scholarly journals Applying a Chemogeographic Strategy for Natural Product Discovery from the Marine Cyanobacterium Moorena bouillonii

Marine Drugs ◽  
2020 ◽  
Vol 18 (10) ◽  
pp. 515
Author(s):  
Christopher A. Leber ◽  
C. Benjamin Naman ◽  
Lena Keller ◽  
Jehad Almaliti ◽  
Eduardo J. E. Caro-Diaz ◽  
...  
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Feature Detection ◽  
Polyketide Synthase ◽  
Biologically Active ◽  
Combinatorial Biosynthesis ◽  
Marine Cyanobacterium ◽  
Natural Product Discovery ◽  
Fragmentation Patterns

The tropical marine cyanobacterium Moorena bouillonii occupies a large geographic range across the Indian and Western Tropical Pacific Oceans and is a prolific producer of structurally unique and biologically active natural products. An ensemble of computational approaches, including the creation of the ORCA (Objective Relational Comparative Analysis) pipeline for flexible MS1 feature detection and multivariate analyses, were used to analyze various M. bouillonii samples. The observed chemogeographic patterns suggested the production of regionally specific natural products by M. bouillonii. Analyzing the drivers of these chemogeographic patterns allowed for the identification, targeted isolation, and structure elucidation of a regionally specific natural product, doscadenamide A (1). Analyses of MS2 fragmentation patterns further revealed this natural product to be part of an extensive family of herein annotated, proposed natural structural analogs (doscadenamides B–J, 2–10); the ensemble of structures reflect a combinatorial biosynthesis using nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) components. Compound 1 displayed synergistic in vitro cancer cell cytotoxicity when administered with lipopolysaccharide (LPS). These discoveries illustrate the utility in leveraging chemogeographic patterns for prioritizing natural product discovery efforts.

scholarly journals Expanding the Fluorine Chemistry of Living Systems Using Engineered Polyketide Synthase Pathways

Science ◽  
2013 ◽  
Vol 341 (6150) ◽  
pp. 1089-1094 ◽  
Author(s):  
Mark C. Walker ◽  
Benjamin W. Thuronyi ◽  
Louise K. Charkoudian ◽  
Brian Lowry ◽  
Chaitan Khosla ◽  
...  
Keyword(s):  
Natural Products ◽  
Synthetic Biology ◽  
Natural Product ◽  
Polyketide Synthase ◽  
Building Blocks ◽  
Living Systems ◽  
Synthetic Compounds ◽  
Fluorinated Building Blocks

Organofluorines represent a rapidly expanding proportion of molecules that are used in pharmaceuticals, diagnostics, agrochemicals, and materials. Despite the prevalence of fluorine in synthetic compounds, the known biological scope is limited to a single pathway that produces fluoroacetate. Here, we demonstrate that this pathway can be exploited as a source of fluorinated building blocks for introduction of fluorine into natural-product scaffolds. Specifically, we have constructed pathways involving two polyketide synthase systems, and we show that fluoroacetate can be used to incorporate fluorine into the polyketide backbone in vitro. We further show that fluorine can be inserted site-selectively and introduced into polyketide products in vivo. These results highlight the prospects for the production of complex fluorinated natural products using synthetic biology.

scholarly journals Discovery of the leinamycin family of natural products by mining actinobacterial genomes

2017 ◽  
Vol 114 (52) ◽  
pp. E11131-E11140 ◽  
Author(s):  
Guohui Pan ◽  
Zhengren Xu ◽  
Zhikai Guo ◽  
Hindra ◽  
Ming Ma ◽  
...  
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Structural Diversity ◽  
Building Blocks ◽  
Combinatorial Biosynthesis ◽  
Pathway Engineering ◽  
Natural Product Discovery ◽  
Knowledge Based ◽  
Metabolic Pathway Engineering ◽  
Strain Collection

