Structural Analysis of Class I Lanthipeptides from NL19 Reveals an Unusual Ring Pattern

Overview

Journal ACS Chem Biol

Publisher American Chemical Society

Specialties Biochemistry
Biology

Date 2021 Jun 4

PMID 34085816

Citations 21

Authors

Ian R Bothwell

Tania Caetano

Raymond Sarksian

Sonia Mendo

Wilfred A van der Donk

Affiliations

Soon will be listed here.

Abstract

Lanthipeptides are ribosomally synthesized and post-translationally modified peptide natural products characterized by the presence of lanthionine and methyllanthionine cross-linked amino acids formed by dehydration of Ser/Thr residues followed by conjugate addition of Cys to the resulting dehydroamino acids. Class I lanthipeptide dehydratases utilize glutamyl-tRNA as a cosubstrate to glutamylate Ser/Thr followed by glutamate elimination. A vast majority of lanthipeptides identified from class I synthase systems have been from Gram-positive bacteria. Herein, we report the heterologous expression and modification in of two lanthipeptides from the Gram-negative Bacteroidetes NL19. These peptides are representative of a group of compounds frequently encoded in genomes. Structural characterization of the lanthipeptides revealed a novel ring pattern as well as an unusual ll-lanthionine stereochemical configuration and a cyclase that lacks the canonical zinc ligands found in most LanC enzymes.

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References

Havarstein L, Diep D, Nes I . A family of bacteriocin ABC transporters carry out proteolytic processing of their substrates concomitant with export. Mol Microbiol. 1995; 16(2):229-40. DOI: 10.1111/j.1365-2958.1995.tb02295.x. View

Walker M, Eslami S, Hetrick K, Ackenhusen S, Mitchell D, van der Donk W . Precursor peptide-targeted mining of more than one hundred thousand genomes expands the lanthipeptide natural product family. BMC Genomics. 2020; 21(1):387. PMC: 7268733. DOI: 10.1186/s12864-020-06785-7. View

Montalban-Lopez M, Scott T, Ramesh S, Rahman I, van Heel A, Viel J . New developments in RiPP discovery, enzymology and engineering. Nat Prod Rep. 2020; 38(1):130-239. PMC: 7864896. DOI: 10.1039/d0np00027b. View

Huo L, van der Donk W . Discovery and Characterization of Bicereucin, an Unusual d-Amino Acid-Containing Mixed Two-Component Lantibiotic. J Am Chem Soc. 2016; 138(16):5254-7. PMC: 4851115. DOI: 10.1021/jacs.6b02513. View

Singh M, Sareen D . Novel LanT associated lantibiotic clusters identified by genome database mining. PLoS One. 2014; 9(3):e91352. PMC: 3951391. DOI: 10.1371/journal.pone.0091352. View

Hudson G, Mitchell D . RiPP antibiotics: biosynthesis and engineering potential. Curr Opin Microbiol. 2018; 45:61-69. PMC: 6131089. DOI: 10.1016/j.mib.2018.02.010. View

Kodani S, Lodato M, Durrant M, Picart F, Willey J . SapT, a lanthionine-containing peptide involved in aerial hyphae formation in the streptomycetes. Mol Microbiol. 2005; 58(5):1368-80. DOI: 10.1111/j.1365-2958.2005.04921.x. View

Meindl K, Schmiederer T, Schneider K, Reicke A, Butz D, Keller S . Labyrinthopeptins: a new class of carbacyclic lantibiotics. Angew Chem Int Ed Engl. 2010; 49(6):1151-4. DOI: 10.1002/anie.200905773. View

Li B, Sher D, Kelly L, Shi Y, Huang K, Knerr P . Catalytic promiscuity in the biosynthesis of cyclic peptide secondary metabolites in planktonic marine cyanobacteria. Proc Natl Acad Sci U S A. 2010; 107(23):10430-5. PMC: 2890784. DOI: 10.1073/pnas.0913677107. View

10.

Repka L, Chekan J, Nair S, van der Donk W . Mechanistic Understanding of Lanthipeptide Biosynthetic Enzymes. Chem Rev. 2017; 117(8):5457-5520. PMC: 5408752. DOI: 10.1021/acs.chemrev.6b00591. View

11.

Li B, Yu J, Brunzelle J, Moll G, van der Donk W, Nair S . Structure and mechanism of the lantibiotic cyclase involved in nisin biosynthesis. Science. 2006; 311(5766):1464-7. DOI: 10.1126/science.1121422. View

12.

Lohans C, Li J, Vederas J . Structure and biosynthesis of carnolysin, a homologue of enterococcal cytolysin with D-amino acids. J Am Chem Soc. 2014; 136(38):13150-3. DOI: 10.1021/ja5070813. View

13.

Mavaro A, Abts A, Bakkes P, Moll G, Driessen A, Smits S . Substrate recognition and specificity of the NisB protein, the lantibiotic dehydratase involved in nisin biosynthesis. J Biol Chem. 2011; 286(35):30552-30560. PMC: 3162415. DOI: 10.1074/jbc.M111.263210. View

14.

van Heel A, Kloosterman T, Montalban-Lopez M, Deng J, Plat A, Baudu B . Discovery, Production and Modification of Five Novel Lantibiotics Using the Promiscuous Nisin Modification Machinery. ACS Synth Biol. 2016; 5(10):1146-1154. DOI: 10.1021/acssynbio.6b00033. View

15.

Acedo J, Bothwell I, An L, Trouth A, Frazier C, van der Donk W . -Methyltransferase-Mediated Incorporation of a β-Amino Acid in Lanthipeptides. J Am Chem Soc. 2019; 141(42):16790-16801. PMC: 6812601. DOI: 10.1021/jacs.9b07396. View

16.

McClerren A, Cooper L, Quan C, Thomas P, Kelleher N, van der Donk W . Discovery and in vitro biosynthesis of haloduracin, a two-component lantibiotic. Proc Natl Acad Sci U S A. 2006; 103(46):17243-8. PMC: 1859917. DOI: 10.1073/pnas.0606088103. View

17.

Lu J, Wu Y, Li Y, Wang H . The Utilization of Lanthipeptide Synthetases Is a General Strategy for the Biosynthesis of 2-Aminovinyl-Cysteine Motifs in Thioamitides*. Angew Chem Int Ed Engl. 2020; 60(4):1951-1958. DOI: 10.1002/anie.202012871. View

18.

Koponen O, Tolonen M, Qiao M, Wahlstrom G, Helin J, Saris P . NisB is required for the dehydration and NisC for the lanthionine formation in the post-translational modification of nisin. Microbiology (Reading). 2002; 148(Pt 11):3561-3568. DOI: 10.1099/00221287-148-11-3561. View

19.

Paul M, Patton G, van der Donk W . Mutants of the zinc ligands of lacticin 481 synthetase retain dehydration activity but have impaired cyclization activity. Biochemistry. 2007; 46(21):6268-76. PMC: 2517114. DOI: 10.1021/bi7000104. View

20.

Scherlach K, Hertweck C . Mediators of mutualistic microbe-microbe interactions. Nat Prod Rep. 2017; 35(4):303-308. DOI: 10.1039/c7np00035a. View