Mannose-6-phosphate (M6P) is a molecule bound by
lectin
Lectins are carbohydrate-binding proteins that are highly specific for sugar groups that are part of other molecules, so cause agglutination of particular cells or precipitation of glycoconjugates and polysaccharides. Lectins have a role in r ...
in the
immune system
The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinter ...
. M6P is converted to
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. ...
by
mannose phosphate isomerase.
M6P is a key targeting signal for
acid hydrolase precursor proteins that are destined for transport to
lysosome
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 p ...
s. The M6P tag is added to such proteins in the ''cis''-
Golgi apparatus
The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic cells. Part of the endomembrane system in the cytoplasm, it packages proteins into membrane-bound vesicles insi ...
. Specifically, in a reaction involving
uridine diphosphate
Uridine diphosphate, abbreviated UDP, is a nucleotide diphosphate. It is an ester of pyrophosphoric acid with the nucleoside uridine. UDP consists of the pyrophosphate group, the pentose sugar ribose, and the nucleobase uracil.
UDP is an ...
(UDP) and
''N''-acetylglucosamine, the enzyme
N-acetylglucosamine-1-phosphate transferase catalyzes the
''N''-linked glycosylation of
asparagine
Asparagine (symbol Asn or N) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), an α-carboxylic acid group (which is in the depro ...
residues with M6P. Once appropriately marked with the M6P targeting signal, these proteins are moved to the ''trans''-Golgi network. There, the M6P
moiety is recognized and bound by
mannose 6-phosphate receptor
The mannose 6-phosphate receptors (MPRs) are transmembrane glycoproteins that target enzymes to lysosomes in vertebrates.
Mannose 6-phosphate receptors bind newly synthesized lysosomal hydrolases in the trans-Golgi network (TGN) and deliver the ...
(MPR) proteins at pH 6.5–6.7.
The M6P-tagged lysosomal enzymes are shipped to the late
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 can ...
via vesicular transport.
Enzyme replacement therapy
Enzyme replacement therapy (ERT) is a medical treatment which replaces an enzyme that is deficient or absent in the body. Usually, this is done by giving the patient an intravenous (IV) infusion of a solution containing the enzyme.
ERT is availab ...
(ERT) for several
lysosomal storage diseases
Lysosomal storage diseases (LSDs; ) are a group of over 70 rare inherited metabolic disorders that result from defects in lysosomal function. Lysosomes are sacs of enzymes within cells that digest large molecules and pass the fragments on to other ...
relies on this pathway to efficiently direct synthetic enzymes to the lysosome where each can metabolize its particular substrate.
The pH in the late endosome can reach 6.0, which causes dissociation of M6P from its receptor.
Upon release, the enzymes are ferried to their final destination in the lysosomes.
The MPRs are packed into vesicles that bud off the late endosome and return to the ''trans''-Golgi network.
In this way, the MPRs can be recycled.
See also
*
I-cell disease
Inclusion-cell (I-cell) disease, also referred to as mucolipidosis II (ML II), is part of the lysosomal storage disease family and results from a defective phosphotransferase (an enzyme of the Golgi apparatus). This enzyme transfers phosphate to m ...
*
Insulin-like growth factor 2 receptor
Insulin-like growth factor 2 receptor (IGF2R), also called the cation-independent mannose-6-phosphate receptor (CI-MPR) is a protein that in humans is encoded by the ''IGF2R'' gene. IGF2R is a multifunctional protein receptor that binds insuli ...
*
Mannose
Mannose is a sugar monomer of the aldohexose series of carbohydrates. It is a C-2 epimer of glucose. Mannose is important in human metabolism, especially in the glycosylation of certain proteins. Several congenital disorders of glycosylation ar ...
*
Mannose 1-phosphate
References
External links
*
Role of M6P in protein modification(video)
{{Fructose and galactose metabolic intermediates
Monosaccharide derivatives
Organophosphates