Generation of New Landomycins with Altered Saccharide Patterns through Over‐expression of the Glycosyltransferase Gene lanGT3 in the Biosynthetic Gene Cluster of Landomycin A in Streptomyces cyanogenus S‐136

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Abstract
Two novel landomycin compounds, landomycins I and J, were generated with a new mutant strain of Streptomyces cyanogenus in which the glycosyltransferase that is encoded by lanGT3 was over‐expressed. This mutant also produced the known landomycins A, B, and D. All these compounds consist of the same polyketide‐derived aglycon but differ in their sugar moieties, which are chains of different lengths. The major new metabolite, landomycin J, was found to consist of landomycinone with a tetrasaccharide chain attached. Combined with previous results of the production of landomycin E (which contains three sugars) by the LanGT3− mutant strain (obtained by targeted gene deletion of lanGT3), it was verified that LanGT3 is a D‐olivosyltransferase responsible for the transfer of the fourth sugar required for landomycin A biosynthesis. The experiments also showed that gene over‐expression is a powerful method for unbalancing biosynthetic pathways in order to generate new metabolites. The cytotoxicity of the new landomycins—compared to known ones—was assessed by using three different tumor cell lines, and their structure–activity relationship (SAR) with respect to the length of the deoxysugar side chain was deduced from the results.