scholarly journals Metabolic disassembler for understanding and predicting the biosynthetic units of natural products

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Kohei Amano ◽  
Tsubasa Matsumoto ◽  
Kenichi Tanaka ◽  
Kimito Funatsu ◽  
Masaaki Kotera
Keyword(s):  
Natural Products ◽  
Kegg Pathway ◽  
Functional Materials ◽  
Computational Time ◽  
Biosynthetic Pathways ◽  
Target Molecule ◽  
Kegg Pathway Database ◽  
Chemical Structures ◽  
Calculation Results ◽  
Synthetic Biology Approach

Abstract Background Natural products are the source of various functional materials such as medicines, and understanding their biosynthetic pathways can provide information that is helpful for their effective production through the synthetic biology approach. A number of studies have aimed to predict biosynthetic pathways from their chemical structures in a retrosynthesis manner; however, sometimes the calculation finishes without reaching the starting material from the target molecule. In order to address this problem, the method to find suitable starting materials is required. Results In this study, we developed a predictive workflow named the Metabolic Disassembler that automatically disassembles the target molecule structure into relevant biosynthetic units (BUs), which are the substructures that correspond to the starting materials in the biosynthesis pathway. This workflow uses a biosynthetic unit library (BUL), which contains starting materials, key intermediates, and their derivatives. We obtained the starting materials from the KEGG PATHWAY database, and 765 BUs were registered in the BUL. We then examined the proposed workflow to optimize the combination of the BUs. To evaluate the performance of the proposed Metabolic Disassembler workflow, we used 943 molecules that are included in the secondary metabolism maps of KEGG PATHWAY. About 95.8% of them (903 molecules) were correctly disassembled by our proposed workflow. For comparison, we also implemented a genetic algorithm-based workflow, and found that the accuracy was only about 52.0%. In addition, for 90.7% of molecules, our workflow finished the calculation within one minute. Conclusions The Metabolic Disassembler enabled the effective disassembly of natural products in terms of both correctness and computational time. It also outputs automatically highlighted color-coded substructures corresponding to the BUs to help users understand the calculation results. The users do not have to specify starting molecules in advance, and can input any target molecule, even if it is not in databases. Our workflow will be very useful for understanding and predicting the biosynthesis of natural products.

scholarly journals Mining of Cyanobacterial Genomes Indicates That Plasmids Are Involved in the Production of Natural Products

2020 ◽  
Author(s):  
Rafael Popin ◽  
Danillo Alvarenga ◽  
Raquel Castelo-Branco ◽  
David Fewer ◽  
Kaarina Sivonen
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Biological Activities ◽  
Gene Clusters ◽  
Biosynthetic Pathways ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Chemical Structures ◽  
Wide Range ◽  
Genes Encoding

Abstract Background Microbial natural products have unique chemical structures and diverse biological activities. Cyanobacteria commonly possess a wide range of biosynthetic gene clusters to produce natural products. Several studies have mapped the distribution of natural product biosynthetic gene clusters in cyanobacterial genomes. However, little attention has been paid to natural product biosynthesis in plasmids. Some genes encoding cyanobacterial natural product biosynthetic pathways are believed to be dispersed by plasmids through horizontal gene transfer. Thus, we examined complete cyanobacterial genomes to assess if plasmids are involved in the production and dissemination of natural products by cyanobacteria.Results The 185 analyzed genomes possessed 1 to 42 gene clusters and an average of 10. In total, 1816 biosynthetic gene clusters were found. Approximately 95% of these clusters were present in chromosomes. The remaining 5% were present in plasmids, from which homologs of the biosynthetic pathways for aeruginosin, anabaenopeptin, ambiguine, cryptophycin, hassallidin, geosmin, and microcystin were manually curated. The cryptophycin pathway was previously described as active while the other gene cluster include all genes for biosynthesis. Approximately 12% of the 424 analyzed cyanobacterial plasmids contained homologs of genes involved in conjugation. Large plasmids, previously named as “chromids”, were also observed to be widespread in cyanobacteria. Sixteen cryptic natural product biosynthetic gene clusters and geosmin biosynthetic gene clusters were located in those mobile plasmids.Conclusion Homologues of genes involved in the production of toxins, protease inhibitors, odorous compounds, antimicrobials, antitumorals, and other unidentified natural products are located in cyanobacterial plasmids. Some of these plasmids are predicted to be conjugative. The present study provides in silico evidence that plasmids are involved in the distribution of natural product biosynthetic pathways in cyanobacteria.

