Chemistry Reference
In-Depth Information
Enzymatic thioglycosylation: current
knowledge and challenges
Laure Guillotin, Pierre Lafite and Richard Daniellou*
DOI: 10.1039/9781849739986-00178
Carbohydrates play an important part in a vast array of biological processes and therefore
glycomimetics are currently becoming a powerful class of novel therapeutics.
1
Amongst
them, thioglycosides, in which a sulfur atom has replaced the glycosidic oxygen atom, are
tolerated by most biological systems. Their major advantages rely on the fact that they
adopt similar conformations than the corresponding O-glycosides and especially that they
prove to be less sensitive to acid/base or enzyme-mediated hydrolysis. Such compounds
have already demonstrated to be valuable tools as good chemical donors for synthetic
purposes,
2,3
as stable intermediates in X-ray crystallographic analysis of proteins
4
and, of
particular interest, as competitive inhibitors of a wide range of glycosidases (or glycoside
hydrolases, GH) involved in numerous diseases.
5
Besides the synthetic methodologies
developed throughout the years by organic chemists, the presence of natural S-
glycosylconjugates was recently assessed and led to the discovery of the enzymes
involved in such rare biocatalytic processes. In parallel, the increase of knowledge on the
mechanism and the structure of glycosidases has conducted to the development of
original catalyst with greatly improved synthetic properties for thioglycosidic linkages.
1
S
-glycosyltransferases
The glycosyltransferases (GTs) family catalyzes the formation of O-, N-,
C- and S-glycosidic bonds by the attachment of a sugar moiety, from
an activated-sugar donor, to a variety of acceptors (sugars, lipids,
proteins, ...).
6
They are classified according to the mechanism of the
catalytic reaction, which refers to the configuration of the glycosidic
linkage formed: retaining GTs and inverting GTs (Fig. 1). As for other
carbohydrate-active enzymes, a classification of GTs according to their
amino-acid sequence was proposed.
7
However, unlike their primary
sequence, the secondary and tertiary structures of GTs are well conserved
and thus these enzymes are also classified according to their overall fold.
GTs exhibit few canonic folds (mainly GT-A and GT-B), depending on the
orientation of the two b/a/b Rossmann fold domains.
6
Up to date, more
than 100 000 characterized or putative GTs have been identified, but only
139 individual GT protein structures has been solved.
w
Glycosylation of peptides and proteins has been identified since many
decades as one of the most important post-translational modifications.
8
These chemical modifications are of highly importance in protein
expression, correct folding, thermal and proteolytic stability. In Nature,
oligosaccharides are usually bound to peptides by the oxygen O
g
of Serine
or Threonine (O-glycans) or the nitrogen N
d
of Asparagine (N-glycans).
9,10
Many GTs involved in the biosynthesis of such linkages have been
Search WWH ::
Custom Search