Mannose-6 phosphate isomerase (MPI), alternately phosphomannose isomerase (PMI) (EC:5.3.1.8) is an enzyme

Enzyme

Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

 which facilitates the interconversion of fructose 6-phosphate

Fructose 6-phosphate

Fructose 6-phosphate is fructose sugar phosphorylated on carbon 6 . The β-D-form of this compound is very common in cells. The vast majority of glucose and fructose entering a cell will become converted to this at some point...

(F6P) and mannose-6-phosphate

Mannose-6-phosphate

Mannose-6-phosphate is a molecule bound by lectin in the immune system. M6P is converted to fructose 6-phosphate by mannose phosphate isomerase....

(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

Glycolysis

Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...

 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 .

Mechanism

MPI must convert a ketose (mannose) to an aldose (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.

Structure

MPI is composed of 440 Amino Acid residues, with one active site and one zinc ion Ligand

Ligand

In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...

. 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 .

Biological Relevance

PMI has several contributions to necessary metabolic pathways. It enables cells to transform M6P into F6P, which can then be entered into Glycolysis. PMI also allows cells to convert F6P into M6P, which is a common glycolytic cellular identifier for cellular transport and cell membrane identification in prokaryotic and eukaryotic organisms .

Medical Relevance

PMI may be helpful in the development of new antifungal treatments, as lack of PMI activity in yeast cells can lead to cell lysis and the enzyme may be a target for inhibition. This may be due to the role of PMI in the formation cell walls and capsular polysaccharide biosynthesis. Additionally M6P is an important signaling molecule, especially for transport to lysosomes: disorders affecting MPI activity may affect cellular ability to quickly produce M6P from plentiful F6P, and therefore vesicle traffic to lysosomes and endosomes may be altered, potentially negatively impacting the cell.

External links

• GeneReviews/NCBI/NIH/UW entry on Congenital Disorders of Glycosylation Overview