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trisaccharides.
109
In this contribution, acetylated saccharides were presynthesized
and coupled with trichloroacetimidate chemistry to the vancomycin aglycon at the
phenole of
4
Hpg. The general disadvantages of these chemical aproaches are the
lenghty protection/deprotection of glycopeptides and the relatively poor yields.
Besides chemical glycosylations, the evaluation of biotechnological methods has
also been performed. An early example is the heterologous expression of glycosyl-
transferases in E. coli followed by the in vitro conversion of aglycon substrates with
NDP-sugars to hybrid glycopeptides.
110
The authors of this contribution also used a
genetically modified glycopeptide producer strain with a glycosyltransferase gene,
which produced a glucosylated glycopeptide. Novel hybrid teicoplanins have been
synthesized by enzymatic conversion of aglycones with heterologously expressed
and purified glycosyltransferases.
111
Currently, the substrate specificity and the
availability of novel glycosyltransferases together with the availability of a broad
substrate range of NDP-sugars poses some restrictions for a broad applicability
of this approach. However, with the future developments in this field, such as the
availability of novel glycosyltransferase genes and carbohydrate biosynthesis genes
from genome mining, considerable progress has to be expected. The next stage
would then represent the cloning of glycosyltransferase genes and their carbohy-
drate biosynthesis genes into glycopeptide producing strains to generate novel
glycopeptides by combinatorial biosynthesis.
2.8.1.3 Variations and Modifications of Amino Acids
of the Aglycon Heptapeptide
From the aglycon portion of the naturally occurring glycopeptides (types I-IV), five
amino acids (
2
Hty/
2
Tyr,
4
Hpg,
5
Hpg,
6
Hty, and
7
Dpg) are highly conserved and
cross-linked in the aromatic side chains by one biaryl and two diarylethers. The
conformational rigidity that is established by these cross-links is mandatory
for tight D-Ala-D-Ala-binding. The hydrolytic cleavage of amide bonds of the
peptide backbone,
102
their acidic rearrangement to CDP-1,
112
or the lack of one
biayl/diarylether cross-link
63-65
immediately leads to a significant decrease in
D-Ala-D-Ala binding mostly cocomittant with the complete loss of antibiotic
activity.
Unfortunately, the D-Ala-D-Ala binding region of the aglycon core is hardly
accessible to chemical modification reactions. As a consequence, the options for
the introduction of synthetic variations in the peptide core region are limited. We
herein currently present established modifications of amino acids of the heptapep-
tide aglycon by chemical and biotechnological approaches.
Modification of AA1 The NMR- and x-ray data of glycopeptide-D-Ala-D-Ala-
complexes strongly underline a crucial role of a positive charge located at the
N-terminus of AA1, for D-Ala-D-Ala binding.
113,114
In this context, a variation
in N-methylation does not significantly alter the antibiotic activity.
115
The exchange
of side chains of AA1 can be achieved by Edman-degradation to the antibiotically
inactive hexapeptide aglycon,
100,116,117
which is then aminoacylated with other
amino
acids.
Early
aminoacylation
experiments
of
vancomycin-derived
or
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