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biochemistry in health and disease complete samenvatting
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Glycans and lipids are secondary gene productswhich means that they are not directly determined
by our DNA sequence -> but genes determinate the
expression of enzymes -> the variety composition
of enzymes determine the production of complex
glycans and lipids.
The enzymes can also be influenced by other
factors -> e.g. physiological situation of the cell, the presence of an infection and homeostatic
conditions
HC. GLYCOSYLATION: DIVERSITY AND FUNCTIONS
glucose is a component of a structural element in our body, these are glycans. The most common
complex molecule coming out of glucose is sucrose -> disaccharide consisting of 2 glucose units ->
glucose and fructose -> mainly used as energy in the form of sugar granules.
Terms:
- Glycoconjugates -> a molecule in which one or more glycan units are covalently linked to a
noncarbohydrate entity ->
• Aglycone: non-carbohydrate portion of a glycoconjugate or glycoside that is
glycosidically linked to the glycan through the reducing terminal sugar
• Glycone: carbohydrate component of a glycoconjugate
• Glycoforms: different molecular forms of a glycoprotein, resulting from variable
glycan structure and/or glycan attachment site occupancy
- Carbohydrates, glycans and sugars ->
• Carbohydrate: a generic term used interchangeably with sugar, saccharide, or
glycan. Includes monosaccharides, oligosaccharides and polysaccharides as well as
derivatives of these compounds
• Glycan: a generic term for any sugar or assembly of sugars, in free form or attached
to another molecule, used interchangeably with saccharide or carbohydrate.
• Sugar: a generic term often used to refer to any carbohydrate, but most frequently
to low molecular-weight carbohydrates that are sweet in taste. Table sugar, sucrose,
is a nonreducing disaccharide (Fruβ2-1αGlc). Oligosaccharides are sometimes called
sugar chains and individual monosaccharides in a sugar chain are sometimes referred
to as sugar residues.
- Glycosylation VS glycation ->
• Glycosylation: the enzyme-catalyzed covalent attachment of a carbohydrate to a
polypeptide, lipid, polynucleotide, carbohydrate or other organic compound,
generally catalyzed by glycosyltransferases, utilizing specific sugar nucleotide donor
substrates.
• Glycation: the nonenzymatic, chemical modification of proteins by addition of
carbohydrate, usually trough a Schiff-base reaction with the amino acid group of the
side chain of lysine and subsequent Amadori rearrangement to give stable conjugate.
Passively or actively.
many different monosaccharides involved in the biosynthesis of glycoconjugates. Glucose is obtained
from our diet as well as mannose, fructose and galactose and GalNAc. From glucose we can generate
all the different monosaccharide building blocks for all type of glycoconjugates.
phosphate is a source of energy needed for an enzyme to catalyze a reaction. So all the reactions in
the biosynthesis are needed so we can generate an activated sugar form that can be transformed to
a glycan with the help of an enzyme. All monosaccharides can be generated from glucose, but we can
also get other types of sugars from our diet.
,Once the glycans are made they start to form all kinds of molecules that
can be found in the cell membrane and in the circulatory pathways (ER,
Golgi etc.) Glycans are intermediate between cells and their environment
and often change in disease
Sugars are very good at retaining water -> obtain right environment at the
surface of the cells -> enough water is retained around the cells.
Glycosylation – biological functions:
- Cell-cell communication
➔ Immune system
➔ Development -> when cells grow and differentiate they change glycosylated surface ->
change in cell interaction -> cell adjust and grow in organized tissue
- Cell migration
- Infectious disease
- Tumor metastasis
➔ Genetic glycosylation defects
Functions and roles of glycans:
- Each tissue will have a different glycosylation profile -> important for cell identity
- Glycosylation is also involved in quality control
of glycoprotein biosynthesis -> as proteins are
being synthesized in the secondary pathway
they need to be folded properly -> quality
control of folding is glycosylation dependent.
When properly folded the glycol will be cleaved
and the protein can continue to do its job.
- Role in the protection of cells and proteins
through the glycocalyx
- Also used in the biopharmaceutical industry to
engineer proteins that have particular function
or enhanced properties -> used as a drug
- Some pathogens use receptors to target glycans on specific cells to be able to infect them
- The immune system has receptors that are able to recognize pathogens -> combat infections
Glycoconjugates:
Glycan molecule coupled to a carrier for example a protein or lipid ->
- Glycoproteins: glycans linked to protein (N/O-linked)
- Glycolipids: glycans linked to lipid
- Proteoglycans: glycosaminoglycans coupled to protein carrier (extracellular matrix)
- Glycogen: polysaccharide coupled to small carrier protein, glycogenin. only used for the
storage of energy.
