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An Amidinohydrolase Provides the Missing Link in the Biosynthesis of Amino Marginolactone Antibiotics.

Published version
Peer-reviewed

Repository DOI


Type

Article

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Authors

Hong, Hui 
Samborskyy, Markiyan  ORCID logo  https://orcid.org/0000-0002-6946-0385
Lindner, Frederick 
Leadlay, Peter F 

Abstract

Desertomycin A is an aminopolyol polyketide containing a macrolactone ring. We have proposed that desertomycin A and similar compounds (marginolactones) are formed by polyketide synthases primed not with γ-aminobutanoyl-CoA but with 4-guanidinylbutanoyl-CoA, to avoid facile cyclization of the starter unit. This hypothesis requires that there be a final-stage de-amidination of the corresponding guanidino-substituted natural product, but no enzyme for such a process has been described. We have now identified candidate amidinohydrolase genes within the desertomycin and primycin clusters. Deletion of the putative desertomycin amidinohydrolase gene dstH in Streptomyces macronensis led to the accumulation of desertomycin B, the guanidino form of the antibiotic. Also, purified DstH efficiently catalyzed the in vitro conversion of desertomycin B into the A form. Hence this amidinohydrolase furnishes the missing link in this proposed naturally evolved example of protective-group chemistry.

Description

Keywords

amidinohydrolases, biosynthesis, marginolactones, polyketide synthases, streptomyces, Amidohydrolases, Anti-Bacterial Agents, Chromatography, High Pressure Liquid, Macrolides, Mass Spectrometry

Journal Title

Angew Chem Int Ed Engl

Conference Name

Journal ISSN

1433-7851
1521-3773

Volume Title

55

Publisher

Wiley
Sponsorship
We gratefully acknowledge BBSRC (project grants BB/J007250/1 and BB/K002341/1 to P.F.L.), Shilo Dickens and colleagues (Nextgen Sequencing Facility, Department of Biochemistry, University of Cambridge) for help with genome sequencing, and Prof. Dr. Wolfgang Wohlleben, University of Tübingen, for the gift of Streptomyces olivaceus Tü4018. P.F.L. is an International Research Awardee of the Alexander von Humboldt Foundation.