title: Structural investigation of ribosomally synthesized natural products by hypothetical structure enumeration and evaluation using tandem MS.
abstract: Ribosomally synthesized and posttranslationally modified peptides (RiPPs) are a growing class of natural products that are found in all domains of life. These compounds possess vast structural diversity and have a wide range of biological activities, promising a fertile ground for exploring novel natural products. One challenging aspect of RiPP research is the difficulty of structure determination due to their architectural complexity. We here describe a method for automated structural characterization of RiPPs by tandem mass spectrometry. This method is based on the combined analysis of multiple mass spectra and evaluation of a collection of hypothetical structures predicted based on the biosynthetic gene cluster and molecular weight. We show that this method is effective in structural characterization of complex RiPPs, including lanthipeptides, glycopeptides, and azole-containing peptides. Using this method, we have determined the structure of a previously structurally uncharacterized lanthipeptide, prochlorosin 1.2, and investigated the order of the posttranslational modifications in three biosynthetic systems.
authors.affiliation: Howard Hughes Medical Institute,Departments of Chemistry.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Howard Hughes Medical Institute,Biochemistry, and.
authors.forename: Manuel
authors.initials: M
authors.lastname: Ortega
authors.affiliation: Howard Hughes Medical Institute,Departments of Chemistry.
authors.forename: Yanxiang
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Howard Hughes Medical Institute,Departments of Chemistry.
authors.forename: Huan
authors.initials: H
authors.lastname: Wang
authors.affiliation: Departments of Chemistry,Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801.
authors.forename: Joel O
authors.initials: JO
authors.lastname: Melby
authors.affiliation: Howard Hughes Medical Institute,Departments of Chemistry.
authors.forename: Weixin
authors.initials: W
authors.lastname: Tang
authors.affiliation: Departments of Chemistry,Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801Microbiology, and.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Mitchell
authors.affiliation: Howard Hughes Medical Institute,Departments of Chemistry,Biochemistry, andInstitute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801 vddonk@illinois.edu.
authors.forename: Wilfred A
authors.initials: WA
authors.lastname: van der Donk
mesh_terms: D000595:Amino Acid Sequence; D001688:Biological Products / Q000737:chemistry* / Q000378:metabolism; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D012270:Ribosomes / Q000378:metabolism*; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: D001688:Biological Products; D010455:Peptides
keywords: dehydration; directionality; genome mining; lantibiotics
references.citation: Nucleic Acids Res. 2008 Jan;36(Database issue):D326-31
references.pmid: 17913739
references.citation: Proc Natl Acad Sci U S A. 2013 Jul 9;110(28):E2611-20
references.pmid: 23798442
references.citation: Nat Prod Rep. 2013 Jan;30(1):108-60
references.pmid: 23165928
references.citation: J Am Chem Soc. 2012 Mar 21;134(11):5309-16
references.pmid: 22401305
references.citation: J Antibiot (Tokyo). 2014 Jan;67(1):23-30
references.pmid: 24022605
references.citation: Nat Chem Biol. 2011 Feb;7(2):78-80
references.pmid: 21196935
references.citation: Nat Chem Biol. 2012 Apr 22;8(6):569-75
references.pmid: 22522320
references.citation: Anal Chem. 2011 Feb 15;83(4):1243-51
references.pmid: 21182243
references.citation: Biochemistry. 2007 May 22;46(20):5884-95
references.pmid: 17469849
references.citation: J Nat Prod. 2013 Sep 27;76(9):1686-99
references.pmid: 24025162
references.citation: Proc Natl Acad Sci U S A. 2010 Jun 8;107(23):10430-5
references.pmid: 20479271
references.citation: J Am Chem Soc. 2004 Mar 24;126(11):3386-7
references.pmid: 15025441
references.citation: Proc Natl Acad Sci U S A. 2012 Nov 6;109(45):18361-6
references.pmid: 23071302
references.citation: Nucleic Acids Res. 2013 Jul;41(Web Server issue):W204-12
references.pmid: 23737449
references.citation: ACS Chem Biol. 2014 Jul 18;9(7):1545-51
references.pmid: 24802639
references.citation: J Ind Microbiol Biotechnol. 2006 Jul;33(7):507-13
references.pmid: 16418869
references.citation: PLoS One. 2012;7(3):e34064
references.pmid: 22479523
references.citation: Proc Natl Acad Sci U S A. 2006 Nov 14;103(46):17243-8
references.pmid: 17085596
references.citation: Proc Natl Acad Sci U S A. 2010 Jul 27;107(30):13461-6
references.pmid: 20628010
references.citation: J Biol Chem. 2009 Sep 18;284(38):25962-72
references.pmid: 19620240
references.citation: Curr Opin Chem Biol. 2011 Jun;15(3):369-78
references.pmid: 21429787
references.citation: J Nat Prod. 2009 Apr;72(4):605-7
references.pmid: 19301921
references.citation: Chem Biol. 2008 Oct 20;15(10):1035-45
references.pmid: 18940665
references.citation: Nucleic Acids Res. 2013 Jul;41(Web Server issue):W448-53
references.pmid: 23677608
references.citation: Curr Drug Discov Technol. 2009 Mar;6(1):1-18
references.pmid: 19275538
references.citation: Nucleic Acids Res. 1996 Jan 1;24(1):21-5
references.pmid: 8594581
references.citation: Chem Biol. 2008 Jan;15(1):22-31
references.pmid: 18215770
references.citation: Nat Chem Biol. 2011 Oct 09;7(11):794-802
references.pmid: 21983601
references.citation: J Am Chem Soc. 2011 Mar 2;133(8):2338-41
references.pmid: 21114289
references.citation: J Am Chem Soc. 2009 Sep 2;131(34):12258-64
references.pmid: 19663480
references.citation: Acc Chem Res. 2011 Apr 19;44(4):261-8
references.pmid: 21366289
references.citation: Biochemistry. 2004 Mar 23;43(11):3049-56
references.pmid: 15023056
references.citation: Anal Chem. 2012 Apr 3;84(7):3417-26
references.pmid: 22390817
references.citation: Mol Biosyst. 2012 Oct;8(10):2535-44
references.pmid: 22610447
references.citation: Science. 2009 Jul 10;325(5937):161-5
references.pmid: 19589993
references.citation: Biochemistry. 1999 Nov 23;38(47):15623-30
references.pmid: 10569947
references.citation: Nat Biotechnol. 2005 Dec;23(12):1562-7
references.pmid: 16311586
references.citation: Bioinformatics. 2009 Jan 15;25(2):218-24
references.pmid: 19015140
references.citation: Nat Biotechnol. 2010 Jul;28(7):659-64
references.pmid: 20622832
references.citation: Annu Rev Biochem. 2012;81:479-505
references.pmid: 22404629
references.citation: Proc Natl Acad Sci U S A. 2013 Apr 30;110(18):7258-63
references.pmid: 23589847
references.citation: Appl Environ Microbiol. 2009 Sep;75(17):5451-60
references.pmid: 19561184
references.citation: Biochemistry. 2010 Aug 3;49(30):6462-72
references.pmid: 20578714