Iterative polyketide synthases (PKS) are large multifunctional enzymes that resemble eukaryotic fatty acid synthases, but can make highly functionalized secondary metabolites using complex and unresolved programming rules. During biosynthesis of the kinase inhibitor hypothemycin by Hypomyces subiculosus, a highly-reducing iterative PKS, Hpm8, cooperates with a non-reducing iterative PKS, Hpm3, to construct the advanced intermediate dehydrozearalenol (DHZ). The identity of putative intermediates in the formation of the highly reduced hexaketide portion of DHZ could be confirmed by incorporation of 13C-labeled N-acetylcysteamine (SNAC) thioesters using the purified enzymes. The results show that Hpm8 can accept SNAC thioesters of intermediates ready for transfer from its acyl carrier protein (ACP) domain to its ketosynthase (KS) domain and assemble them into DHZ in cooperation with Hpm3. Addition of certain structurally modified analogs of intermediates to Hpm8 and Hpm3 can produce DHZ derivatives.

The tRNA synthetase enzymes are promising targets for development of therapeutic agents against infections by parasitic protozoans (e.g. malaria), fungi and yeast, as well as bacteria resistant to current antibiotics.

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