fructokinase

Fructokinase, also known as ketohexokinase (KHK), is a cytosolic enzyme that phosphorylates fructose to fructose-1-phosphate (F1P) using ATP as the phosphate donor. In humans, it is the first enzyme in fructose metabolism and is expressed mainly in the liver, with activity also reported in the kidney and small intestine. The human KHK gene encodes two major isoforms through alternative splicing: KHK-C, which has high catalytic efficiency for fructose and is predominantly expressed in liver and intestine, and KHK-A, which is more widely expressed at lower activity.

The enzymatic reaction is Fructose + ATP → Fructose-1-phosphate + ADP, requiring Mg2+. After phosphorylation, F1P is cleaved by aldolase B into dihydroxyacetone phosphate and glyceraldehyde, feeding into glycolytic and lipogenic pathways. Because fructose phosphorylation bypasses the rate-limiting step of glycolysis catalyzed by phosphofructokinase-1, rapid fructose metabolism can occur, particularly under high sugar intake, contributing to hepatic lipogenesis and, indirectly, uric acid production through ATP depletion and purine metabolism.

Clinical and metabolic relevance includes a deficiency of fructokinase, which causes essential fructosuria. This condition is typically benign and asymptomatic, characterized by fructose appearing in the urine after ingestion. It is distinct from hereditary fructose intolerance, which results from aldolase B deficiency and leads to accumulation of fructose-1-phosphate with hypoglycemia and other metabolic disturbances when fructose is consumed.

Fructokinase activity is a focal point in studies of fructose metabolism, dietary sugar processing, and related metabolic disorders.