title: The crystal structure of human phosphoglucose isomerase at 1.6 A resolution: implications for catalytic mechanism, cytokine activity and haemolytic anaemia.
abstract: Phosphoglucose isomerase (PGI) is a multifunctional protein, which, inside the cell, functions as a housekeeping enzyme of glycolysis and gluconeogenesis and, outside the cell, exerts wholly unrelated cytokine properties. We have determined the structure of human PGI to a resolution of 1.6 A using X-ray crystallography. The structure is highly similar to other PGIs, especially the architecture of the active site. Fortuitous binding of a sulphate molecule from the crystallisation solution has facilitated an accurate description of the substrate phosphate-binding site. Comparison with both native and inhibitor-bound rabbit PGI structures shows that two loops move closer to the active site upon binding inhibitor. Interestingly, the human structure most closely resembles the inhibitor-bound structure, suggesting that binding of the phosphate moiety of the substrate may trigger this conformational change. We suggest a new mechanism for catalysis that uses Glu357 as the base catalyst for the isomerase reaction rather than His388 as proposed previously. The human PGI structure has also provided a detailed framework with which to map mutations associated with non-spherocytic haemolytic anaemia.
authors.affiliation: School of Medical Sciences, University of Bristol, Bristol BS8 1TD, UK.
authors.forename: J
authors.initials: J
authors.lastname: Read
authors.forename: J
authors.initials: J
authors.lastname: Pearce
authors.forename: X
authors.initials: X
authors.lastname: Li
authors.forename: H
authors.initials: H
authors.lastname: Muirhead
authors.forename: J
authors.initials: J
authors.lastname: Chirgwin
authors.forename: C
authors.initials: C
authors.lastname: Davies
mesh_terms: D000595:Amino Acid Sequence; D000743:Anemia, Hemolytic / Q000201:enzymology* / Q000235:genetics; D000818:Animals; D001665:Binding Sites; D002384:Catalysis; D003460:Crystallization; D018360:Crystallography, X-Ray; D016207:Cytokines / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D005956:Glucose-6-Phosphate Isomerase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D007536:Isomerism; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009068:Movement / Q000187:drug effects; D020125:Mutation, Missense / Q000235:genetics; D010710:Phosphates / Q000378:metabolism; D017433:Protein Structure, Secondary / Q000187:drug effects; D011817:Rabbits; D013329:Structure-Activity Relationship; D013431:Sulfates / Q000378:metabolism
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; D008024:Ligands; D010710:Phosphates; D013431:Sulfates; D018698:Glutamic Acid; D005956:Glucose-6-Phosphate Isomerase