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J Nat Prod. 2014 Aug 22;77(8):1902-9. doi: 10.1021/np500370c. Epub 2014 Aug 12.

NRPquest: Coupling Mass Spectrometry and Genome Mining for Nonribosomal Peptide Discovery.

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†Department of Electrical and Computer Engineering, ‡Department of Chemistry and Biochemistry, §Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, ⊥Skaggs School of Pharmacy and Pharmaceutical Sciences, and ∥Department of Computer Science and Engineering, University of California San Diego, La Jolla, California 92093, United States.


Nonribosomal peptides (NRPs) such as vancomycin and daptomycin are among the most effective antibiotics. While NRPs are biomedically important, the computational techniques for sequencing these peptides are still in their infancy. The recent emergence of mass spectrometry techniques for NRP analysis (capable of sequencing an NRP from small amounts of nonpurified material) revealed an enormous diversity of NRPs. However, as many NRPs have nonlinear structure (e.g., cyclic or branched-cyclic peptides), the standard de novo sequencing tools (developed for linear peptides) are not applicable to NRP analysis. Here, we introduce the first NRP identification algorithm, NRPquest, that performs mutation-tolerant and modification-tolerant searches of spectral data sets against a database of putative NRPs. In contrast to previous studies aimed at NRP discovery (that usually report very few NRPs), NRPquest revealed nearly a hundred NRPs (including unknown variants of previously known peptides) in a single study. This result indicates that NRPquest can potentially make MS-based NRP identification as robust as the identification of linear peptides in traditional proteomics.

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