Biomedical Engineering Reference
In-Depth Information
O
H
2
N
HO
HO
OH
O
O
16
R
O
O
N
O
F
OH
O
O
O
HO
17
OH
R
O
O
O
HO
15
Incorporation of alternative
sugars has also been
observed
H
2
N
18
SCHEME 14.4
Incorporation of various amino acids for the production of novel jadomycin
analogues.
This biosynthetic scheme presents a unique opportunity for precursor-directed
biosynthesis in that the substitution around the oxazolone ring is dependent on which
amino acid forms the imine. Neither this condensation nor the subsequent decarbox-
ylative cyclization is enzymatically catalyzed process, and thus the issue of enzymatic
promiscuity is not nearly as problematic as often seen in these systems. In this
approach, the introduction of diversity is so late in the biosynthesis of these
compounds that only a single enzyme, the glycosyltransferase JadL, need to act on
an unnatural substrate.
In a series of studies, researchers have illustrated that jadomycin biosynthesis is
very amenable to precursor-directed approaches. Jadomycin production was induced
in
S. venezuelae
cultures in which the sole nitrogen source was an amino acid other
than the wild-type L-isoleucine. Not only were several proteinogenic amino acids
successfully incorporated, giving rise to differentially substituted oxazolone rings,
but also many nonproteinogenic amino acids, both
a
- and
b
-, were successfully
incorporated. Scheme 14.4 illustrates this approach, with
17
and
18
being successful
examples of its application [22-25].
After the observation that the glycosyltransferase JadL was able to transfer L-
digitoxose to unnatural aglycones, the authors expanded this work and demonstrated
that it was possible to make small modifications to the NDP-sugar and still observe
successful coupling to the natural aglycone [26]. Several jadomycin analogues
produced through these efforts have been assayed against human breast cancer cell
lines and showed promising activity.
The work presented here is by no means an exhaustive presentation of the work
that has been done in the area of incorporation of simple precursors to give complex
natural product analogues. These studies do, however, provide a breadth of approaches
that have hopefully given the reader a better appreciation for the power of precursor-
directed techniques to produce, with minimal synthetic effort, novel compounds that
would be difficult to access through total synthetic or traditional semisynthetic efforts.
14.4.2. Intermediate Precursors
In the examples of the previous section, unnatural primer and extender units were
introduced into biosynthetic pathways for polyketides and nonribosomal peptides.
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