Elucidation of salicylate attachment in celesticetin biosynthesis opens the door to create a library of more efficient hybrid lincosamide antibiotics

Chemical Science
Stanislav KadlčíkJiri Janata

Abstract

Lincosamides, which are produced by streptomycetes, compose a small but clinically important class of antibiotics. The recent elucidation of the condensation and post-condensation biosynthetic steps of the lincosamides lincomycin and celesticetin revealed several unexpected reaction mechanisms. Here, we prepared recombinant proteins involved in the celesticetin biosynthetic pathway and used them for in vitro assays that were monitored by LC-MS. Our results elucidate the last biosynthetic step of celesticetin: the attachment of salicylic acid is catalyzed by the Ccb2 acyl-CoA ligase and the Ccb1 acyltransferase. Ccb1 belongs to the WS/DGAT protein family and, in contrast to the characterized members of the family, has unusual substrate specificity. To the best of our knowledge, Ccb1 is the first protein in this family that transfers a benzoyl derivative-CoA conjugate and is the first WS/DGAT protein involved in the biosynthesis of secondary metabolites. Furthermore, we exploited the relaxed substrate specificities of Ccb1 and Ccb2, as well as three additional upstream post-condensation biosynthetic proteins in the celesticetin pathway, and combined the lincomycin and the celesticetin biosynthetic pathways in vitro. In this way, ...Continue Reading

References

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Citations

Feb 2, 2019·Organic & Biomolecular Chemistry·Mads J GrüningerJennifer N Andexer
Oct 21, 2018·Applied and Environmental Microbiology·Yurong XuBuchang Zhang
Aug 14, 2020·ACS Chemical Biology·Simon VobrubaJiri Janata
May 1, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Lais Pessanha de CarvalhoJana Held

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Datasets Mentioned

BETA
ADB92576.1
ADB92559.1

Methods Mentioned

BETA
deamination
gel
electrophoresis
NMR

Software Mentioned

BLASTp

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