Dinghupeptins A–D, Chymotrypsin Inhibitory Cyclodepsipeptides Produced by a Soil-Derived Streptomyces

Li, Yang; Li, Hanxiang; Wu, Ping; Mahal, Ahmed; Xue, Jinghua; Xu, Liangxiong; Wei, Xiaoyi

doi:10.1021/acs.jnatprod.7b01009

“…MolDiscovery search results for this dataset are available at https://github.com/mohimanilab/molDiscovery . MolDiscovery identified dinghupeptins A–D 45 in multiple Streptomyces strains, including Streptomyces sp. NRRL B-5680, S. varsoviensis NRRL B-3589, Ampullariella violaceochromogenes NRRL B-16710 and S. californicus NRRL B-3320.…”

Section: Resultsmentioning

confidence: 99%

MolDiscovery: learning mass spectrometry fragmentation of small molecules

Cao

¹

,

Guler

²

,

Tagirdzhanov

³

et al. 2021

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Identification of small molecules is a critical task in various areas of life science. Recent advances in mass spectrometry have enabled the collection of tandem mass spectra of small molecules from hundreds of thousands of environments. To identify which molecules are present in a sample, one can search mass spectra collected from the sample against millions of molecular structures in small molecule databases. The existing approaches are based on chemistry domain knowledge, and they fail to explain many of the peaks in mass spectra of small molecules. Here, we present molDiscovery, a mass spectral database search method that improves both efficiency and accuracy of small molecule identification by learning a probabilistic model to match small molecules with their mass spectra. A search of over 8 million spectra from the Global Natural Product Social molecular networking infrastructure shows that molDiscovery correctly identify six times more unique small molecules than previous methods.

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“…MolDiscovery search results for this dataset are available at https://github.com/mohimanilab/molDiscovery. MolDiscovery identified dinghu-peptins A-D [46] in Streptomyces sp. NRRL B-5680 and several other Streptomyces strains (Supplementary Table S2).…”

Section: Resultsmentioning

confidence: 99%

MolDiscovery: Learning Mass Spectrometry Fragmentation of Small Molecules

Cao

¹

,

Guler

²

,

Tagirdzhanov

³

et al. 2020

Preprint

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Identification of small molecules is a critical task in various areas of life science. Recent advances in mass spectrometry have enabled the collection of tandem mass spectra of small molecules from hundreds of thousands of environments. To identify which molecules are present in a sample, one can search mass spectra collected from the sample against millions of molecular structures in small molecule databases. This is a challenging task as currently it is not clear how small molecules are fragmented in mass spectrometry. The existing approaches use the domain knowledge from chemistry to predict fragmentation of molecules. However, these rule-based methods fail to explain many of the peaks in mass spectra of small molecules. Recently, spectral libraries with tens of thousands of labelled mass spectra of small molecules have emerged, paving the path for learning more accurate fragmentation models for mass spectral database search. We present molDiscovery, a mass spectral database search method that improves both efficiency and accuracy of small molecule identification by (i) utilizing an efficient algorithm to generate mass spectrometry fragmentations, and (ii) learning a probabilistic model to match small molecules with their mass spectra. We show our database search is an order of magnitude more efficient than the state-of-the-art methods, which enables searching against databases with millions of molecules. A search of over 8 million spectra from the Global Natural Product Social molecular networking infrastructure shows that our probabilistic model can correctly identify nearly six times more unique small molecules than previous methods. Moreover, by applying molDiscovery on microbial datasets with both mass spectral and genomics data we successfully discovered the novel biosynthetic gene clusters of three families of small molecules.AvailabilityThe command-line version of molDiscovery and its online web service through the GNPS infrastructure are available at https://github.com/mohimanilab/molDiscovery.

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“…Some other works addressing the docking near the catalytic site do not reveal the complex binding energy for the association of a molecule to the protein [29,30]. Other larger molecules have been described to efficiently bind to α-chymotrypsin, however these molecules are used as inhibitors, and therefore cannot be compared to our work [30]. The lack of similar docking approaches makes it difficult to compare our binding preferences and energies with other studies.…”

Section: Molecular Dynamics Simulationsmentioning

confidence: 90%

“…However, the complexes were not formed in the active site, where the catalytic triad take place. Some other works addressing the docking near the catalytic site do not reveal the complex binding energy for the association of a molecule to the protein [29,30]. Other larger molecules have been described to efficiently bind to α-chymotrypsin, however these molecules are used as inhibitors, and therefore cannot be compared to our work [30].…”

Section: Molecular Dynamics Simulationsmentioning

confidence: 93%

α-Chymotrypsin catalyses the synthesis of methotrexate oligomers

Noro

¹

,

Castro

²

,

Cavaco‐Paulo

³

et al. 2020

Process Biochemistry

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The enzymatic synthesis of methotrexate (MTX) catalysed by α -chymotrypsin was studied for the first time. The proteolytic enzyme displayed activity for the synthesis of MTX oligomers composed by 6 repeating units (DP avg = 1.5). For longer oligomers, molecular dynamics simulations confirmed that as the oligomeric chain grows its accommodation in the enzymes' active site is hindered, which is evidenced by a decrease of the binding energy associated. The full characterization of the oligomers produced was performed by nuclear magnetic resonance (NMR, 1 H and 13 C), matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF), electrospray ionization (ESI) and differential scanning calorimetry (DSC).

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Dinghupeptins A–D, Chymotrypsin Inhibitory Cyclodepsipeptides Produced by a Soil-Derived Streptomyces

Cited by 23 publications

References 31 publications

MolDiscovery: learning mass spectrometry fragmentation of small molecules

MolDiscovery: learning mass spectrometry fragmentation of small molecules

MolDiscovery: Learning Mass Spectrometry Fragmentation of Small Molecules

α-Chymotrypsin catalyses the synthesis of methotrexate oligomers

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