10 research outputs found
The Natural Products Atlas : an open access knowledge base for microbial natural products discovery
Despite rapid evolution in the area of microbial natural products chemistry, there is currently no open access database containing all microbially produced natural product structures. Lack of availability of these data is preventing the implementation of new technologies in natural products science. Specifically, development of new computational strategies for compound characterization and identification are being hampered by the lack of a comprehensive database of known compounds against which to compare experimental data. The creation of an open access, community-maintained database of microbial natural product structures would enable the development of new technologies in natural products discovery and improve the interoperability of existing natural products data resources. However, these data are spread unevenly throughout the historical scientific literature, including both journal articles and international patents. These documents have no standard format, are often not digitized as machine readable text, and are not publicly available. Further, none of these documents have associated structure files (e.g., MOL, InChI, or SMILES), instead containing images of structures. This makes extraction and formatting of relevant natural products data a formidable challenge. Using a combination of manual curation and automated data mining approaches we have created a database of microbial natural products (The Natural Products Atlas, www.npatlas.org) that includes 24 594 compounds and contains referenced data for structure, compound names, source organisms, isolation references, total syntheses, and instances of structural reassignment. This database is accompanied by an interactive web portal that permits searching by structure, substructure, and physical properties. The Web site also provides mechanisms for visualizing natural products chemical space and dashboards for displaying author and discovery timeline data. These interactive tools offer a powerful knowledge base for natural products discovery with a central interface for structure and property-based searching and presents new viewpoints on structural diversity in natural products. The Natural Products Atlas has been developed under FAIR principles (Findable, Accessible, Interoperable, and Reusable) and is integrated with other emerging natural product databases, including the Minimum Information About a Biosynthetic Gene Cluster (MIBiG) repository, and the Global Natural Products Social Molecular Networking (GNPS) platform. It is designed as a community-supported resource to provide a central repository for known natural product structures from microorganisms and is the first comprehensive, open access resource of this type. It is expected that the Natural Products Atlas will enable the development of new natural products discovery modalities and accelerate the process of structural characterization for complex natural products libraries
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Manipulations of Sucrose/Proton Symporters and Proton-pumping Pyrophosphatase Lead to Enhanced Phloem Transport But Have Contrasting Effects on Plant Biomass
Delivery of photoassimilate, mainly sucrose (Suc) from photoautotrophic source leaves provides the substrate for the growth and maintenance of sink tissues such as roots, storage tissues, flowers and fruits, juvenile organs, and seeds. Phloem loading is the energized process of accumulating solute in the sieve element/companion cell complex of source leaf phloem to generate the hydrostatic pressure that drives long-distance transport. In many plants this is catalyzed by Suc/Proton (H+) symporters (SUTs) which are energized by the proton motive force (PMF). Overexpression of SUTs was tested as means to enhance phloem transport and plant productivity. Phloem specific overexpression of AtSUC2 in wild type (WT) tobacco resulted in enhanced Suc loading and transport, but against the hypothesis, plants were stunted and accumulated carbohydrates in the leaves, possibly due to lack of sufficient energy to support enhanced phloem transport. The energy for SUT mediated phloem loading is provided from the PMF, which is ultimately supplied by the oxidation of a small proportion of the loaded photoassimilates. It was previously shown that inorganic pyrophosphate (PPi) is necessary for this oxidation and overexpressing a proton-pumping pyrophosphatase (AVP1) enhanced both shoot and root growth, and augmented several energized processes like nutrient acquisition and stress responses. We propose that AVP1 localizes to the PM of phloem cells and uses PMF to synthesize PPi rather than hydrolyze it, and in doing so, maintains PPi levels for efficient Suc oxidation and ATP production. Enhanced ATP production in turn strengthens the PMF via plasma membrane (PM) ATPase, increasing phloem energization and phloem transport. Phloem-specific and constitutive AVP1 overexpressing lines showed increased growth and more efficiently moved carbohydrates to sink organs compared to WT. This suggested changes in metabolic flux but diagnostic metabolites of central metabolism did not show changes in steady state levels. This research focuses on fundamental aspects of carbon utilization and transport, and has a strong applied component, since increased H+-PPase activity enhances plant biomass, nutrient up-take capacities, and stress tolerance for as yet not fully characterized reasons
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High-throughput functional annotation of natural products by integrated activity profiling
Determining mechanism of action (MOA) is one of the biggest challenges in natural products discovery. Here, we report a comprehensive platform that uses Similarity Network Fusion (SNF) to improve MOA predictions by integrating data from the cytological profiling high-content imaging platform and the gene expression platform Functional Signature Ontology, and pairs these data with untargeted metabolomics analysis for de novo bioactive compound discovery. The predictive value of the integrative approach was assessed using a library of target-annotated small molecules as benchmarks. Using Kolmogorov-Smirnov (KS) tests to compare in-class to out-of-class similarity, we found that SNF retains the ability to identify significant in-class similarity across a diverse set of target classes, and could find target classes not detectable in either platform alone. This confirmed that integration of expression-based and image-based phenotypes can accurately report on MOA. Furthermore, we integrated untargeted metabolomics of complex natural product fractions with the SNF network to map biological signatures to specific metabolites. Three examples are presented where SNF coupled with metabolomics was used to directly functionally characterize natural products and accelerate identification of bioactive metabolites, including the discovery of the azoxy-containing biaryl compounds parkamycins A and B. Our results support SNF integration of multiple phenotypic screening approaches along with untargeted metabolomics as a powerful approach for advancing natural products drug discovery
Modulation of <i>in Vitro</i> SARS-CoV‑2 Infection by <i>Stephania tetrandra</i> and Its Alkaloid Constituents
Botanical natural products have been widely consumed
for their
purported usefulness against COVID-19. Here, six botanical species
from multiple sources and 173 isolated natural product compounds were
screened for blockade of wild-type (WT) SARS-CoV-2 infection in human
293T epithelial cells overexpressing ACE-2 and TMPRSS2 protease (293TAT).
