The crystal structure of human phosphoglucose isomerase at 1.6 Å resolution: Implications for catalytic mechanism, cytokine activity and haemolytic anaemia

Jon Read, Jake Pearce, Xiaochun Li, Hilary Muirhead, John Chirgwin, Christopher Davies

Research output: Contribution to journalArticle

79 Scopus citations

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 Å 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.

Original languageEnglish (US)
Pages (from-to)447-463
Number of pages17
JournalJournal of molecular biology
Volume309
Issue number2
DOIs
StatePublished - Jun 1 2001

Keywords

  • Aldose-ketose isomerases
  • Cytokine
  • Haemolytic anaemia
  • Neuroleukin
  • X-ray crystallography

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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