title: Insights into quinaldic acid moiety formation in thiostrepton biosynthesis facilitating fluorinated thiopeptide generation.
abstract: Thiostrepton (TSR), often referred as to a parent compound in the thiopeptide family, is a bimacrocyclic member that features a quinaldic acid (QA) moiety-containing side ring appended to the characteristic core system. QA biosynthesis requires an unusual ring-expanding conversion, showing a methyl transfer onto and a rearrangement of the indole part of L-tryptophan to give a quinoline ketone. Herein, we report that the process involves the activities of the radical methyltransferase TsrT, aminotransferase TsrA, dehydrogenase TsrE, and cyclase TsrD. TsrU, a stereospecific oxidoreductase, catalyzes the further conversion of the ketone into an enantiomerically pure S-alcohol. Elucidation of this chemistry, which is common in the biosynthesis of a number of thiopeptides sharing a QA side ring system, facilitates analog generation, as shown by the achievement of region-specific fluorination of thiostrepton with the improved antibacterial activity.
authors.affiliation: State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China.
authors.forename: Lian
authors.initials: L
authors.lastname: Duan
authors.forename: Shoufeng
authors.initials: S
authors.lastname: Wang
authors.forename: Rijing
authors.initials: R
authors.lastname: Liao
authors.forename: Wen
authors.initials: W
authors.lastname: Liu
mesh_terms: D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D054879:Halogenation; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism; D011804:Quinolines / Q000378:metabolism*; D013302:Streptomyces / Q000201:enzymology; D013883:Thiostrepton / Q000096:biosynthesis*
chemical_list: D001426:Bacterial Proteins; D011804:Quinolines; D010088:Oxidoreductases; D013883:Thiostrepton; C008898:quinaldic acid