Chemistry Reference
In-Depth Information
biosynthesis is catalyzed by a thioesterase (TE) domain located at the carboxy
terminus of the final elongation module. The activity of this domain results in
the cleavage of the acyl chain from the adjacent ACP; typically, intramolecular
cyclization results in the formation and release of a macrolactone ring. Tailoring
enzymes, such as hydroxylases and glycosyl transferases, often serve to further
modify the polyketide to yield the final bioactive compound.
The modular organization of type I PKSs has made them particularly attractive
targets for rational bioengineering. Combinatorial biosynthetic efforts centered
on prototypical modular PKSs have been the topic of many recent outstand-
ing review articles (20 - 23). Currently, several strategies are being pursued that
attempt to leverage PKS systems for the generation of structurally diverse polyke-
tides. For example, it has been demonstrated that alterations of individual catalytic
domains (i.e., inactivation, substitution, addition, deletion) within a PKS module
can result in predicted structural alterations of the final PKS product. Like-
wise, the addition, deletion, or exchange of intact modules can also impart
structural variety into polyketide metabolites. Using these and other approaches,
hundreds of novel polyketide structures have been generated, which established
the tremendous potential of these applications. However, these successes seem
to be more the exception rather than the rule, as many efforts result in trace
levels, or they fail to provide the desired metabolite. This finding suggests
that much remains to be learned regarding the molecular intricacies of these
complex biosynthetic machines. This review provides new perspectives on impor-
tant mechanisms that contribute to structural diversity in modular PKSs. These
mechanisms include control of double-bond configuration and regiochemistry,
introduction of
β
-branching during polyketide chain assembly, and other pro-
cesses that contribute to introduction of unique chemical functionality into these
fascinating systems.
7.2 POLYKETIDE DOUBLE BONDS
7.2.1 Trans Double Bonds
The presence of unsaturated carbon - carbon bonds within most polyketide com-
pounds exemplifies the overall structural diversity that is a hallmark of this class
of important natural products. Typically, the installation of double bonds into
nascent polyketide chains relies on the two-step processing at the
β
-keto group
by the successive activity of KR and DH domains that are embedded within a
given PKS elongation module. After KS catalyzed chain elongation that extends
the growing chain by two carbon atoms, the KR domain, when present, directs
the NADPH-dependent reduction of the
β
-ketone to yield a 3-hydroxyacyl inter-
mediate. Subsequently, an embedded DH domain within the elongation module
catalyzes dehydration of the 3-hydroxyacyl intermediate, normally which results
in the incorporation of an
(E)-
trans
α
,
β
unsaturated bond into the growing polyke-
tide chain (Fig. 7.3a).
