Department of Chemistry
Date of this Version
2014
Citation
Angew Chem Int Ed Engl. 2014 July 14; 53(29): 7524–7530.
Abstract
HSAF (1) was isolated from the biocontrol agent Lysobacter enzymogenes (Figure 1).[1-4]
This bacterial metabolite belongs to polycyclic tetramate macrolactams (PTM) that are
emerging as a new class of natural products with distinct structural features. [5, 6] HSAF
exhibits a potent antifungal activity and shows a novel mode of action.[1-4] The HSAF
biosynthetic gene cluster contains only a single-module hybrid polyketide synthasenonribosomal
peptide synthetase (PKS-NRPS), although the PTM scaffold is apparently
derived from two separate hexaketide chains and an ornithine residue.[1-4] This suggests that
the same PKS module would act not only iteratively, but also separately, in order to link the
two hexaketide chains with the NRPS-activated ornithine to form the characteristic PTM
scaffold. Recently, the Gulder group reported heterologous expression of the ikarugamycin
(4) biosynthetic gene cluster in E. coli,[7] and the Zhang group reported the enzymatic
mechanism for formation of the inner 5-memebered ring and demonstrated the polyketide
origin of the ikarugamycin skeleton.[8] Ikarugamycin is a Streptomyces-derived PTM which
has a 5,6,5-tricyclic system (Figure 1). Both the Gulder and Zhang groups showed that a
three-gene cluster is sufficient for ikarugamycin biosynthesis. Despite the progress, this
iterative polyketide biosynthetic mechanism had not been demonstrated using purified PKS
and NRPS. In addition, HSAF has a 5,5,6-tricyclic system, and its gene cluster contains at
least six genes.[3] Finally, unlike most PTM compounds, HSAF is produced by a Gramnegative
bacterium, L. enzymogenes. Here, we report the heterologous production of HSAF
analogs in Gram-positive Streptomyces hosts, in which the native PKS have been deleted.
We also obtained evidence for the formation of the polyene tetramate intermediate in
Streptomyces when only the single-module hybrid PKS-NRPS gene was expressed. Finally,
we showed the in vitro production of the polyene tetramate using the individually purified
PKS and NRPS. The results provide direct evidence for this iterative polyketide biosynthetic
mechanism that is likely general for the PTM-type hybrid polyketide-peptides.
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