Mannose-6 phosphate isomerase (MPI), alternately phosphomannose isomerase (PMI) () is an

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...

which facilitates the interconversion of

fructose 6-phosphate Fructose 6-phosphate (sometimes called the Neuberg ester) is a derivative of fructose, which has been phosphorylated at the 6-hydroxy group. It is one of several possible fructosephosphates. The β-D-form of this compound is very common in cells. ...

(F6P) and mannose-6-phosphate (M6P). Mannose-6-phosphate isomerase may also enable the synthesis of GDP-mannose in

eukaryotic Eukaryotes () are organisms whose Cell (biology), cells have a cell nucleus, nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the ...

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 Erythrose 4-phosphate is a phosphate of the simple sugar erythrose. It is an intermediate in the pentose phosphate pathway and the Calvin cycle. In addition, it serves as a precursor in the biosynthesis of the aromatic amino acids tyrosine, pheny ...

, mannitol 1-phosphate, and to a lesser extent, the alpha anomer of M6P.

Mechanism

MPI must convert an aldose (mannose) to a

ketose A ketose is a monosaccharide containing one ketone group per molecule. The simplest ketose is dihydroxyacetone, which has only three carbon atoms. It is the only ketose with no optical activity. All monosaccharide ketoses are reducing sugars, be ...

(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. 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 Glucose-6-phosphate isomerase (GPI), alternatively known as phosphoglucose isomerase/phosphoglucoisomerase (PGI) or phosphohexose isomerase (PHI), is an enzyme ( ) that in humans is encoded by the ''GPI'' gene on chromosome 19. This gene enc ...

(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 (Zn²⁺)

ligand In coordination chemistry, a ligand is an ion or molecule ( functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's elec ...

. 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 A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane prote ...

: disorders affecting MPI activity may affect cellular ability to quickly produce M6P from plentiful F6P, and therefore vesicle traffic to lysosomes and

endosomes Endosomes are a collection of intracellular sorting organelles in eukaryotic cells. They are parts of endocytic membrane transport pathway originating from the trans Golgi network. Molecules or ligands internalized from the plasma membrane ca ...

may be altered, potentially negatively impacting the cell.

Notes

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