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Structures of alternatively spliced isoforms of human ketohexokinase

DOI: 10.1107/S0907444908041115 DOI Help
PMID: 19237742 PMID Help

Authors: Aruna Asipu (University of Leeds) , David Bonthron (University of Leeds) , Simon Phillips (Diamond Light Source) , Chi Trinh (University of Leeds)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acta Crystallographica Section D Biological Crystallography , VOL 65 (3) , PAGES 201–211

State: Published (Approved)
Published: March 2009

Open Access Open Access

Abstract: A molecular understanding of the unique aspects of dietary fructose metabolism may be the key to understanding and controlling the current epidemic of fructose-related obesity, diabetes and related adverse metabolic states in Western populations. Fructose catabolism is initiated by its phosphorylation to fructose 1-phosphate, which is performed by ketohexokinase (KHK). Here, the crystal structures of the two alternatively spliced isoforms of human ketohexokinase, hepatic KHK-C and the peripheral isoform KHK-A, and of the ternary complex of KHK-A with the substrate fructose and AMP-PNP are reported. The structure of the KHK-A ternary complex revealed an active site with both the substrate fructose and the ATP analogue in positions ready for phosphorylation following a reaction mechanism similar to that of the pfkB family of carbohydrate kinases. Hepatic KHK deficiency causes the benign disorder essential fructosuria. The effects of the disease-causing mutations (Gly40Arg and Ala43Thr) have been modelled in the context of the KHK structure.

Journal Keywords: Ketohexokinase; Alternatively Spliced Isoforms; Fructokinase; Fructosuria.

Subject Areas: Biology and Bio-materials

Technical Areas: