[HTML][HTML] Structures of alternatively spliced isoforms of human ketohexokinase

CH Trinh, A Asipu, DT Bonthron… - … Section D: Biological …, 2009 - scripts.iucr.org
CH Trinh, A Asipu, DT Bonthron, SEV Phillips
Acta Crystallographica Section D: Biological Crystallography, 2009scripts.iucr.org
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 …
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.
International Union of Crystallography