Structures of alternatively spliced isoforms of human ketohexokinase.
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.
Trinh
Chi H
CH
Astbury Centre for Structural Molecular Biology, Institute of Molecular and Cellular Biology, University of Leeds, Leeds, England.
Asipu
Aruna
A
Bonthron
David T
DT
Phillips
Simon E V
SE
D000255:Adenosine Triphosphate / Q000378:metabolism; D000266:Adenylyl Imidodiphosphate / Q000378:metabolism; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D005631:Fructokinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D005632:Fructose / Q000378:metabolism; D006801:Humans; D008274:Magnesium / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010766:Phosphorylation; D017354:Point Mutation; D011487:Protein Conformation; D055550:Protein Stability; D017433:Protein Structure, Secondary; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
D011993:Recombinant Fusion Proteins; D000266:Adenylyl Imidodiphosphate; D005632:Fructose; D000255:Adenosine Triphosphate; D005631:Fructokinases; C021475:ketohexokinase; D008274:Magnesium