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.
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.
Zhu
Lili
L
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 725 Rose Street, Lexington, KY 40536-0082, USA.
Luzhetskyy
Andriy
A
Luzhetska
Martha
M
Mattingly
Cynthia
C
Adams
Val
V
Bechthold
Andreas
A
Rohr
Jürgen
J
D000617:Aminoglycosides / Q000737:chemistry*; D053898:Biosynthetic Pathways; D002851:Chromatography, High Pressure Liquid; D003001:Cloning, Molecular; D004926:Escherichia coli / Q000378:metabolism; D005786:Gene Expression Regulation; D016695:Glycosyltransferases / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D005810:Multigene Family; D009154:Mutation; D011134:Polysaccharides / Q000737:chemistry*; D013302:Streptomyces / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000617:Aminoglycosides; D011134:Polysaccharides; C113593:landomycin E; C064648:landomycin A; D016695:Glycosyltransferases