Nature’s ability to generate diverse natural products from simple building blocks has inspired combinatorial biosynthesis. The knowledge-based approach to combinatorial biosynthesis has allowed the production of designer analogs by rational metabolic pathway engineering. While successful, structural alterations are limited, with designer analogs often produced in compromised titers. The discovery-based approach to combinatorial biosynthesis complements the knowledge-based approach by exploring the vast combinatorial biosynthesis repertoire found in Nature. Here we showcase the discovery-based approach to combinatorial biosynthesis by targeting the domain of unknown function and cysteine lyase domain (DUF–SH) didomain, specific for sulfur incorporation from the leinamycin (LNM) biosynthetic machinery, to discover the LNM family of natural products. By mining bacterial genomes from public databases and the actinomycetes strain collection at The Scripps Research Institute, we discovered 49 potential producers that could be grouped into 18 distinct clades based on phylogenetic analysis of the DUF–SH didomains. Further analysis of the representative genomes from each of the clades identified 28 lnm-type gene clusters. Structural diversities encoded by the LNM-type biosynthetic machineries were predicted based on bioinformatics and confirmed by in vitro characterization of selected adenylation proteins and isolation and structural elucidation of the guangnanmycins and weishanmycins. These findings demonstrate the power of the discovery-based approach to combinatorial biosynthesis for natural product discovery and structural diversity and highlight Nature’s rich biosynthetic repertoire. Comparative analysis of the LNM-type biosynthetic machineries provides outstanding opportunities to dissect Nature’s biosynthetic strategies and apply these findings to combinatorial biosynthesis for natural product discovery and structural diversity.

scholarly journals Accessing Nature’s diversity through metabolic engineering and synthetic biology

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 397 ◽  
Author(s):  
Jason R. King ◽  
Steven Edgar ◽  
Kangjian Qiao ◽  
Gregory Stephanopoulos
Keyword(s):  
Natural Products ◽  
Metabolic Engineering ◽  
Synthetic Biology ◽  
Natural Product ◽  
Chemical Space ◽  
Single Step ◽  
Enzyme Engineering ◽  
Biologically Active ◽  
Combinatorial Biosynthesis ◽  
Pathway Engineering

In this perspective, we highlight recent examples and trends in metabolic engineering and synthetic biology that demonstrate the synthetic potential of enzyme and pathway engineering for natural product discovery. In doing so, we introduce natural paradigms of secondary metabolism whereby simple carbon substrates are combined into complex molecules through “scaffold diversification”, and subsequent “derivatization” of these scaffolds is used to synthesize distinct complex natural products. We provide examples in which modern pathway engineering efforts including combinatorial biosynthesis and biological retrosynthesis can be coupled to directed enzyme evolution and rational enzyme engineering to allow access to the “privileged” chemical space of natural products in industry-proven microbes. Finally, we forecast the potential to produce natural product-like discovery platforms in biological systems that are amenable to single-step discovery, validation, and synthesis for streamlined discovery and production of biologically active agents.

Recent Progress Towards Synthesis of the Indolizidine Alkaloid 195B

2020 ◽  
Vol 17 (2) ◽  
pp. 82-90 ◽  
Author(s):  
Ghodsi Mohammadi Ziarani ◽  
Fatemeh Mohajer ◽  
Zohreh kheilkordi
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Recent Progress ◽  
Human Life ◽  
Natural Compounds ◽  
Biologically Active ◽  
Pharmaceutical Chemistry ◽  
Biological Perspective ◽  
Highly Active

Background: Natural products have been received attention due to their importance in human life as those are biologically active. In this review, there are some reports through different methods related to the synthesis of the indolizidine 195B which was extracted from poisonous frog; however, due to respect nature, the synthesis of natural compounds such as indolizidine has been attracted much attention among scientists and researchers. Objective: This review discloses the procedures and methods to provide indolizidine 195B from 1989 to 2018 due to their importance as a natural product. Conclusion: There are several methods to give rise to the indolizidine 195B as a natural product that is highly active from the biological perspective in pharmaceutical chemistry. In summary, many protocols for the preparations of indolizidine 195B from various substrates, several reagents, and conditions have been reported from different aromatic and aliphatic.