Antiviral activity was demonstrated by an extract from Stephania
tetrandra. Extract fractionation, liquid chromatography–mass
spectrometry (LC-MS), antiviral assays, and computational analyses
revealed that the alkaloid fraction and purified alkaloids tetrandrine,
fangchinoline, and cepharanthine inhibited WT SARS-CoV-2 infection.
The alkaloids and alkaloid fraction also inhibited the delta variant
of concern but not WT SARS-CoV-2 in VeroAT cells. Membrane permeability
assays demonstrate that the alkaloids are biologically available,
although fangchinoline showed lower permeability than tetrandrine.
At high concentrations, the extract, alkaloid fractions, and pure
alkaloids induced phospholipidosis in 293TAT cells and less so in
VeroAT cells. Gene expression profiling during virus infection suggested
that alkaloid fraction and tetrandrine displayed similar effects on
cellular gene expression and pathways, while fangchinoline showed
distinct effects on cells. Our study demonstrates a multifaceted approach
to systematically investigate the diverse activities conferred by
complex botanical mixtures, their cell-context specificity, and their
pleiotropic effects on biological systems
Modulation of <i>in Vitro</i> SARS-CoV‑2 Infection by <i>Stephania tetrandra</i> and Its Alkaloid Constituents
Botanical natural products have been widely consumed
for their
purported usefulness against COVID-19. Here, six botanical species
from multiple sources and 173 isolated natural product compounds were
screened for blockade of wild-type (WT) SARS-CoV-2 infection in human
293T epithelial cells overexpressing ACE-2 and TMPRSS2 protease (293TAT).
Antiviral activity was demonstrated by an extract from Stephania
tetrandra. Extract fractionation, liquid chromatography–mass
spectrometry (LC-MS), antiviral assays, and computational analyses
revealed that the alkaloid fraction and purified alkaloids tetrandrine,
fangchinoline, and cepharanthine inhibited WT SARS-CoV-2 infection.
The alkaloids and alkaloid fraction also inhibited the delta variant
of concern but not WT SARS-CoV-2 in VeroAT cells. Membrane permeability
assays demonstrate that the alkaloids are biologically available,
although fangchinoline showed lower permeability than tetrandrine.
At high concentrations, the extract, alkaloid fractions, and pure
alkaloids induced phospholipidosis in 293TAT cells and less so in
VeroAT cells. Gene expression profiling during virus infection suggested
that alkaloid fraction and tetrandrine displayed similar effects on
cellular gene expression and pathways, while fangchinoline showed
distinct effects on cells. Our study demonstrates a multifaceted approach
to systematically investigate the diverse activities conferred by
complex botanical mixtures, their cell-context specificity, and their
pleiotropic effects on biological systems
Modulation of <i>in Vitro</i> SARS-CoV‑2 Infection by <i>Stephania tetrandra</i> and Its Alkaloid Constituents
Botanical natural products have been widely consumed
for their
purported usefulness against COVID-19. Here, six botanical species
from multiple sources and 173 isolated natural product compounds were
screened for blockade of wild-type (WT) SARS-CoV-2 infection in human
293T epithelial cells overexpressing ACE-2 and TMPRSS2 protease (293TAT).
Antiviral activity was demonstrated by an extract from Stephania
tetrandra. Extract fractionation, liquid chromatography–mass
spectrometry (LC-MS), antiviral assays, and computational analyses
revealed that the alkaloid fraction and purified alkaloids tetrandrine,
fangchinoline, and cepharanthine inhibited WT SARS-CoV-2 infection.
The alkaloids and alkaloid fraction also inhibited the delta variant
of concern but not WT SARS-CoV-2 in VeroAT cells. Membrane permeability
assays demonstrate that the alkaloids are biologically available,
although fangchinoline showed lower permeability than tetrandrine.
