Hepatic fructokinase

Hepatic fructokinase, also known as ketohexokinase, is an enzyme that plays a crucial role in the metabolism of fructose in the liver. It catalyzes the phosphorylation of fructose to fructose-1-phosphate, which is the first step in the fructolysis pathway. This enzyme is encoded by the KHK gene in humans.

Structure

Structure of hepatic fructokinase

Hepatic fructokinase is a protein that belongs to the hexokinase family. It is distinct from other hexokinases due to its specificity for fructose. The enzyme is composed of two isoforms, KHK-A and KHK-C, which are produced by alternative splicing of the KHK gene. The KHK-C isoform is predominantly expressed in the liver, kidney, and intestine, while KHK-A is found in a wider range of tissues.

Function

Structure of beta-D-fructofuranose, the substrate for hepatic fructokinase

Hepatic fructokinase catalyzes the conversion of beta-D-fructofuranose to fructose-1-phosphate by transferring a phosphate group from ATP to the fructose molecule. This reaction is the first step in the metabolism of dietary fructose, which is absorbed from the intestine and transported to the liver. The production of fructose-1-phosphate is a key regulatory step in fructose metabolism, as it allows for the subsequent cleavage by aldolase B into dihydroxyacetone phosphate and glyceraldehyde, which can enter glycolysis or gluconeogenesis.

Clinical Significance

Deficiencies in hepatic fructokinase activity can lead to metabolic disorders. One such condition is essential fructosuria, a benign genetic disorder caused by mutations in the KHK gene, resulting in the inability to properly metabolize fructose. Individuals with this condition excrete excess fructose in their urine, but typically do not experience serious health issues.

Pathway

Structure of beta-D-fructose-1-phosphate, the product of the reaction catalyzed by hepatic fructokinase

The fructolysis pathway begins with the phosphorylation of fructose by hepatic fructokinase to form fructose-1-phosphate. This compound is then cleaved by aldolase B into dihydroxyacetone phosphate and glyceraldehyde. These intermediates can be further metabolized to produce energy or serve as substrates for gluconeogenesis. The pathway is distinct from glycolysis, which primarily metabolizes glucose.

Regulation

Hepatic fructokinase activity is regulated by the availability of its substrate, fructose, and the energy status of the cell. Unlike other hexokinases, it is not inhibited by its product, fructose-1-phosphate, allowing for rapid metabolism of fructose when it is present in the diet.

Related Pages

• Fructose metabolism
• Hexokinase
• Essential fructosuria
• Aldolase B