The Crystal Structure of Human Phosphoglucose Isomerase at 1.6 angstrom resolution: Implications for catalytic mechanism, cytokine activity and haemolytic anaemia

Phosphoglucose isomerase (PGI) is a multifunctional protein, which, inside the cell, functions as a housekeeping enzyme of glycolysis and gluconeogene sis and, outside the cell, exerts wholly unrelated cytokine properties. We have determined the structure of human PGI to a resolution of 1.6 Angstrom using X-ray crystallography. The structure is highly similar to other PGIs, especially the architecture of the active site. Fortuitous binding of a su lphate molecule from the crystallisation solution has facilitated an accura te description of the substrate phosphate-binding site. Comparison with bot h native and inhibitor-bound rabbit PCI structures shows that two loops mov e closer to the active site upon binding inhibitor. Interestingly, the huma n structure most closely resembles the inhibitor-bound structure, suggestin g that binding of the phosphate moiety of the substrate may trigger this co nformational change. We suggest a new mechanism for catalysis that uses Glu 357 as the base catalyst for the isomerase reaction rather than His388 as p roposed previously. The human PGI structure has also provided a detailed fr amework with which to map mutations associated with non-spherocytic haemoly tic anaemia. (C) 2001 Academic Press.