Ketohexokinase C (KHK-C)

Ketohexokinase C (KHK-C) is a highly specific carbohydrate kinase isoform of the ketohexokinase (fructokinase) enzyme, responsible for the initial and rate-limiting step of fructose metabolism: the phosphorylation of fructose to fructose 1-phosphate, using ATP as a cofactor[1][4][7]. KHK-C is predominantly expressed in liver, kidney, and intestine[4][9]. It has a high affinity for fructose and is essential for the catabolism of dietary fructose, distinguishing it from the low-affinity isoform KHK-A, which is poorly active at physiological fructose concentrations and has distinct biological roles[2][5]. KHK-C-driven fructolysis bypasses key regulatory steps of glycolysis, leading to rapid substrate flow into lipogenesis and the generation of uric acid, implicating it in the pathogenesis of obesity, metabolic syndrome, diabetes, and fatty liver disease[4]. Loss or alteration of KHK-C expression, such as the isoform switch to KHK-A in hepatocellular carcinoma, is associated with reduced fructose metabolism and cancer progression[2][3][5]. Due to its pivotal metabolic role, KHK-C is considered a promising therapeutic target for metabolic diseases, with selective small-molecule inhibitors (e.g., PF-06835919, LY-3522348) in clinical development intended to attenuate fructose-driven pathology[7]. Therapeutic inhibition of KHK-C is associated with challenges, including the need for isoform-specific targeting, potential effects on glucose handling, and uncertain long-term metabolic consequences[6]. KHK-C activity can be monitored indirectly by measuring fructose-1-phosphate levels or changes in KHK expression in tissues, serving as potential biomarkers of efficacy or disease involvement[3][2].

Other names

Fructokinase CKHK isoform C

Competitive inhibition of fructose binding site (for small-molecule inhibitors); Inhibition of fructose phosphorylation, reducing downstream lipogenesis/metabolic effects