Download Mini symposium The role of carbohydrates in reproduction Introduction

Human Reproduction Update 1999, Vol. 5, No.4 pp. 277–279
E European Society of Human Reproduction and Embryology
Mini symposium
The role of carbohydrates in reproduction
Editor: Richard Ivell
Institute for Hormone and Fertility Research, University of Hamburg, Grandweg 64, D-22529 Hamburg, Germany
Introduction
It is not only in popular songs and love poetry that ‘sugar,
sugar’ is associated with procreation. In this special minisymposium six international research groups have summarized
the role of sugars and carbohydrates in a diverse range of
molecules and tissues of the reproductive system. All are
involved in some way with the co-ordination and functioning
of the complex interactions which are essential for successful
fertility. Carbohydrates in the reproductive system have been
neglected for a long time, mostly because they have been
difficult to describe at the molecular level. There are two
reasons for this difficulty. Firstly, they can be extremely
variable even when attached to the same substrate molecule.
Secondly, we have not until recently had adequate and
sufficiently sensitive methods to estimate the molecular
structures involved in any particular carbohydrate moiety. With
improvement in purification and separation technologies, and
especially in the use of nuclear magnetic resonance and mass
spectroscopy techniques, scientists are now beginning to
unravel the intricacies and structural flexibility of what the
glycosidic bond can achieve.
Proteins and nucleic acids are made up of relatively simple
linear strings of the component units (amino acids or
nucleotides), which themselves can only be linked in a single
way with no stereotopic variations. This means that
determination of at least the primary structure can be
determined from the sequential removal of one building block
after another. And at least in the case of nucleic acids, a lot of
information about the secondary structure can then be
predicted from this primary sequence. In the case of
carbohydrates this is quite different. There are a relatively large
number of simple monosaccharides, e.g. fructose or fucose,
which can be linked together. These links can occur in more
than one way, so that for carbohydrates we have both branching
of chains, and stereoisomerism at the glycosidic bonds. Then,
nucleic acids and proteins are constructed following very
precise linear templates in specialized molecular machines (e.g.
ribosomes, transcriptional complexes), such that variation for
any gene product is limited to minor heterogeneities only. For
carbohydrates, the blueprints are determined more by the
sequential functioning of different enzymes, each of only
limited specificity, and in a less organized fashion. The result is
much more heterogeneity of the resulting carbohydrate moiety,
even though the initial substrate for glycosylation, for example
the protein backbone of a particular glycoprotein, is the same.
Nevertheless, carbohydrates can have several very specific
functions depending on their structures, locations and
dimensions. Because the sugar residues can co-ordinate large
amounts of water, they effectively shift the pI of any protein to
which they are attached. Good examples are the glycoproteohormones (Willey, 1999) or their receptors (Wheatley
and Hawtin, 1999), which denuded of their glycosylation have
a highly basic pI. This can have drastic consequences on any
interactions involving either a conformational change in the
protein, or an ionic interaction with another molecule.
Secondly, by co-ordinating large numbers of water molecules
the carbohydrate moiety can become quite bulky, though of
low relative density. Many extracellular molecules, whether
cell surface proteins or secreted proteins are glycosylated.
Partly this is to create specific recognition surfaces, but partly
also to act as lubricants in a three-dimensional extracellular
environment where shear forces at the molecular level could
cause substantial damage to cell surfaces. A good example here
is the production of mucins in the gut and reproductive tract
(Lagow et al., 1999). An extension of this role is seen within the
cervix during cervical dilatation in the perinatal period. Here
the proportion of the small proteoglycans such as decorin,
biglycan or fibromodulin relative to collagen increases
markedly, these small glycosylated molecules apparently
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intercalating between the collagen fibres, thus allowing
cervical distension without extensive injury (Kokenyesi and
Woesner, 1991; Leppert, 1995). A further example is suggested
in this issue (Salustri et al., 1999), where one of the functions
for ovarian proteoglycans may be to increase the viscosity of
follicular fluid, as well as encourage desirable intercellular
interactions.
