Biomedical Engineering Reference
In-Depth Information
O
SNAC
O
DEBS (KS1
o
)
R
4
O
OH
HO
O
OH
R
3
31
O
SNAC
HO
O
O
HO
OH
DEBS (KS1
o
)
OH
R
4
O
R
4
O
OH
HO
R
3
O
R
4
O
OH
R
3
R
3
32
(R
3
= Me; R
4
= Me)
33
(R
3
= Me; R
4
= H)
34
(R
3
= H; R
4
= Me)
35
(R
3
= H; R
4
= H)
SCHEME 14.7
Precursor-directed biosynthesis of selected analogues of erythromycin.
included the incorporation of unnatural functional groups at the C15 position as seen
in compounds
(Scheme 14.6) [36,37].
Scheme 14.7 illustrates a situation in which precursor-directed biosynthesis
was not only used for the production of novel compounds, but also it yielded
an interesting result with respect to the tolerance of varied stereochemistry by the
various modules of the DEBS system. In this study, synthetic triketides in which the
portion analogous to the second ketide unit had undergone a dehydration, yielding
the 2,3-anhydro compound, were fed to the previously mentioned KS1
mutant. Just
as diketides mimicked the natural substrate and were predicted to load module 2, it
was anticipated that these compounds, extended by one ketide unit, would load
module 3. This was indeed the case when the methyl group extending from the C4
position was
syn
- to the C5 hydroxyl group. This situation mimicked the wild-type
stereochemistry and led, as expected, to the production of
29
and
30
. The diastereomer of this
triketide in which the C4 methyl and C5 hydroxyl are
anti
- to each other appeared to
prevent the recognition of this precursor by module 3 and was instead loaded onto
module 2, resulting in the production of a ring-expanded 16-membered ring macro-
lactone. These products were then further modified through attack of the C5 hydroxyl
on the C9 ketone, yielding the hemiketals
32
-
35
[38,39].
Rather than inactivate the loading didomain and KS1, some researchers have
chosen to effect unnatural priming of DEBS through the creation of hybrid PKS
systems. In Section 14.4.1.3, the broad substrate specificity of the avermectin
biosynthetic systemwas discussed. This promiscuity has been exploited in macrolide
production by grafting the loading didomain from the avermectin system in the place
31
Search WWH ::
Custom Search