KHK-A

Ketohexokinase (KHK) initiates fructose metabolism by catalyzing ATP-dependent phosphorylation of fructose to fructose 1-phosphate^[1]. KHK-A is produced ubiquitously at low levels, while KHK-C is highly expressed in liver, kidney, and intestine and shows greater fructose-phosphorylation activity^[1]^[2]. Mechanistically, KHK-C drives hepatic fructolysis, lipogenic precursor accumulation, ER stress, steatosis, and fibrogenic responses in NAFLD/NASH models^[3]^[4]. In disease biology, KHK-A becomes prominent in hepatocellular carcinoma cells, where it functions as a protein kinase and phosphorylates PRPS1 to promote nucleotide synthesis^[5]. Compared with KHK-C, KHK-A has lower fructokinase efficiency but distinct protein-kinase activity, making isoform selection important for experimental design^[5]^[6]. For experimental applications, KHK inhibitors such as PF-06835919 and LY3522348 support studies of hepatic fructose metabolism, liver exposure, and dose-dependent inhibition of fructose metabolism^[7]^[8].

References:

[1]. Diggle CP, et al. Ketohexokinase: expression and localization of the principal fructose-metabolizing enzyme. J Histochem Cytochem. 2009 Aug;57(8):763-74. [Content Brief]

[2]. Gasper WC, et al. Michaelis-like complex of mouse ketohexokinase isoform C. Acta Crystallogr D Struct Biol. 2024 Jun 1;80(Pt 6):377-385. [Content Brief]

[3]. Shepherd EL, et al. Ketohexokinase inhibition improves NASH by reducing fructose-induced steatosis and fibrogenesis. JHEP Rep. 2020 Nov 20;3(2):100217. [Content Brief]

[4]. Park SH, et al. Fructose induced KHK-C can increase ER stress independent of its effect on lipogenesis to drive liver disease in diet-induced and genetic models of NAFLD. Metabolism. 2023 Aug;145:155591. [Content Brief]

[5]. Li X, et al. Fructokinase A acts as a protein kinase to promote nucleotide synthesis. Cell Cycle. 2016 Oct 17;15(20):2689-90. [Content Brief]

[6]. Bae SY, et al. Dual Substrate Binding stabilizes the Catalytic State in Ketohexokinase. Struct Dyn. 2025;12(5 Suppl):A6.

[7]. Weng Y, et al. Transporter-Enzyme Interplay in the Pharmacokinetics of PF-06835919, A First-in-class Ketohexokinase Inhibitor for Metabolic Disorders and Non-alcoholic Fatty Liver Disease. Drug Metab Dispos. 2022 Jul 2;50(9):DMD-AR-2022-000953. [Content Brief]

[8]. Fukuda T, et al. LY3522348, A New Ketohexokinase Inhibitor: A First-in-Human Study in Healthy Adults. Diabetes Ther. 2025 Jul;16(7):1399-1415. [Content Brief]

KHK-A Inhibitor (1)

KHK-A Related Products (1):

Cat. No.	Product Name	Effect	Purity

HY-180921

GS-1291269	Inhibitor
GS-1291269 is a potent and neutral ketohexokinase (KHK) inhibitor, with IC₅₀s of 0.38 and 2.1 nM against KHK-C and KHK-A, respectively. GS-1291269 demonstrates liver and kidney fructose-1-phosphate (F1P) reduction in a fructose challenge model in rats. GS-1291269 can be used for kidney disease and metabolic-dysfunction-associated steatotic liver disease (MASLD) research.

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