KHKs

Ketohexokinases, abbreviated as KHKs, are a family of enzymes that catalyze the ATP-dependent phosphorylation of fructose to fructose-1-phosphate, the first step in fructose metabolism (fructolysis). In humans and other mammals, two major isoforms are produced by alternative splicing of the KHK gene: KHK-C and KHK-A. KHK-C is predominantly expressed in liver and, to a lesser extent, the intestine and has high catalytic efficiency for fructose. KHK-A is more widely distributed across tissues and exhibits lower affinity for fructose.

Biochemical role and tissue distribution: The product fructose-1-phosphate enters glycolysis through aldolase B–mediated cleavage, linking fructose to energy production. Because KHK activity can rapidly consume ATP, high fructose intake can lead to transient ATP depletion and, in some settings, increased uric acid production via purine metabolism. The two isoforms vary in kinetic properties and regulatory regulation, contributing to tissue-specific fructose handling.

Genetics and regulation: In humans, the KHK gene generates two main isoforms, KHK-C and KHK-A, through alternative splicing. Expression of these isoforms is influenced by tissue type, dietary fructose exposure, and hormonal factors. Species differences exist in isoform prevalence and regulation, affecting fructose metabolism across organisms.

Clinical significance and research directions: Genetic deficiency of ketohexokinase causes essential fructosuria, a usually benign condition characterized by fructose excretion in urine. By contrast, pharmacological inhibition of KHK, particularly the KHK-C isoform, is being explored as a strategy to reduce hepatic lipogenesis and treat metabolic diseases such as obesity and nonalcoholic fatty liver disease. Ongoing research investigates isoform-specific roles, regulation of expression, and potential therapeutic applications.