scholarly journals The Tripod for Bacterial Natural Product Discovery: Genome Mining, Silent Pathway Induction, and Mass Spectrometry-Based Molecular Networking

mSystems ◽  
2018 ◽  
Vol 3 (2) ◽  
Author(s):  
Daniela B. B. Trivella ◽  
Rafael de Felicio
Keyword(s):  
Mass Spectrometry ◽  
Natural Products ◽  
Natural Product ◽  
Biosynthetic Pathway ◽  
Genome Mining ◽  
Chemical Compounds ◽  
Gene Clusters ◽  
Tandem Mass ◽  
Molecular Networking ◽  
Natural Product Discovery

ABSTRACT Natural products are the richest source of chemical compounds for drug discovery. Particularly, bacterial secondary metabolites are in the spotlight due to advances in genome sequencing and mining, as well as for the potential of biosynthetic pathway manipulation to awake silent (cryptic) gene clusters under laboratory cultivation. Further progress in compound detection, such as the development of the tandem mass spectrometry (MS/MS) molecular networking approach, has contributed to the discovery of novel bacterial natural products. The latter can be applied directly to bacterial crude extracts for identifying and dereplicating known compounds, therefore assisting the prioritization of extracts containing novel natural products, for example. In our opinion, these three approaches—genome mining, silent pathway induction, and MS-based molecular networking—compose the tripod for modern bacterial natural product discovery and will be discussed in this perspective.

scholarly journals Regulation of Antimycin Biosynthesis Is Controlled by the ClpXP Protease

mSphere ◽  
2020 ◽  
Vol 5 (2) ◽  
Author(s):  
Bohdan Bilyk ◽  
Sora Kim ◽  
Asif Fazal ◽  
Tania A. Baker ◽  
Ryan F. Seipke
Keyword(s):  
Natural Products ◽  
Rna Polymerase ◽  
Natural Product ◽  
Morphological Differentiation ◽  
Dynamic Responses ◽  
Biosynthetic Pathways ◽  
Recognition Sequence ◽  
Σ Factor

ABSTRACT The survival of any microbe relies on its ability to respond to environmental change. Use of extracytoplasmic function (ECF) RNA polymerase sigma (σ) factors is a major strategy enabling dynamic responses to extracellular signals. Streptomyces species harbor a large number of ECF σ factors, nearly all of which are uncharacterized, but those that have been characterized generally regulate genes required for morphological differentiation and/or response to environmental stress, except for σAntA, which regulates starter-unit biosynthesis in the production of antimycin, an anticancer compound. Unlike a canonical ECF σ factor, whose activity is regulated by a cognate anti-σ factor, σAntA is an orphan, raising intriguing questions about how its activity may be controlled. Here, we reconstituted in vitro ClpXP proteolysis of σAntA but not of a variant lacking a C-terminal di-alanine motif. Furthermore, we show that the abundance of σAntA in vivo was enhanced by removal of the ClpXP recognition sequence and that levels of the protein rose when cellular ClpXP protease activity was abolished. These data establish direct proteolysis as an alternative and, thus far, unique control strategy for an ECF RNA polymerase σ factor and expands the paradigmatic understanding of microbial signal transduction regulation. IMPORTANCE Natural products produced by Streptomyces species underpin many industrially and medically important compounds. However, the majority of the ∼30 biosynthetic pathways harbored by an average species are not expressed in the laboratory. This unrevealed biochemical diversity is believed to comprise an untapped resource for natural product drug discovery. Major roadblocks preventing the exploitation of unexpressed biosynthetic pathways are a lack of insight into their regulation and limited technology for activating their expression. Our findings reveal that the abundance of σAntA, which is the cluster-situated regulator of antimycin biosynthesis, is controlled by the ClpXP protease. These data link proteolysis to the regulation of natural product biosynthesis for the first time to our knowledge, and we anticipate that this will emerge as a major strategy by which actinobacteria regulate production of their natural products. Further study of this process will advance understanding of how expression of secondary metabolism is controlled and will aid pursuit of activating unexpressed biosynthetic pathways.

