Biosynthesis of the tunicamycin antibiotics proceeds via unique exo-glycal intermediates

Wyszynski, F. J., Lee, S. S., Yabe, T., Wang, H. , Gomez-Escribano, J. P., Bibb, M. J., Lee, S. J., Davies, G. J. and Davis, B. G. (2012) Biosynthesis of the tunicamycin antibiotics proceeds via unique exo-glycal intermediates. Nature Chemistry, 4, pp. 539-546. (doi: 10.1038/nchem.1351) (PMID:22717438)

Abstract

The tunicamycins are archetypal nucleoside antibiotics targeting bacterial peptidoglycan biosynthesis and eukaryotic protein N-glycosylation. Understanding the biosynthesis of their unusual carbon framework may lead to variants with improved selectivity. Here, we demonstrate in vitro recapitulation of key sugar-manipulating enzymes from this pathway. TunA is found to exhibit unusual regioselectivity in the reduction of a key α,β-unsaturated ketone. The product of this reaction is shown to be the preferred substrate for TunF—an epimerase that converts the glucose derivative to a galactose. In Streptomyces strains in which another gene (tunB) is deleted, the biosynthesis is shown to stall at this exo-glycal product. These investigations confirm the combined TunA/F activity and delineate the ordering of events in the metabolic pathway. This is the first time these surprising exo-glycal intermediates have been seen in biology. They suggest that construction of the aminodialdose core of tunicamycin exploits their enol ether motif in a mode of C–C bond formation not previously observed in nature, to create an 11-carbon chain.

• Item Type: Articles
• Additional Information: The authors gratefully acknowledge B. Odell (Oxford University) for help with the NMR experiments. This work was supported by the EPSRC (DTA studentship for F.J.W.), the Bill and Melinda Gates Foundation (S.S.L.) and BBSRC (J.P.G-E. and M.J.B). G.J.D and B.G.D. are Royal Society Wolfson Research Merit Award recipients. This manuscript is dedicated to the memory of Professor David Gin.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Wang, Dr Hua
• Authors: Wyszynski, F. J., Lee, S. S., Yabe, T., Wang, H., Gomez-Escribano, J. P., Bibb, M. J., Lee, S. J., Davies, G. J., and Davis, B. G.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Nature Chemistry
• Publisher: Nature Research
• ISSN: 1755-4330
• ISSN (Online): 1755-4349