Unzipping Natural Products: Improved Natural Product Structure Predictions by Ensemble Modeling and Fingerprint Matching

2018 ◽  
Author(s):  
William A. Shirley ◽  
Brian P. Kelley ◽  
Yohann Potier ◽  
John H. Koschwanez ◽  
Robert Bruccoleri ◽  
...  
Keyword(s):  
Natural Products ◽  
Open Source ◽  
Natural Product ◽  
Gene Cluster ◽  
Public Domain ◽  
Product Structure ◽  
Fingerprint Matching ◽  
Ensemble Modeling ◽  
Chemical Structures ◽  
Source Gene

This pre-print explores ensemble modeling of natural product targets to match chemical structures to precursors found in large open-source gene cluster repository antiSMASH. Commentary on method, effectiveness, and limitations are enclosed. All structures are public domain molecules and have been reviewed for release.

Novel Phytochemical Constituents and their Potential to Manage Diabetes

2020 ◽  
Vol 26 ◽  
Author(s):  
Shaik Ibrahim Khalivulla ◽  
Arifullah Mohammed ◽  
Kokkanti Mallikarjuna
Keyword(s):  
Natural Products ◽  
Large Population ◽  
World Health ◽  
In Vivo Studies ◽  
Antidiabetic Activity ◽  
Therapeutic Drug ◽  
Pharmacological Activities ◽  
Chemical Structures

Background: Diabetes is a chronic disease affecting a large population worldwide and stands as one of the major global health challenges to be tackled. According to World Health Organization, about 400 million are having diabetes worldwide and it is the seventh leading cause of deaths in 2016. Plant based natural products had been in use from ancient time as ethnomedicine for the treatment of several diseases including diabetes. As a result of that, there are several reports on plant based natural products displaying antidiabetic activity. In the current review, such antidiabetic potential compounds reported from all plant sources along with their chemical structures are collected, presented and discussed. This kind of reports are essential to pool the available information to one source followed by statistical analysis and screening to check the efficacy of all known compounds in a comparative sense. This kind of analysis can give rise to few numbers of potential compounds from hundreds, whom can further be screened through in vitro and in vivo studies, and human trails leading to the drug development. Methods: Phytochemicals along with their potential antidiabetic property were classified according to their basic chemical skeleton. The chemical structures of all the compounds with antidiabetic activities were elucidated in the present review. In addition to this, the distribution and their other remarkable pharmacological activities of each species is also included. Results: The scrutiny of literature led to identification of 44 plants with antidiabetic compounds (70) and other pharmacological activities. For the sake of information, the distribution of each species in the world is given. Many plant derivatives may exert antidiabetic properties by improving or mimicking the insulin production or action. Different classes of compounds including sulfur compounds (1-4), alkaloids (5-11), phenolic compounds (12-17), tannins (18-23), phenylpropanoids (24-27), xanthanoids (28-31), amino acid (32), stilbenoid (33), benzofuran (34), coumarin (35), flavonoids (36-49) and terpenoids (50-70) were found to be active potential compounds for antidiabetic activity. Of the 70 listed compounds, majorly 17 compounds are from triterpenoids, 13 flavonoids and 7 are from alkaloids. Among all the 44 plant species, maximum number (7) of compounds are reported from Lagerstroemia speciosa followed by Momordica charantia (6) and S. oblonga with 5 compounds. Conclusion: This is the first paper to summarize the established chemical structures of phytochemicals that have been successfully screened for antidiabetic potential and their mechanisms of inhibition. The reported compounds could be considered as potential lead molecules for the treatment of type-2 diabetes. Further, molecular and clinical trials are required to select and establish the therapeutic drug candidates.

