Chemistry Reference
In-Depth Information
In addition to disorazole
5
, several other known examples of polyketide natu-
ral products exist that have
cis
double bonds installed by an embedded KR-DH
domain pair. The potent antitumor compound curacin A
3
contains many interest-
ing structural features. Among them is the presence of a
cis
double bond between
carbon atoms 3 and 4. Sequence alignment of the KR domain encoded by
curG
(encoding the module responsible for generation of the
cis
double bond) sug-
gests that it belongs to the “A” class of KR domains (35). Thus, this particular
KR is predicted to generate a L-3-hydroxyacyl intermediate that is subsequently
dehydrated to the
cis
double bond. Likewise, the KR domains that set up the
3
cis
double bonds found in the linear mixed NRPS-polyketide natural prod-
uct bacillaene
1
are predicted to produce L-3-hydroxyacyl intermediates (36).
Interestingly, two of the elongation modules that incorporate
cis
olefins are split
between two polypeptides (36). As in disorazole biosynthesis, it is possible that
these modular dissections contribute to the configuration of the unsaturated bond
that is introduced by these modules.
Finally, we consider the conjugated
cis
olefins that span carbon atoms 12-15
of the phoslactomycins
13
. Analysis of the KR sequences of elongation modules
1 and 2 could not clearly predict whether these reductive domains belonged to
the “A” or “B” class. Therefore, Alhamadsheh et al. (37) employed a compre-
hensive biochemical study to elucidate the mechanism of
cis
olefin formation by
the first elongation module. Two hypotheses were considered. First, the config-
uration of the double bond could develop directly from the combined activities
of the embedded KR-DH domain pair. Alternatively, the KR-DH domains might
establish a
trans
olefin that is isomerized subsequently to the observed
cis
con-
figuration. To distinguish between these two possibilities, Alhamadsheh et al.
(37) genetically inactivated both the loading module and elongation module of
Plm1 and conducted feeding experiments with diketide analogs containing both
cis
and
trans
olefins. Results from this work indicated clearly that only the
cis
olefin containing diketide is accepted as a substrate for elongation module
2, suggesting that the product of module 1 must contain the
cis
double bond.
Furthermore, this work demonstrated nicely that the phoslactomycin biosyn-
thetic pathway cannot process
trans
diketide intermediates into mature prod-
ucts, which rules out the possibility of an isomerization domain in downstream
modules.
7.2.3 Terminal Double Bonds
Termination of polyketide biosynthesis typically involves the TE mediated cleav-
age of the ACP-bound thioester, followed by cyclization to generate a macro-
lactone. Alternatively, the TE catalyzes the simple hydrolysis of the thioester to
generate a linear free acid product. Here, we consider two of the relatively few
known examples of polyketide natural products that are neither a macrocycle nor
a free acid, but instead terminate with a double bond.
Aside from containing a
cis
double bond noted above, the antitumor polyketide
compound curacin A
3
also features a terminal olefin. Previously reported feeding
