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Biosynthesis of Streptolidine Involved Two Unexpected IntermediatesProduced by a Dihydroxylase and a Cyclase through UnusualMechanisms

By Chin-Yuan Chang, Syue-Yi Lyu, Yu-Chen Liu, Ning-Shian Hsu, Chih-Chung Wu, Cheng-Fong Tang, Kuan-Hung Lin, Jin-Yuan Ho, Chang-Jer Wu, Ming-Daw Tsai and and Tsung-Lin Li


Streptothricin-F (STT-F), one of the early-discovered antibiotics, consists of three components, a β-lysine homopolymer, an aminosugar d-gulosamine, and an unusual bicyclic streptolidine. The biosynthesis of streptolidine is a long-lasting but unresolved puzzle. Herein, a combination of genetic/biochemical/structural approaches was used to unravel this problem. The STT gene cluster was first sequenced from a Streptomyces variant BCRC 12163, wherein two gene products OrfP and OrfR were characterized in vitro to be a dihydroxylase and a cyclase, respectively. Thirteen high-resolution crystal structures for both enzymes in different reaction intermediate states were snapshotted to help elucidate their catalytic mechanisms. OrfP catalyzes an FeII-dependent double hydroxylation reaction converting l-Arg into (3R,4R)-(OH)2-l-Arg via (3S)-OH-l-Arg, while OrfR catalyzes an unusual PLP-dependent elimination/addition reaction cyclizing (3R,4R)-(OH)2-l-Arg to the six-membered (4R)-OH-capreomycidine. The biosynthetic mystery finally comes to light as the latter product was incorporation into STT-F by a feeding experiment

Topics: biosynthesis, enzymes, isotopic labeling, protein structures, reaction mechanisms
Year: 2014
DOI identifier: 10.1002/anie.201307989
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