The Natural Products as Hydroxymethylglutaryl-Coa Reductase Inhibitors

2019 ◽  
Vol 16 (10) ◽  
pp. 1130-1137
Author(s):  
Hayrettin Ozan Gulcan ◽  
Serkan Yigitkan ◽  
Ilkay Erdogan Orhan
Keyword(s):  
Natural Products ◽  
Cardiovascular System ◽  
High Cholesterol ◽  
Chemical Structures ◽  
Reductase Inhibitors ◽  
Key Enzyme ◽  
Serious Disease ◽  
Coa Reductase ◽  
Hydroxymethylglutaryl Coa Reductase ◽  
Alternative Drugs

High cholesterol and triglyceride levels are mainly related to further generation of lifethreating metabolism disorders including cardiovascular system diseases. Therefore, hypercholesterolemia (i.e., also referred to as hyperlipoproteinemia) is a serious disease state, which must be controlled. Currently, the treatment of hypercholesterolemia is mainly achieved through the employment of statins in the clinic, although there are alternative drugs (e.g., ezetimibe, cholestyramine). In fact, the original statins are natural products directly obtained from fungi-like molds and mushrooms and they are potent inhibitors of hydroxymethylglutaryl-CoA reductase, the key enzyme in the biosynthesis of cholesterol. This review focuses on the first identification of natural statins, their synthetic and semi-synthetic analogues, and the validation of hydroxymethylglutaryl-CoA reductase as a target in the treatment of hypercholesterolemia. Furthermore, other natural products that have been shown to possess the potential to inhibit hydroxymethylglutaryl-CoA reductase are also reviewed with respect to their chemical structures.

scholarly journals Diverse Taxonomies for Diverse Chemistries: Enhanced Representation of Natural Product Metabolism in UniProtKB

Metabolites ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 48
Author(s):  
Marc Feuermann ◽  
Emmanuel Boutet ◽  
Anne Morgat ◽  
Kristian Axelsen ◽  
Parit Bansal ◽  
...  
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Semantic Web Technologies ◽  
Knowledge Resources ◽  
Web Technologies ◽  
Chemical Structures ◽  
Biological Interest ◽  
Catalyzed Reactions ◽  
Enzyme Catalyzed Reactions ◽  
Practical Demonstration

The UniProt Knowledgebase UniProtKB is a comprehensive, high-quality, and freely accessible resource of protein sequences and functional annotation that covers genomes and proteomes from tens of thousands of taxa, including a broad range of plants and microorganisms producing natural products of medical, nutritional, and agronomical interest. Here we describe work that enhances the utility of UniProtKB as a support for both the study of natural products and for their discovery. The foundation of this work is an improved representation of natural product metabolism in UniProtKB using Rhea, an expert-curated knowledgebase of biochemical reactions, that is built on the ChEBI (Chemical Entities of Biological Interest) ontology of small molecules. Knowledge of natural products and precursors is captured in ChEBI, enzyme-catalyzed reactions in Rhea, and enzymes in UniProtKB/Swiss-Prot, thereby linking chemical structure data directly to protein knowledge. We provide a practical demonstration of how users can search UniProtKB for protein knowledge relevant to natural products through interactive or programmatic queries using metabolite names and synonyms, chemical identifiers, chemical classes, and chemical structures and show how to federate UniProtKB with other data and knowledge resources and tools using semantic web technologies such as RDF and SPARQL. All UniProtKB data are freely available for download in a broad range of formats for users to further mine or exploit as an annotation source, to enrich other natural product datasets and databases.

