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Biosynthesis of Cittilins, Unusual Ribosomally Synthesized and Post-translationally Modified Peptides from Myxococcus xanthus

Hug, Joachim J.
; 
Dastbaz, Jan
; 
Adam, Sebastian
; 
Revermann, Ole
; 
Koehnke, Jesko
; 
Krug, Daniel
; 
Müller, Rolf
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Issue Date
2020-07-08
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bioRxiv preprint
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Abstract
Cittilins are secondary metabolites from myxobacteria comprised of three l-tyrosines and one l-isoleucine forming a bicyclic tetrapeptide scaffold with biaryl and aryl-oxygen-aryl ether bonds. Here we reveal that cittilins belong to the ribosomally synthesized and post-translationally modified peptide (RiPP) family of natural products, for which only the crocagins have been reported from myxobacteria. A 27 amino acid precursor peptide harbors a C-terminal four amino acid core peptide, which is enzymatically modified and finally exported to yield cittilins. The small biosynthetic gene cluster responsible for cittilin biosynthesis also encodes a cytochrome P450 enzyme and a methyltransferase, whereas a gene encoding a prolyl endopeptidase for the cleavage of the precursor peptide is located outside of the cittilin biosynthetic gene cluster. We confirm the roles of the biosynthetic genes responsible for the formation of cittilins using targeted gene inactivation and heterologous expression in Streptomyces ssp. We also report first steps toward the biochemical characterization of the proposed biosynthetic pathway in vitro. An investigation of the cellular uptake properties of cittilin A connected it to a potential biological function as an inhibitor of the prokaryotic carbon storage regulator A (CsrA).
Citation
ACS Chem Biol. 2020;15(8):2221-2231. doi:10.1021/acschembio.0c00430.
Affiliation
HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.
Publisher
American Chemical Society (ACS)
Journal
ACS chemical biology
URI
http://hdl.handle.net/10033/622447
DOI
10.1021/acschembio.0c00430
PubMed ID
32639716
PubMed Central ID
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Article
Language
en
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ISSN
1554-8929
EISSN
1554-8937
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Sponsors
Bundesministerium für Bildung und Forschung
License
Attribution-NonCommercial-ShareAlike 4.0 International
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publications of the research group of microbial natural substances([HIPS]MINS)