast, glucagon decreases the concentration of fructose 2,6-bisphosphate during fasting, thus activating FBPase and promoting gluconeogenesis.

Research Directions

Current research on FBPase is focused on understanding its role in metabolic diseases such as type 2 diabetes and obesity. Inhibitors of FBPase are being explored as potential therapeutic agents for controlling excessive glucose production in these conditions. Additionally, the enzyme's structure and function are being studied to design more effective drugs with fewer side effects.