TY - JOUR

T1 - Increased diversity of peptidic natural products revealed by modification-tolerant database search of mass spectra

AU - Гуревич, Алексей Александрович

AU - Михеенко, Алла Александровна

AU - Шлемов, Александр Юрьевич

AU - Коробейников, Антон Иванович

AU - Mohimani, Hosein

AU - Певзнер, Павел Аркадьевич

PY - 2018/3/1

Y1 - 2018/3/1

N2 - Peptidic natural products (PNPs) include many antibiotics and other bioactive compounds. While the recent launch of the Global Natural Products Social (GNPS) molecular networking infrastructure is transforming PNP discovery into a high-throughput technology, PNP identification algorithms are needed to realize the potential of the GNPS project. GNPS relies on the assump- tion that each connected component of a molecular network (representing related metabolites) illuminates the ‘dark matter of metabolomics’ as long as it contains a known metabolite present in a database. We reveal a surprising diversity of PNPs produced by related bacteria and show that, contrary to the ‘comparative metabolomics’ assumption, two related bacteria are unlikely to produce identical PNPs (even though they are likely to produce similar PNPs). Since this observation undermines the utility of GNPS, we developed a PNP identification tool, VarQuest, that illuminates the connected components in a molecular network even if they do not contain known PNPs and only contain their variants. VarQuest reveals an order of magnitude more PNP variants than all previous PNP discovery efforts and demonstrates that GNPS already contains spectra from 41% of the currently known PNP families. The enormous diversity of PNPs suggests that biosynthetic gene clusters in various microorgan- isms constantly evolve to generate a unique spectrum of PNP variants that differ from PNPs in other species.

AB - Peptidic natural products (PNPs) include many antibiotics and other bioactive compounds. While the recent launch of the Global Natural Products Social (GNPS) molecular networking infrastructure is transforming PNP discovery into a high-throughput technology, PNP identification algorithms are needed to realize the potential of the GNPS project. GNPS relies on the assump- tion that each connected component of a molecular network (representing related metabolites) illuminates the ‘dark matter of metabolomics’ as long as it contains a known metabolite present in a database. We reveal a surprising diversity of PNPs produced by related bacteria and show that, contrary to the ‘comparative metabolomics’ assumption, two related bacteria are unlikely to produce identical PNPs (even though they are likely to produce similar PNPs). Since this observation undermines the utility of GNPS, we developed a PNP identification tool, VarQuest, that illuminates the connected components in a molecular network even if they do not contain known PNPs and only contain their variants. VarQuest reveals an order of magnitude more PNP variants than all previous PNP discovery efforts and demonstrates that GNPS already contains spectra from 41% of the currently known PNP families. The enormous diversity of PNPs suggests that biosynthetic gene clusters in various microorgan- isms constantly evolve to generate a unique spectrum of PNP variants that differ from PNPs in other species.

KW - Computational biology and bioinformatics

KW - Metabolomics

KW - Natural products

KW - Mass Spectrometry

KW - NONRIBOSOMAL PEPTIDES

KW - SEQUENCES

KW - DEREPLICATION

KW - MOLECULAR NETWORKING

KW - POSTTRANSLATIONAL MODIFICATIONS

KW - BACTERIAL

KW - IDENTIFICATION

KW - DISCOVERY

KW - BIOSYNTHETIC GENE-CLUSTER

KW - SPECTROMETRY

UR - http://www.scopus.com/inward/record.url?scp=85040793388&partnerID=8YFLogxK

UR - http://www.mendeley.com/research/increased-diversity-peptidic-natural-products-revealed-modificationtolerant-database-search-mass-spe

U2 - 10.1038/s41564-017-0094-2

DO - 10.1038/s41564-017-0094-2

M3 - Article

C2 - 29358742

VL - 3

SP - 319

EP - 327

JO - Nature Microbiology

JF - Nature Microbiology

SN - 2058-5276

IS - 3

ER -