An enumeration of natural products from microbial, marine and terrestrial sources

2020 ◽  
Vol 5 (8) ◽  
Author(s):  
Fidele Ntie-Kang ◽  
Daniel Svozil
Keyword(s):  
Amino Acids ◽  
Natural Products ◽  
Biologically Active ◽  
Lead Compound ◽  
Chemical Databases ◽  
Natural Sources ◽  
Chemical Structures ◽  
Chemically Modified ◽  
Marine Habitats ◽  
Metabolic Properties

AbstractThe discovery of a new drug is a multidisciplinary and very costly task. One of the major steps is the identification of a lead compound, i.e. a compound with a certain degree of potency and that can be chemically modified to improve its activity, metabolic properties, and pharmacokinetics profiles. Terrestrial sources (plants and fungi), microbes and marine organisms are abundant resources for the discovery of new structurally diverse and biologically active compounds. In this chapter, an attempt has been made to quantify the numbers of known published chemical structures (available in chemical databases) from natural sources. Emphasis has been laid on the number of unique compounds, the most abundant compound classes and the distribution of compounds in terrestrial and marine habitats. It was observed, from the recent investigations, that ~500,000 known natural products (NPs) exist in the literature. About 70 % of all NPs come from plants, terpenoids being the most represented compound class (except in bacteria, where amino acids, peptides, and polyketides are the most abundant compound classes). About 2,000 NPs have been co-crystallized in PDB structures.

scholarly journals Analysis of a large food chemical database: chemical space, diversity, and complexity

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 993 ◽  
Author(s):  
J. Jesús Naveja ◽  
Mariel P. Rico-Hidalgo ◽  
José L. Medina-Franco
Keyword(s):  
Natural Products ◽  
Chemical Space ◽  
Structural Complexity ◽  
Chemical Diversity ◽  
Chemical Structures ◽  
Novel Approach ◽  
Chemical Database ◽  
Protein Interactome ◽  
Limited Basis ◽  
Future Direction

Background: Food chemicals are a cornerstone in the food industry. However, its chemical diversity has been explored on a limited basis, for instance, previous analysis of food-related databases were done up to 2,200 molecules. The goal of this work was to quantify the chemical diversity of chemical compounds stored in FooDB, a database with nearly 24,000 food chemicals. Methods: The visual representation of the chemical space of FooDB was done with ChemMaps, a novel approach based on the concept of chemical satellites. The large food chemical database was profiled based on physicochemical properties, molecular complexity and scaffold content. The global diversity of FooDB was characterized using Consensus Diversity Plots. Results: It was found that compounds in FooDB are very diverse in terms of properties and structure, with a large structural complexity. It was also found that one third of the food chemicals are acyclic molecules and ring-containing molecules are mostly monocyclic, with several scaffolds common to natural products in other databases. Conclusions: To the best of our knowledge, this is the first analysis of the chemical diversity and complexity of FooDB. This study represents a step further to the emerging field of “Food Informatics”. Future study should compare directly the chemical structures of the molecules in FooDB with other compound databases, for instance, drug-like databases and natural products collections. An additional future direction of this work is to use the list of 3,228 polyphenolic compounds identified in this work to enhance the on-going polyphenol-protein interactome studies.

scholarly journals Advances in Phenazines over the Past Decade: Review of Their Pharmacological Activities, Mechanisms of Action, Biosynthetic Pathways and Synthetic Strategies

Marine Drugs ◽  
2021 ◽  
Vol 19 (11) ◽  
pp. 610
Author(s):  
Junjie Yan ◽  
Weiwei Liu ◽  
Jiatong Cai ◽  
Yiming Wang ◽  
Dahong Li ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Pharmacological Activity ◽  
Biological Activities ◽  
Natural Compounds ◽  
Mechanisms Of Action ◽  
Biosynthetic Pathways ◽  
Pharmacological Activities ◽  
Chemical Structures ◽  
The Past ◽  
Synthetic Derivatives

Phenazines are a large group of nitrogen-containing heterocycles, providing diverse chemical structures and various biological activities. Natural phenazines are mainly isolated from marine and terrestrial microorganisms. So far, more than 100 different natural compounds and over 6000 synthetic derivatives have been found and investigated. Many phenazines show great pharmacological activity in various fields, such as antimicrobial, antiparasitic, neuroprotective, insecticidal, anti-inflammatory and anticancer activity. Researchers continued to investigate these compounds and hope to develop them as medicines. Cimmino et al. published a significant review about anticancer activity of phenazines, containing articles from 2000 to 2011. Here, we mainly summarize articles from 2012 to 2021. According to sources of compounds, phenazines were categorized into natural phenazines and synthetic phenazine derivatives in this review. Their pharmacological activities, mechanisms of action, biosynthetic pathways and synthetic strategies were summarized. These may provide guidance for the investigation on phenazines in the future.