No difference between glycoproteins and proteoglycans but proteoglycans have much more glycans
than protein -> capture a lot more water -> form the glycocalyx. Glycoproteins have much more
protein than glycan in its structure.
Examples of glycoconjugates:
- Glycoprotein hormones (LH/FSH/TSH)
- Lysosomal enzymes
- Erythropoietin (erythropoiesis)
- Skin molecules (tenascin, collagen)
- Immune system (antibodies, complement)
, - Brain proteins (MAG)
- Muscle proteins (dystroglycan)
- Blood group antigens (ABO)
Extracellular/membrane molecules
Protein N-linked and O-linked glycans:
Glycans are very flexible molecules. Can be attached to proteins in two ways -> N linked and O linked.
The difference is the type of amino acid to which they are attached. N-linked glycans are attached to
asparagine, O-linked are attached to serine or threonine (Ho2 group). They have different properties
in which makes them N linked or O linked.
Glycans are very flexible.
Monosaccharides:
Are carbohydrates that cannot be hydrolyzed into a simpler unit, formula is (CH2 O)n with n=3-9, (N-
linked has 8-12, O-linked 3-10 monosaccharides). They are composed of carbon, oxygen and
hydrogen. It has a potential carbonyl group:
- The end of the carbon chain (an
aldehyde group) -> aldose
- An inner carbon (a ketone group) ->
ketose
In the case of the glyceraldehyde, the middle
carbon, the hydroxyl group can be either be on
the right or on the left → glyceraldehyde contains an asymmetric
(chiral) carbon atom.
Common monosaccharides in human glycoproteins:
The diversity that can be achieved by combining the monosaccharides is considerably bigger then by
combining nucleotides or amino-acids ->
this is because we consider here not
only diverse monosaccharide units, but
also different chiral structures and how
the monosaccharides are built with each
other.
- D-Galactose (Gal) is a chiral form of
glucose.
- N- Acetyl-D-galactosamine (GalNAc) is a chiral form of GlcNAc.
- Mannose is also a chiral form of glucose as well as galactose
these two monosaccharides are often terminal and are
sialic acids.
Sialic acid: 9 carbon atoms
The special thing about sialic acids is that it has a carboxyl group and that at pH 7.4 it is ionized ->
sialic acid is negatively charged at physiological pH -> this means that all proteins that contain sialic
acids -> contributes to lowering the isoelectric point of that protein because of the negative charge.
, In oligosaccharides or polysaccharides: monosaccharides are present in the ring form
In the ring form carbon 1 interacts with carbon 5 to close the ring form, carbon 6
is left above carbon 5 -> most seen glucose form. The hydroxyl groups may be
resting underneath or above the plane -> depending on which way they are in
the molecule -> determines properties of the molecule and will have an
implication how the molecules interact with each other →
The aldehyde of the C1 is the reactive component: the aldehyde of C1 of one
monosaccharide can form a covalent bond with an OH group of C2, C3, C4 or C6
of another monosaccharide.
Difference between alpha and
beta bond.
This all shows that the diversity
that can be achieved with
monosaccharides is very big and
much bigger than in peptide formation through amino acids.
Glycan structures are very diverse:
Several different monosaccharides can be coupled to each other via different linkages at different
positions.
They can be coupled to proteins as N-glycans or O-
glycans and also to lipids.
Glycosylation:
The amount of glycosyltransferases that can put these structures together is limited. So even though
there are four carbons with which any monosaccharide can interact, if a certain glycosyltransferase
doesn’t exist in that cell a certain linkage won’t be formed -> so only linkages possible if the
glycosyltransferase is there that is available to do it.
Enzyme mediated
process that take
place in the ER and
Golgi in nucleus
cells.
Monosaccharides
are added to a
growing glycan on a protein or lipid as that they are being synthesized. If there is a right sequence in
the protein a glycan will be attached to it -> glycan will keep growing dependent on the enzymes in
the ER and Golgi (glycosyltransferase reaction)
This action depends on GDP and fucose (rood-driehoek)
The question is if this is genetically determined?
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