Ketohexokinase (or hepatic fructokinase) is an enzyme that catalyzes the phosphorylation of fructose to produce fructose-1-phosphate.
ATP + ADP + ATP + D-fructose → ADP + D-fructose-1-phosphate
Isoforms In humans, ketohexokinase is encoded by the KHK gene, which produces two isoforms, KHK-A and KHK-C, through alternative splicing.
KHK-C is primarily expressed in the liver, kidney, and intestine. It has a high affinity for fructose (low Km) and is responsible for the majority of fructose metabolism. KHK-A is ubiquitously expressed in many tissues at low levels. It has a significantly lower affinity for fructose (high Km) compared to the C isoform.
Role in fructose metabolism
Ketohexokinase catalyzes the first step of fructolysis by phosphorylating fructose to form fructose 1-phosphate. The resulting fructose 1-phosphate is subsequently cleaved by aldolase B, producing intermediates that enter central carbohydrate metabolism.
In humans, the KHK-C isoform is responsible for most fructose metabolism in the liver, kidney, and intestine. Unlike glucose metabolism, fructose metabolism through ketohexokinase bypasses phosphofructokinase, a major regulatory step in glycolysis, allowing fructose to enter downstream metabolic pathways through fructolysis.
KHK is not allosterically inhibited by ATP or by its immediate product, fructose 1-phosphate.
Essential fructosuria
Loss-of-function mutations in KHK cause essential fructosuria, a generally benign inherited condition. After consuming fructose, affected people can have increased circulating fructose and excrete a portion of the fructose in urine.
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