Ketohexokinase A (KHK-A)

Ketohexokinase A (KHK-A) is one of two major isoforms of ketohexokinase, an ATP-dependent enzyme that catalyzes the phosphorylation of D-fructose to fructose 1-phosphate, initiating dietary fructose metabolism. While KHK-C is highly efficient and predominantly expressed in the liver and kidney, KHK-A is ubiquitously expressed across tissues and has lower fructokinase activity. Recent findings show that KHK-A also functions as a nuclear protein kinase, phosphorylating other proteins (e.g., PRPS1, YWHAH), thus promoting nucleic acid synthesis and cell proliferation. This activity links KHK-A to metastatic signaling and tumor progression, making it relevant as a therapeutic target in cancer. The enzyme forms a homodimer with unique structural properties mediated by alternative splicing, and its substrate binding involves induced-fit conformational changes. Disease associations include metabolic pathologies (due to fructose processing) and cancer, where its non-metabolic roles have become a major focus of research.

Other names

Fructokinase AKHK-AKetohexokinase isoform A

Drug inhibition of KHK (fructokinase) blocks phosphorylation of fructose, thus reducing fructose catabolism and its downstream metabolic and signaling effects. Targeting protein kinase activity of KHK-A could block cancer cell proliferation