How recent knowledge on furano-specific enzymes has renewed interest for the synthesis of glycofuranosyl-containing conjugates - Carbohydrate Chemistry: Chemical and Biological Approaches - page 402

D -galactose ( D -Gal) in fungi, and N-acetyl- D -galactosamine ( D -GalNAc)
in bacteria. Owing to such a wide distribution, their related biology
was increasingly studied in conjunction with biological properties,
biosynthesis, and metabolism. 4 It clearly appears now that furanosyl-
containing conjugates as well as the mechanisms of the pathways
by which they are biosynthesized or degraded represent important
innovative sources of novel therapeutics.
This chapter will focus more especially on how studying the enzymatic
mechanisms involved in the biosynthesis of such furanosyl-containing
conjugates and glycans has inspired chemists to produce new molecular
tools, and to design novel inhibitors. The subsequent molecules found
particular applications for mechanistic elucidation of the related
enzymes, or to explore therapeutic alternatives. Three families of
enzymes will be discussed: the mutases, the glycofuranosyl transferases,
and the glycofuranosyl hydrolases. These headings result from recent
knowledge acquired on enzymes present in Mycobacterium tuberculosis
for the two first families and from degradation of plant biomass for the
last one. M. tuberculosis (millions of patients affected through over the
world) is extremely interesting since its cell wall contains an arabinoga-
lactan where both D -arabinose and D -galactose are present in a furanose
form ( D -Araf and D -Galf, respectively). 4-7 Many discoveries have been
made during the past 30 years on the enzymes involved in the building of
this complex cell wall. For instance, it was shown that the galactofuran,
resulting from the action of a mutase and two transferases, is essential to
ensure survival of this mycobacteria. Therefore, selective inhibition of
the related enzymes will disrupt the stability of the pathogenic agent. 2
Finally, D -Galf units are also found in other pathogenic microorganisms
such as Aspergillus, Leishmania, Trypanosoma, Klebsiella species, 1,2,7 thus
increasing the need for the design of new chemical methodologies and
innovative glycofuranoconjugates.
2 Furanosyl conjugates and mutases
The biosynthesis of glycoconjugates generally begins with the transfer
of a glycosyl donor to an acceptor. In the case of furanosides, the
donors are polyprenyl-phospho-Araf, nucleotide-sugars, or glycosides like
D -fructofuranoside (Fig. 1). The biosynthesis of fructans was reviewed
recently 8-11 and so will not be described herein.
While the activated polyprenyl b- D -arabinosyl phosphate derivative was
shown as the only intermediate involved in the D -arabinan biosynthesis,
the uridinediphospho (UDP)-a- D -Galf donor is naturally provided by a
specific enzyme, the UDP- D -galactopyranose mutase (UGM). This unique
enzyme requires bonding to the FAD cofactor to be active 12-16 and is able
to convert the thermodynamically more stable UDP-a- D -Galp into the
less favored furanosyl donor. 17,18 At thermodynamic equilibrium,
the UDP-a- D -Galp/UDP-a- D -Galf ratio is near 95 : 5. A decade after the
discovery of UGM, a plant UDP- L -Araf mutase (UAM) was isolated. 19 As for
UGM, UAM allows ring contraction to balance the fact that at
equilibrium, UDP-b- L -Arap is favored over UDP-b- L -Araf (90 : 10). Both