A major role of glycosylation, however, is in the creation of
specific molecular surfaces which allow equally specific
intermolecular recognition. Most commonly we consider the
interactions between carbohydrate moieties and plant lectins in
this category. While in general these are thought of as useful
tools for analytical histochemistry, they are in fact only one
example of a more widespread phenomenon with great
importance in biological systems. For the reproductive
biologist, one of the best examples is the interaction between
the spermatozoa and the zona pellucida of the oocyte
(Benoff, 1997; Töpfer-Petersen, 1999). There may be very
high specificity in some of these interactions. The recent
studies on the protein glycodelin are a good illustration of this.
This protein is made in both male and female reproductive
tracts and in both locations is glycosylated. However, the types
of glycosylation differ, giving rise to so-called glycodelin A
from the female tract and glycodelin S from the male tract, even
though the peptide backbone in each case is identical. Whereas
glycodelin S is either neutral or possibly protective toward
sperm functions, glycodelin A has been shown to have clear
inhibitory effects on sperm–oocyte interaction (Morris et al.,
1996) and has been implicated as contributing to the
contraceptive activity of levonorgestrel-releasing intrauterine
devices (Mandelin et al., 1997). A similar tissue-specific
differential glycosylation has also been described for the
principal sperm surface antigen CD52 (Schröter et al., 1999).
This small glycoprotein is made both by lymphocytes and by
the epididymal epithelium from where it is transferred to the
maturing sperm surface. However, the nature of the
glycosylation by the two cell types is quite different. This
interesting molecule also highlights another potential role for
glycosylation in the context of reproduction and fertility. CD52
is a product predominantly of the cauda epididymis and the vas
deferens and appears to coat the whole of the sperm surface
fairly indiscriminately to form the major sperm surface antigen.
The peptide backbone is very small, but this is mostly obscured
from extracellular interactions by the large degree of
glycosylation. This has led to the speculation that the CD52
coating antigen is first transferred to the sperm surface after the
majority of other surface maturation events involving
interactions in the epididymis have occurred, and thus could
serve to block subsequent sperm interactions. This blocking
effect of glycosylation is similar to that described for the
MUC1 gene product in the uterus at implantation
(Lagow et al., 1999). Only when this gene is down-regulated
can the blastocyst–endometrial interactions occur which lead to
implantation.
Finally, because of the different possibilities to form
branched chains in the core structure of a carbohydrate sidechain, and together with the different types of monosaccharides
that can be attached peripherally to this core, there is an
enormous potential for variability in the resulting tree-like
structure. In some cases this variability per se might be of
biological importance. It has been suggested that it might be
responsible in part for the so-called immunosuppressive
properties of the sperm glycocalyx. The variability of the
exposed surface functioning somewhat like the variable
surface of some invading parasites, although the underlying
mechanisms are certainly different. Quite how this would work
is not clear, and one should not forget at the same time that
injected spermatozoa are quite immunogenic, and that a large
number of monoclonal antibodies raised against the sperm
surface recognize defined glycosyl moieties, which may be
involved in specific sperm interactions (Koyama et al., 1991;
Kameda et al., 1992).
The last few years have seen a massive input by molecular
biology at the level of amino acid and nucleotide sequences,
which without doubt has led to vast leaps in our understanding
of the physiological processes behind reproduction. Until now
the role of carbohydrates here has been somewhat neglected.
The six articles presented in this special mini-symposium are
intended to illustrate the sort of advances we can expect when
similar technological methods are applied to investigate the
role of glycoslyation in reproductive function. However, in
contrast, to what we have learnt about other types of
biopolymer, the glycoconjugates are likely to prove often
confusing and conflicting in what they tell us about basic
priciples of glycobiology. In an excellent review on the
biological role of oligosaccharides (Varki, 1993), a very
important point is made: ‘Many different theories have been
advanced concerning the biological roles of the
oligosaccharide units of individual classes of glycoconjugates.
Analysis of the evidence indicates that while all of these
theories are correct, exceptions to each can also be found. The
biological roles of oligosaccharides appear to span the
spectrum from those that are trivial, to those that are crucial for
the development, growth, function or survival of an organism’.
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Introduction
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