ketohexokinase

Ketohexokinase, also known as fructokinase, is a cytosolic enzyme that catalyzes the ATP-dependent phosphorylation of ketohexoses, principally fructose, to form fructose-1-phosphate. In humans, the enzyme is encoded by the KHK gene and exists in two major splice variants, KHK-A and KHK-C. KHK-C is the liver- and kidney-enriched isoform with high affinity for fructose and is chiefly responsible for rapid fructose metabolism, while KHK-A is more ubiquitously expressed at lower catalytic efficiency.

The catalytic reaction is fructose plus ATP yielding fructose-1-phosphate and ADP. Fructose-1-phosphate is then cleaved by aldolase B into glyceraldehyde and dihydroxyacetone phosphate, integrating the fructose-derived carbons into glycolytic and gluconeogenic pathways. The rate and tissue distribution of KHK activity influence how rapidly dietary fructose is metabolized and can affect downstream metabolic flux.

Localization and regulation: KHK operates in the cytosol, with tissue expression patterns reflecting isoform distribution. KHK-C expression in liver and kidney drives most hepatic fructose clearance, whereas KHK-A provides more widespread but lower-capacity activity. Diet and nutritional status can modulate overall fructose flux through this pathway, and the balance between KHK and downstream enzymes, notably aldolase B, helps determine metabolic outcomes.

Clinical significance: Deficiency of ketohexokinase leads to essential fructosuria, a benign condition characterized by the excretion of fructose in the urine due to impaired phosphorylation. More severe metabolic consequences arise from defects in downstream aldolase B (hereditary fructose intolerance), rather than KHK deficiency. Pharmacological inhibition of KHK-C has been explored in research as a potential strategy to reduce hepatic fructose metabolism and treat metabolic diseases, though such therapies remain investigational.

See also: fructose metabolism, essential fructosuria, hereditary fructose intolerance, aldolase B.