Interpretation of tandem mass spectra obtained from cyclic nonribosomal peptides.

TitleInterpretation of tandem mass spectra obtained from cyclic nonribosomal peptides.
Publication TypeJournal Article
Year of Publication2009
AuthorsLiu W-T, Ng J, Meluzzi D, Bandeira N, Gutierrez M, Simmons TL, Schultz AW, Linington RG, Moore BS, Gerwick WH, Pevzner PA, Dorrestein PC
JournalAnal Chem
Volume81
Issue11
Pagination4200-9
Date Published2009 Jun 1
ISSN1520-6882
KeywordsAnti-Bacterial Agents, Ions, Molecular Structure, Peptide Biosynthesis, Nucleic Acid-Independent, Peptides, Cyclic, Software, Tandem Mass Spectrometry, Time Factors, Tyrocidine
Abstract

Natural and non-natural cyclic peptides are a crucial component in drug discovery programs because of their considerable pharmaceutical properties. Cyclosporin, microcystins, and nodularins are all notable pharmacologically important cyclic peptides. Because these biologically active peptides are often biosynthesized nonribosomally, they often contain nonstandard amino acids, thus increasing the complexity of the resulting tandem mass spectrometry data. In addition, because of the cyclic nature, the fragmentation patterns of many of these peptides showed much higher complexity when compared to related counterparts. Therefore, at the present time it is still difficult to annotate cyclic peptides MS/MS spectra. In this current work, an annotation program was developed for the annotation and characterization of tandem mass spectra obtained from cyclic peptides. This program, which we call MS-CPA is available as a web tool (http://lol.ucsd.edu/ms-cpa_v1/Input.py). Using this program, we have successfully annotated the sequence of representative cyclic peptides, such as seglitide, tyrothricin, desmethoxymajusculamide C, dudawalamide A, and cyclomarins, in a rapid manner and also were able to provide the first-pass structure evidence of a newly discovered natural product based on predicted sequence. This compound is not available in sufficient quantities for structural elucidation by other means such as NMR. In addition to the development of this cyclic annotation program, it was observed that some cyclic peptides fragmented in unexpected ways resulting in the scrambling of sequences. In summary, MS-CPA not only provides a platform for rapid confirmation and annotation of tandem mass spectrometry data obtained with cyclic peptides but also enables quantitative analysis of the ion intensities. This program facilitates cyclic peptide analysis, sequencing, and also acts as a useful tool to investigate the uncommon fragmentation phenomena of cyclic peptides and aids the characterization of newly discovered cyclic peptides encountered in drug discovery programs.

DOI10.1021/ac900114t
PubMed URLhttp://www.ncbi.nlm.nih.gov/pubmed/19413302?dopt=Abstract
PMCPMC2765223
Alternate TitleAnal. Chem.
PubMed ID19413302