Mannose-6 phosphate isomerase (MPI), alternately phosphomannose isomerase (PMI) (EC 5.3.1.8) is an enzyme which facilitates the interconversion of fructose 6-phosphate(F6P) and mannose-6-phosphate(M6P). Mannose-6-Phosphate Isomerase may also enable the synthesis of GDP-mannose in eukaryotic organisms. M6P can be converted to F6P by Mannose-6-Phosphate Isomerase and subsequently utilized in several metabolic pathways including Glycolysis and capsular polysaccharide biosynthesis. PMI is monomeric and metallodependent on Zinc as a cofactor ligand. PMI is inhibited by erythrose 4-phosphate, mannitol 1-phosphate, and to a lesser extent, the alpha anomer of M6P.

MPI must convert an aldose (mannose) to a ketose (fructose), in addition to opening and closing the rings for these sugars. In humans a mechanism has been suggested which involves a hydrogen transfer between C1 and C2, mediated by Tyr278, and the movement of a proton from O1 and O2 mediated by the associated Zn2+ ion. The ring opening step may be catalyzed by His99 and Asp270, and isomerization is likely a cis-enediol mechanism. A detailed description of the mechanism of phosphomannose isomerase may be found in the 1968 Journal of Biological Chemistry paper written by Robert W. Gracy and Ernst A Noltmann titled "Studies on Phosphomannose Isomerase: A Mechanism for Catalysis and for the Role of Zinc in the Enzymatic and the Nonenzymatic Isomerization."

PMI shows a high degree of selectivity for the beta anomer of M6P, and the alpha anomer has no activity, and may in fact act as an inhibitor. Phosphoglucose Isomerase (PGI) has a very similar function to PMI, (as it catalyzes the interconversion of Glucose 6-Phosphate and F6P) however PGI can anomerize alpha and beta G6P, and may also catalyze the conversion of alpha M6P to beta M6P, while PMI may not anomerize M6P. It is likely the cis-enediol intermediate formed by PMI is the same intermediate formed by PGI.

MPI is composed of 440 Amino Acid residues, with one active site and one zinc ion Ligand. Amino acids GLN 111A, HIS 113A, GLU 138A, HIS 285A, and HOH 798A are involved with the zinc ligand bonding. Structure differs from phosphoglucose isomerase by a threonine residue (Thr291) which creates extra space in the active site of PMI to accommodate the different stereochemistry of M6P. This increased space created by the threonine allows the rotation of the C2-C3 bond, which enables the necessary cis-enediol intermediate to be formed. Because mannose and glucose are stereoisomers at C2, which is crucial to the mechanism for both enzymes, PMI must allow extra space in the active site to allow for rotation of mannose to form the cis-enediol intermediate, which is the same intermediate formed by Phosphoglucose Isomerase.

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