The crystal structure of mouse phosphoglucose isomerase at 1.6 Å resolution and its complex with glucose 6-phosphate reveals the catalytic mechanism of sugar ring opening

J. T. Graham Solomons, Ella M. Zimmerly, Suzanne Burns, N. Krishnamurthy, Michael K. Swan, Sandra Krings, Hilary Muirhead, John Chirgwin, Christopher Davies

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

Phosphoglucose isomerase (PGI) is an enzyme of glycolysis that interconverts glucose 6-phosphate (G6P) and fructose 6-phosphate (F6P) but, outside the cell, is a multifunctional cytokine. High-resolution crystal structures of the enzyme from mouse have been determined in native form and in complex with the inhibitor erythrose 4-phosphate, and with the substrate glucose 6-phosphate. In the substrate-bound structure, the glucose sugar is observed in both straight-chain and ring forms. This structure supports a specific role for Lys518 in enzyme-catalyzed ring opening and we present a "push-pull" mechanism in which His388 breaks the O5-C1 bond by donating a proton to the ring oxygen atom and, simultaneously, Lys518 abstracts a proton from the C1 hydroxyl group. The reverse occurs in ring closure. The transition from ring form to straight-chain substrate is achieved through rotation of the C3-C4 bond, which brings the C1-C2 region into close proximity to Glu357, the base catalyst for the isomerization step. The structure with G6P also explains the specificity of PGI for glucose 6-phosphate over mannose 6-isomerase (M6P). To isomerize M6P to F6P requires a rotation of its C2-C3 bond but in PGI this is sterically blocked by Gln511.

Original languageEnglish (US)
Pages (from-to)847-860
Number of pages14
JournalJournal of molecular biology
Volume342
Issue number3
DOIs
StatePublished - Sep 17 2004

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Keywords

  • X-ray crystallography
  • aldose-ketose isomerase
  • cytokine
  • enzyme mechanism
  • phosphoglucoseisomerase

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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