Download the glycosylation of alpha-1-acid glycoprotein – structurally complex

5th International Colloquium on Animal Acute Phase Proteins – Dublin – March 2005
THE GLYCOSYLATION OF ALPHA-1-ACID GLYCOPROTEIN – STRUCTURALLY
COMPLEX, FUNCTIONALLY IMPORTANT?
Smith, K
Department of Bioscience, University of Strathclyde, Glasgow G1 1XW
Alpha-1-acid glycoprotein (AGP) is a human plasma protein that belongs to the group of positive acutephase proteins that are produced by the liver. It is also has the ability to bind and carry numerous basic
and neutral lipophilic drugs from endogenous (steroid hormones) and exogenous origin. During several
physiological and pathological conditions, the total concentration of AGP increases and has been shown
to be an early indicator of a change in condition, disruption to homeostasis or background illness since it
occurs before the production of antibodies by the immune system or before clinical symptoms are
apparent. AGP levels are also valuable for prognosis and monitoring of treatment and are particularly
useful as a marker for the detection of early stage disease, to judge the extent of progression of a malady
and to assess the effectiveness of treatments or changes related to attempts to improve management or
environment.
Often overlooked is the fact that AGP, like many APP, is glycosylated with oligosaccharide chains
attached to the protein sequence. Oligosaccharide chains are ordered structures composed of various
monosaccharides and charged molecules (sialic acids) in a specific sequences that are important
determinants of biological function mainly because they contribute significantly to the hydrodynamic
mass of individual glycoconjugates. The degree of AGP glycosylation is variable between species but
normally accounts for between 23.5% and 43.5% of the molecular weight (typically 42,000 to 50,000).
Interestingly, during the course of an acute phase reaction the glycosylation of AGP is capable of
becoming uniquely altered in the presence of specific individual diseases. For example our research to
date, has proved that it is possible to distinguish individual liver diseases on the basis of their AGP
glycosylation e.g. hepatitis C the oligosaccharide chains have the highest amount of fucose in
comparison to the other liver diseases and also contain the rare monosaccharide N-acetylgalactosamine
(GalNAc). A further complexity of AGP glycosylation is the fact that, in normal serum, the glycoprotein
does not exist in a single form but as a heterogeneous population of glycosylated variants (glycoforms)
owing to differing occupancy of the five glycosylation sites. Heterogeneity arises through subtle
structural differences in monosaccharide sequence and linkages, degree of branching (bi-, tri-, tetraantennary) and extent of sialylation. The relative proportions of these “normal” AGP glycoforms have
been found to change and abnormal glycoforms are expressed during disease.
Our ongoing research interest is not only interested in the diagnostic potential of AGP glycosylation in
various disease states but also the functional significance of these modifications. In rheumatoid arthritis
(RA), our research has demonstrated hyperfucosylation, hypersialylation and increased chain branching
(from an increased content of biantennary chains in the early acute stages to a reduced content in the
chronic patient) in AGP. Moreover fucosylation is present as part of the tetrasaccharide antigen sialyl
Lewis X which is known to be the simplest structure recognised by the selectin family of cell adhesion
molecules thus suggesting a role for rheumatoid AGP in the restriction of leukocyte extravasation to a
centre of inflammatory activity. Conversely, the increased fucosylation of AGP from the plasma of
burns' patients has been directly correlated with the atypical collagen deposition associated with
hypertrophic scarring.
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