Applied evolution: phylogeny-based approaches in natural products research

2019 ◽  
Vol 36 (9) ◽  
pp. 1295-1312 ◽  
Author(s):  
Martina Adamek ◽  
Mohammad Alanjary ◽  
Nadine Ziemert
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Structure Elucidation ◽  
Phylogenetic Analyses ◽  
Natural Product Discovery

Here we highlight how phylogenetic analyses can be used to facilitate natural product discovery and structure elucidation.

scholarly journals Natural product biosyntheses in cyanobacteria: A treasure trove of unique enzymes

2011 ◽  
Vol 7 ◽  
pp. 1622-1635 ◽  
Author(s):  
Jan-Christoph Kehr ◽  
Douglas Gatte Picchi ◽  
Elke Dittmann
Keyword(s):  
Natural Products ◽  
Synthetic Biology ◽  
Natural Product ◽  
Bioactive Compounds ◽  
Polyketide Synthase ◽  
Biosynthetic Pathways ◽  
Peptide Synthetase ◽  
Biochemical Studies ◽  
Terrestrial Habitats ◽  
The Individual

Cyanobacteria are prolific producers of natural products. Investigations into the biochemistry responsible for the formation of these compounds have revealed fascinating mechanisms that are not, or only rarely, found in other microorganisms. In this article, we survey the biosynthetic pathways of cyanobacteria isolated from freshwater, marine and terrestrial habitats. We especially emphasize modular nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) pathways and highlight the unique enzyme mechanisms that were elucidated or can be anticipated for the individual products. We further include ribosomal natural products and UV-absorbing pigments from cyanobacteria. Mechanistic insights obtained from the biochemical studies of cyanobacterial pathways can inspire the development of concepts for the design of bioactive compounds by synthetic-biology approaches in the future.

scholarly journals Antibiofilm Potential of Medicinal Plants against Candida spp. Oral Biofilms: A Review

Antibiotics ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 1142
Author(s):  
Rafaela Guimarães ◽  
Catarina Milho ◽  
Ângela Liberal ◽  
Jani Silva ◽  
Carmélia Fonseca ◽  
...  
Keyword(s):  
Natural Products ◽  
Medicinal Plants ◽  
Oral Cavity ◽  
Plant Extracts ◽  
Fungal Infections ◽  
High Capacity ◽  
Biologically Active ◽  
Antibiofilm Activity ◽  
Candida Spp

The use of natural products to promote health is as old as human civilization. In recent years, the perception of natural products derived from plants as abundant sources of biologically active compounds has driven their exploitation towards the search for new chemical products that can lead to further pharmaceutical formulations. Candida fungi, being opportunistic pathogens, increase their virulence by acquiring resistance to conventional antimicrobials, triggering diseases, especially in immunosuppressed hosts. They are also pointed to as the main pathogens responsible for most fungal infections of the oral cavity. This increased resistance to conventional synthetic antimicrobials has driven the search for new molecules present in plant extracts, which have been widely explored as alternative agents in the prevention and treatment of infections. This review aims to provide a critical view and scope of the in vitro antimicrobial and antibiofilm activity of several medicinal plants, revealing species with inhibition/reduction effects on the biofilm formed by Candida spp. in the oral cavity. The most promising plant extracts in fighting oral biofilm, given their high capacity to reduce it to low concentrations were the essential oils extracted from Allium sativum L., Cinnamomum zeylanicum Blume. and Cymbopogon citratus (DC) Stapf.

scholarly journals The Combination of Tradition and Future: Data-Driven Natural-Product-Based Treatments for Parkinson’s Disease

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Zhijun Miao ◽  
Jinwei Bai ◽  
Li Shen ◽  
Rajeev K. Singla
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Natural Products ◽  
Natural Product ◽  
Neurodegenerative Disorder ◽  
Data Driven ◽  
Natural Product Discovery ◽  
Challenges And Opportunities ◽  
Future Data ◽  
Personalized Diagnosis

Parkinson’s disease (PD) is a neurodegenerative disorder in elderly people. The personalized diagnosis and treatment remain challenges all over the world. In recent years, natural products are becoming potential therapies for many complex diseases due to their stability and low drug resistance. With the development of informatics technologies, data-driven natural product discovery and healthcare is becoming reality. For PD, however, the relevant research and tools for natural products are quite limited. Here in this review, we summarize current available databases, tools, and models for general natural product discovery and synthesis. These useful resources could be used and integrated for future PD-specific natural product investigations. At the same time, the challenges and opportunities for future natural-product-based PD care will also be discussed.

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