Chemistry Reference
In-Depth Information
known as the mycolactones (Fig. 7.1b) (4). These polyketide toxins are respon-
sible largely for the necrotic lesions that are characteristic of this debilitating
condition. As such, the disruption of mycolactone biosynthesis may lead to an
effective chemotherapy for Buruli ulcer. Recent findings also suggest that the
virulence of another mycobacterial species,
Mycobacterium tuberculosis
, could
be partially dependent on polyketide biosynthesis. The cell surface sulfolipid-1
(SL-1) is among several virulence-associated molecules produced by
M. tuber-
culosis
. SL-1 consists of a sulfated disaccharide core (trehalose-2-sulfate) that
displays four lipidic substituents; all but one substituent seems to be polyketide-
derived (Fig. 7.1b) (5). Finally, the toxic agent in rice seedling blight, which is a
highly destructive fungal disease that inflicts severe agricultural losses worldwide,
has been identified recently as the polyketide metabolite, rhizoxin (Fig. 7.1b) (6).
Interestingly, rhizoxin is not produced directly by the fungus (
Rhizopus
), but
rather by the endosymbiotic bacteria
Burkholderia
that thrives within the fungus.
Together, these three examples suggest that inhibition of polyketide biosynthe-
sis may lead to effective chemotherapy for controlling certain human and plant
bacterial diseases.
7.1 PROTOTYPICAL POLYKETIDE BIOSYNTHESIS
The biosynthesis of many important polyketide compounds occurs via a stepwise,
assembly-line type mechanism that is catalyzed by type I modular polyketide
synthases (PKSs). These modular PKSs are composed of several large, multi-
functional enzymes that are responsible for catalyzing the initiation, elongation,
and processing steps that ultimately give rise to the characteristic macrolactone
scaffold (Fig. 7.2) (7 - 11). Structural studies have been critical in developing a
sophisticated understanding of the overall architecture and mechanism of type I
PKSs and their homologs in recent years (12 - 18). A review from the perspec-
tive of the 6-deoxyerythronolide B synthase (a well-studied type I PKS) was
published recently by Khosla et al. (19).
It is well established that the sequential arrangement of modules within a PKS
system serves effectively as a biosynthetic program, which is responsible for
dictating the final size and structure of the polyketide core. Typically, initiation
of polyketide biosynthesis begins by the acyltransferase (AT) catalyzed linkage
of a coenzyme A (CoA) priming unit (e.g., methylmalonyl-CoA, malonyl-CoA,
propionyl-CoA) to the acyl carrier protein (ACP) of the loading module. Once
initiated, downstream elongation modules carry out repetitive extensions of the
starter unit. In most PKS systems, each elongation module contains at minimum
an AT domain, an ACP domain, and a ketosynthase (KS) domain (Fig. 7.2a).
The AT domain is responsible for loading the appropriate CoA extender unit
onto the ACP domain (i.e., malonyl-CoA, methylmalonyl-CoA, etc.). The KS
domain then, catalyzes a decarboxylative condensation of the extender unit with
the growing polyketide chain obtained from the preceding module to gener-
ate an ACP-bound
β
-ketoacyl product. In addition to the three core domains,
