Interpretation of Tandem Mass Spectra Obtained from Cyclic Nonribosomal Peptides

Liu, Wei-Ting; Ng, John N.; Meluzzi, Dario; Bandeira, Nuno; Gutiérrez, Marcelino; Simmons, Thomas L.; Schultz, Andrew W.; Linington, Roger G.; Moore, Bradley S.; Gerwick, William H.; Pevzner, Pavel A.; Dorrestein, Pieter C.

doi:10.1021/ac900114t

Cited by 84 publications

(77 citation statements)

References 54 publications

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“…An algorithmic description of this procedure is detailed in Ng et al (37). Finally, with the location of the modified residue in hand, all of the ions in a MS 2 spectrum were annotated with our annotation script MS-cyclic peptide annotation (MS-CPA) program (41) (Fig. S6C).…”

Section: Bioassay-guided Isolation and Structural Elucidation Of Portmentioning

confidence: 99%

Synergistic allelochemicals from a freshwater cyanobacterium

Leão

Pereira²,

Liu³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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114

108

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The ability of cyanobacteria to produce complex secondary metabolites with potent biological activities has gathered considerable attention due to their potential therapeutic and agrochemical applications. However, the precise physiological or ecological roles played by a majority of these metabolites have remained elusive. Several studies have shown that cyanobacteria are able to interfere with other organisms in their communities through the release of compounds into the surrounding medium, a phenomenon usually referred to as allelopathy. Exudates from the freshwater cyanobacterium Oscillatoria sp. had previously been shown to inhibit the green microalga Chlorella vulgaris. In this study, we observed that maximal allelopathic activity is highest in early growth stages of the cyanobacterium, and this provided sufficient material for isolation and chemical characterization of active compounds that inhibited the growth of C. vulgaris. Using a bioassay-guided approach, we isolated and structurally characterized these metabolites as cyclic peptides containing several unusually modified amino acids that are found both in the cells and in the spent media of Oscillatoria sp. cultures. Strikingly, only the mixture of the two most abundant metabolites in the cells was active toward C. vulgaris. Synergism was also observed in a lung cancer cell cytotoxicity assay. The binary mixture inhibited other phytoplanktonic organisms, supporting a natural function of this synergistic mixture of metabolites as allelochemicals.allelopathy | chemical ecology | Oscillatoria | cyclic peptides | synergism C yanobacteria are a prolific source of nearly 800 diverse bioactive secondary metabolites, originating mainly from nonribosomal peptide synthetase (NRPS) or mixed polyketide synthase (PKS)-NRPS biosynthesis (1, 2). Efforts to isolate and characterize cyanobacterial metabolites have usually been motivated from a desire to describe either their natural toxicity toward animals in natural settings (e.g., ref.3) or promising activities from in vitro biomedical screening programs (e.g., ref. 4, 5). However, in general the ecological role played by the majority of these metabolites is not well known (6, 7). Functions established to date for cyanobacterial secondary metabolites include nitrogen storage (8), UV protection (9), metal chelation (10), defense against predation (11), and quorum sensing (12).Allelopathy refers to the chemically mediated interaction between plants or microorganisms (13). These interactions are characterized by the release of allelopathic compounds (allelochemicals) into the surrounding medium, eliciting either a positive or deleterious response in a target organism (13). In aquatic ecosystems, allelopathy is regarded as an important process influencing the shaping of microbial communities (14-16). Toxic properties have been attributed to cyanobacteria over the last 130 yr (e.g., ref. 17), and the allelopathic potential of these organisms was described through field-derived observations in the 1970s (18,19). Since th...

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Section: Bioassay-guided Isolation and Structural Elucidation Of Portmentioning

confidence: 99%

Synergistic allelochemicals from a freshwater cyanobacterium

Leão

Pereira²,

Liu³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

114

108

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“…Presence of only b-type product ions and absence of y-type product ions in the product ion spectrum suggest a cyclic sequence for the unknown peptide, because a cyclic peptide, in theory, does not generate any y ions due to the lack of a C-terminal hydroxyl group [24,25].…”

Section: Exploring Amino Acid Sequence Of the Unknown Peptide With CImentioning

confidence: 99%

Sequence Elucidation of an Unknown Cyclic Peptide of High Doping Potential by ETD and CID Tandem Mass Spectrometry