scholarly journals Discovery and Biosynthesis of Natural Products from New Zealand Soil Metagenome Libraries

2021 ◽  
Author(s):  
◽  
Luke Stevenson
Keyword(s):  
Natural Products ◽  
New Zealand ◽  
Heterologous Expression ◽  
Gene Clusters ◽  
Bioinformatic Analysis ◽  
Coli Strain ◽  
Functional Screening ◽  
Functional Difference ◽  
Biosynthetic Pathways ◽  
New Members

<p>Antibiotic discovery rates dramatically declined following the “golden age” of the 1940’s to the 1960’s. The platforms that underpinned that age of discovery rested upon laboratory cultivation of a small clade of bacteria, the actinomycetes, primarily isolated from soil environments. Fermentation extracts of these isolated bacteria have provided the majority of antibiotics and anticancer small molecules still used today. By applying modern genetic analysis techniques to these same environmental sources that have previously yielded such success, we can uncover new biosynthetic pathways, and bioactive compounds. The work described in this thesis investigated New Zealand soil metagenomes for this purpose.  Four large metagenome libraries were constructed from the microbiomes of diverse soil environments. These were then interrogated by a functional screening approach in a knockout Escherichia coli strain, to recover a large collection of the biosynthetic gene clusters responsible for bacterial secondary metabolite production. Using different modes of bioinformatic analysis, these gene clusters were demonstrated to have both phylogenetic divergence, and functional difference from bacterial biosynthesis pathways previously discovered from culture based studies.  Two additional biosynthetic pathways were recovered from one of these metagenome libraries, and in each case found to have novel genetic features. These gene clusters were further studied by heterologous expression within Streptomyces albus production hosts. One of these gene clusters produced small aromatic polyketide compounds, the structure of one of which was solved by chemical analytic techniques, and found to be a new chemical entity.  The second gene cluster was demonstrated to have similarity to known aureolic acid biosynthesis gene clusters – a class of potent anticancer natural products. Heterologous expression resulted in the production of many metabolites, two of which were characterised and found to be new members of this chemical class.  The research in this thesis both validates the use of metagenomic analysis for future natural product discovery efforts, and adds to a growing body of evidence that understudied clades of bacteria have an untapped biosynthetic potential that can be accessed by metagenomic methods.</p>

Functionalization of Cellulose Paper by Coating Nano Metal-Organic Frameworks for Use as Photochromic Material

2021 ◽  
Vol 43 (1) ◽  
pp. 67-67
Author(s):  
Qiang Yang Qiang Yang ◽  
Wei Gong Wei Gong ◽  
Xiaowei Cui Xiaowei Cui ◽  
Chunsheng Zhou Chunsheng Zhou
Keyword(s):  
Functional Materials ◽  
Photochromic Properties ◽  
Coated Paper ◽  
Cellulose Paper ◽  
Chemical Structures ◽  
Coating Method ◽  
Potential Applications ◽  
Metal Organic ◽  
Light Green ◽  
Photochromic Reaction

The cellulose paper-based functional materials modified by Zn-NDI and Cu-NDI were prepared by the coating method. The chemical structures were characterized by FTIR, XRD, UV-vis and SEM, and the photochromic properties of the composite functional materials were studied. The results showed that Zn-NDI and Cu-NDI were successfully prepared and retained on the surface of copy paper, the wavelength of photochromic reaction is between 300-400 nm of MOFs materials. Optical analysis confirmed that the NDI/paper, Zn-NDI/paper and Cu-NDI/paper changed from tan to wheat, light green to olive, and dark tan to brown after 60 seconds of exposure to hernia light irradiations, the MOFs coated paper returned to its original color when it was placed in the dark for 4 hours. The above results indicated that the prepared Zn-NDI and Cu-NDI coated paper composites exhibited excellent photochromic ability and had potential applications in the field of anti-counterfeiting packaging materials.

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