Biomedical Engineering Reference
In-Depth Information
13
HALF-LIFE EXTENSION THROUGH O-GLYCOSYLATION
F UAD F ARES
Department of Human Biology, Faculty of Natural Sciences, University of Haifa,
Mount Carmel, Haifa, Israel
13.1 Introduction
13.2 The role of O-linked oligosaccharide chains in glycoprotein
function
13.3 Designing long-acting agonists of glycoprotein hormones
13.4 Conclusions
References
glycosaminoglycan chains to an initially unglycosylated
“proteoglycan core protein.”
The other group, which called N-linked oligosaccharides,
contains an N-acetylglucosamine (GlcNac) residue at its
reducing terminal and is linked to an amide group of an
asparagine (Asn) residue of a polypeptide. There are three
major classes of N-linked saccharides resulting from this
core: high mannose oligosaccharides, complex oligosac-
charides, and hybrid oligosaccharides. High mannose con-
tains two N-acetylglucosamines with many mannose
residues. Complex oligosaccharides contain almost any
number of the other types of saccharides including more
than the original two N-acetylglucosamines. Hybrid-type
oligosaccharides possesses structural features characteristic
of both types. The addition of N-linked glycans starts in the
lumen of the endoplasmic reticulum (ER), with the transfer
of oligosaccharides to the asparagine residues in the
sequence Asn-X-Ser/Thr (NXS/T) in the nascent poly-
peptide chain where X could be any amino acid except
proline. The N-linked glycosylation process occurs in eukar-
yotes and widely in archaea but very rarely in bacteria. In
eukaryotes, most N-linked oligosaccharides begin with
addition of a 14-sugar precursor to the asparagine in the
polypeptide chain of the target protein. A complex set of
reactions attaches this branched chain to a carrier molecule
called dolichol, and then it is transferred to the appropriate
point on the polypeptide chain as it is translocated into the
ER lumen.
The structures of N- and O-linked oligosaccharides are
different where different sugar residues are found in each
type. O-linked oligosaccharides are generally short and
containing one to four sugar residues. In contrast, N-linked
oligosaccharides usually have several branches
13.1
INTRODUCTION
Recombinant DNA technology has been used to develop
long-acting therapeutic proteins. One strategy is to add
O-linked or N-linked oligosaccharide chains to the backbone
of the protein.
The interest in carbohydrate (COH) chains of glycopro-
teins has grown because of accumulating data concerning
the importance of these chains in a wide array of biological
processes. The COH chains of glycoprotein hormones can
be classified into two groups: one contains an N-acetyl-
galactosamine (GalNac) residue that linked to the hydroxyl
group of either a serine (Ser) or a threonine (Thr) residue of a
polypeptide and is called O-linked oligosaccharides. The
recognition signal of O-linked oligosaccharides is unknown.
O-linked glycosylation occurs at a later stage during protein
processing, probably in the Golgi apparatus. This is the
addition of N-acetyl-galactosamine to serine or threonine
residues by the enzyme UDP-N-acetyl- D -galactosamine:
polypeptide N-acetylgalactosaminyltransferase followed
by other COHs (such as galactose and sialic acid). This
process is important for certain types of proteins such
as
each
proteoglycans, which
involves
the
addition
of
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