Guan

Uboh²,

Soma³

et al. 2011

J. Am. Soc. Mass Spectrom.

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Identification of an unknown substance without any information remains a daunting challenge despite advances in chemistry and mass spectrometry. However, an unknown cyclic peptide in a sample with very limited volume seized at a Pennsylvania racetrack has been successfully identified. The unknown sample was determined by accurate mass measurements to contain a small unknown peptide as the major component. Collision-induced dissociation (CID) of the unknown peptide revealed the presence of Lys (not Gln, by accurate mass), Phe, and Arg residues, and absence of any y-type product ion. The latter, together with the tryptic digestion results of the unusual deamidation and absence of any tryptic cleavage, suggests a cyclic structure for the peptide. Electron-transfer dissociation (ETD) of the unknown peptide indicated the presence of Gln (not Lys, by the unusual deamidation), Phe, and Arg residues and their connectivity. After all the results were pieced together, a cyclic tetrapeptide, cyclo[Arg-Lys-N(C 6 H 9 )Gln-Phe], is proposed for the unknown peptide. Observations of different amino acid residues from CID and ETD experiments for the peptide were interpreted by a fragmentation pathway proposed, as was preferential CID loss of a Lys residue from the peptide. ETD was used for the first time in sequencing of a cyclic peptide; product ions resulting from ETD of the peptide identified were categorized into two types and named pseudo-b and pseudo-z ions that are important for sequencing of cyclic peptides. The ETD product ions were interpreted by fragmentation pathways proposed. Additionally, multi-stage CID mass spectrometry cannot provide complete sequence information for cyclic peptides containing adjacent Arg and Lys residues. The identified cyclic peptide has not been documented in the literature, its pharmacological effects are unknown, but it might be a "designer" drug with athletic performance-enhancing effects.

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“…For example, the ions b k may undergo a further fragmentation, so the spectrum of a cyclic peptide usually represents the superposition of up to k spectra corresponding to different linear sequences [10]. As the peptide is cyclic and lacking its C-terminus, b-ions (or other N-terminal ions) are exclusively observed [20]. Sometimes, a b-ion may cyclize by head-to-tail mechanism; its reopening between other two monomers and further fragmentation provides b-ions corresponding to a scrambled sequence of building blocks [27].…”

Section: Peptide Fragmentationmentioning

confidence: 99%

“…A method based on multiplex de novo sequencing has also been proposed providing much better results [19]. In addition to library matching, there are multiple annotation tools [20][21][22].…”

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confidence: 99%

CycloBranch: De Novo Sequencing of Nonribosomal Peptides from Accurate Product Ion Mass Spectra

Novák

Lemr

Schug

et al. 2015

J. Am. Soc. Mass Spectrom.

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Abstract. Nonribosomal peptides have a wide range of biological and medical applications. Their identification by tandem mass spectrometry remains a challenging task. A new open-source de novo peptide identification engine CycloBranch was developed and successfully applied in identification or detailed characterization of 11 linear, cyclic, branched, and branch-cyclic peptides. CycloBranch is based on annotated building block databases the size of which is defined by the user according to ribosomal or nonribosomal peptide origin. The current number of involved nonisobaric and isobaric building blocks is 287 and 521, respectively. Contrary to all other peptide sequencing tools utilizing either peptide libraries or peptide fragment libraries, CycloBranch represents a true de novo sequencing engine developed for accurate mass spectrometric data. It is a stand-alone and cross-platform application with a graphical and userfriendly interface; it supports mzML, mzXML, mgf, txt, and baf file formats and can be run in parallel on multiple threads. It can be downloaded for free from http://ms.biomed.cas.cz/cyclobranch/, where the User's manual and video tutorials can be found.

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Interpretation of Tandem Mass Spectra Obtained from Cyclic Nonribosomal Peptides

Cited by 84 publications

References 54 publications

Synergistic allelochemicals from a freshwater cyanobacterium

Synergistic allelochemicals from a freshwater cyanobacterium

Sequence Elucidation of an Unknown Cyclic Peptide of High Doping Potential by ETD and CID Tandem Mass Spectrometry

CycloBranch: De Novo Sequencing of Nonribosomal Peptides from Accurate Product Ion Mass Spectra

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