4BC4

Crystal structure of human D-xylulokinase in complex with D-xylulose

Summary for 4BC4

• Entry DOI: 10.2210/pdb4bc4/pdb
• Related: 4B6T 4B6Y 4BC2 4BC3 4BC5
• Descriptor: XYLULOSE KINASE, D-XYLULOSE, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: transferase, glucuronate xylulokinase pathway
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 3
• Total formula weight: 178163.63

Authors

Bunker, R.D.,Loomes, K.M.,Baker, E.N. (deposition date: 2012-10-01, release date: 2012-11-28, Last modification date: 2024-10-23)

Primary citation

Bunker, R.D.,Bulloch, E.M.M.,Dickson, J.M.J.,Loomes, K.M.,Baker, E.N.
Structure and Function of Human Xylulokinase, an Enzyme with Important Roles in Carbohydrate Metabolism
J.Biol.Chem., 288:1643-, 2013

PubMed Abstract: D-Xylulokinase (XK; EC 2.7.1.17) catalyzes the ATP-dependent phosphorylation of d-xylulose (Xu) to produce xylulose 5-phosphate (Xu5P). In mammals, XK is the last enzyme in the glucuronate-xylulose pathway, active in the liver and kidneys, and is linked through its product Xu5P to the pentose-phosphate pathway. XK may play an important role in metabolic disease, given that Xu5P is a key regulator of glucose metabolism and lipogenesis. We have expressed the product of a putative human XK gene and identified it as the authentic human d-xylulokinase (hXK). NMR studies with a variety of sugars showed that hXK acts only on d-xylulose, and a coupled photometric assay established its key kinetic parameters as K(m)(Xu) = 24 ± 3 μm and k(cat) = 35 ± 5 s(-1). Crystal structures were determined for hXK, on its own and in complexes with Xu, ADP, and a fluorinated inhibitor. These reveal that hXK has a two-domain fold characteristic of the sugar kinase/hsp70/actin superfamily, with glycerol kinase as its closest relative. Xu binds to domain-I and ADP to domain-II, but in this open form of hXK they are 10 Å apart, implying that a large scale conformational change is required for catalysis. Xu binds in its linear keto-form, sandwiched between a Trp side chain and polar side chains that provide exquisite hydrogen bonding recognition. The hXK structure provides a basis for the design of specific inhibitors with which to probe its roles in sugar metabolism and metabolic disease.

PubMed: 23179721
DOI: 10.1074/JBC.M112.427997

Experimental method

X-RAY DIFFRACTION (1.79 Å)