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

• Published in: Journal of molecular biology Vol. 342; no. 3; pp. 847 - 860
• Main Authors: Graham Solomons, J.T., Zimmerly, Ella M., Burns, Suzanne, Krishnamurthy, N., Swan, Michael K., Krings, Sandra, Muirhead, Hilary, Chirgwin, John, Davies, Christopher
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 17.09.2004
• Subjects: aldose-ketose isomerase; cytokine; enzyme mechanism; phosphoglucoseisomerase; X-ray crystallography; cytokine; E4P; G6P; F6P; βME; EST; X-ray crystallography; PAB; phosphoglucoseisomerase; PGI; rPGI; mPGI; MF; rms; AMF; PGI/PMI; enzyme mechanism; aldose-ketose isomerase
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1016/j.jmb.2004.07.085

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.