At high concentrations, the extract, alkaloid fractions, and pure
alkaloids induced phospholipidosis in 293TAT cells and less so in
VeroAT cells. Gene expression profiling during virus infection suggested
that alkaloid fraction and tetrandrine displayed similar effects on
cellular gene expression and pathways, while fangchinoline showed
distinct effects on cells. Our study demonstrates a multifaceted approach
to systematically investigate the diverse activities conferred by
complex botanical mixtures, their cell-context specificity, and their
pleiotropic effects on biological systems
Modulation of <i>in Vitro</i> SARS-CoV‑2 Infection by <i>Stephania tetrandra</i> and Its Alkaloid Constituents
Botanical natural products have been widely consumed
for their
purported usefulness against COVID-19. Here, six botanical species
from multiple sources and 173 isolated natural product compounds were
screened for blockade of wild-type (WT) SARS-CoV-2 infection in human
293T epithelial cells overexpressing ACE-2 and TMPRSS2 protease (293TAT).
Antiviral activity was demonstrated by an extract from Stephania
tetrandra. Extract fractionation, liquid chromatography–mass
spectrometry (LC-MS), antiviral assays, and computational analyses
revealed that the alkaloid fraction and purified alkaloids tetrandrine,
fangchinoline, and cepharanthine inhibited WT SARS-CoV-2 infection.
The alkaloids and alkaloid fraction also inhibited the delta variant
of concern but not WT SARS-CoV-2 in VeroAT cells. Membrane permeability
assays demonstrate that the alkaloids are biologically available,
although fangchinoline showed lower permeability than tetrandrine.
At high concentrations, the extract, alkaloid fractions, and pure
alkaloids induced phospholipidosis in 293TAT cells and less so in
VeroAT cells. Gene expression profiling during virus infection suggested
that alkaloid fraction and tetrandrine displayed similar effects on
cellular gene expression and pathways, while fangchinoline showed
distinct effects on cells. Our study demonstrates a multifaceted approach
to systematically investigate the diverse activities conferred by
complex botanical mixtures, their cell-context specificity, and their
pleiotropic effects on biological systems
The Natural Products Atlas - data download
Download files from the Natural Products Atlas (npatlas.org). van Santen, J. A.; Jacob, G.; Leen Singh, A.; Aniebok, V.; Balunas, M. J.; Bunsko, D.; Carnevale Neto, F.; Castaño-Espriu, L.; Chang, C.; Clark, T. N.; Cleary Little, J. L.; Delgadillo, D. A.; Dorrestein, P. C.; Duncan, K. R.; Egan, J. M.; Galey, M. M.; Haeckl, F. P. J.; Hua, A.; Hughes, A. H.; Iskakova, D.; Khadilkar, A.; Lee, J.-H.; Lee, S.; LeGrow, N.; Liu, D. Y.; Macho, J. M.; McCaughey, C. S.; Medema, M. H.; Neupane, R. P.; O’Donnell, T. J.; Paula, J. S.; Sanchez, L. M.; Shaikh, A. F.; Soldatou, S.; Terlouw, B. R.; Tran, T. A.; Valentine, M.; van der Hooft, J. J. J.; Vo, D. A.; Wang, M.; Wilson, D.; Zink, K. E.; Linington, R. G.* "The Natural Products Atlas: An Open Access Knowledge Base for Microbial Natural Products Discovery”, ACS Central Science, 2019, 5, 11, 1824-1833. 10.1021/acscentsci.9b00806 Now includes ontological data from: NP Classifier - https://npclassifier.ucsd.edu/ ClassyFire - http://classyfire.wishartlab.com/ Including archived versions, extra data download types, and new MIBiG and GNPS IDs Includes dump of compounds deemed out of scope and removed from DB on May 19, 2021. The latest versions (v2021_08 onward) include the ontological data in the full JSON download
The Natural Products Atlas - data download
Download files from the Natural Products Atlas (npatlas.org). van Santen, J. A.; Jacob, G.; Leen Singh, A.; Aniebok, V.; Balunas, M. J.; Bunsko, D.; Carnevale Neto, F.; Castaño-Espriu, L.; Chang, C.; Clark, T. N.; Cleary Little, J. L.; Delgadillo, D. A.; Dorrestein, P. C.; Duncan, K. R.; Egan, J. M.; Galey, M. M.; Haeckl, F. P. J.; Hua, A.; Hughes, A. H.; Iskakova, D.; Khadilkar, A.; Lee, J.-H.; Lee, S.; LeGrow, N.; Liu, D. Y.; Macho, J. M.; McCaughey, C. S.; Medema, M. H.; Neupane, R. P.; O’Donnell, T. J.; Paula, J. S.; Sanchez, L. M.; Shaikh, A. F.; Soldatou, S.; Terlouw, B. R.; Tran, T. A.; Valentine, M.; van der Hooft, J. J. J.; Vo, D. A.; Wang, M.; Wilson, D.; Zink, K. E.; Linington, R. G.* "The Natural Products Atlas: An Open Access Knowledge Base for Microbial Natural Products Discovery”, ACS Central Science, 2019, 5, 11, 1824-1833. 10.1021/acscentsci.9b00806 Now includes ontological data from: NP Classifier - https://npclassifier.ucsd.edu/ ClassyFire - http://classyfire.wishartlab.com/ Including archived versions, extra data download types, and new MIBiG and GNPS IDs Includes dump of compounds deemed out of scope and removed from DB on May 19, 2021. The latest versions (v2021_08 onward) include the ontological data in the full JSON download