Secondary metabolites, their structural diversity, bioactivity, and ecological functions: An overview

2019 ◽  
Vol 4 (6) ◽  
Author(s):  
Berhanu M. Abegaz ◽  
Henok H. Kinfe
Keyword(s):  
Natural Products ◽  
Secondary Metabolites ◽  
Structural Diversity ◽  
Building Blocks ◽  
Narrative Texts ◽  
Ecological Functions ◽  
Acetyl Coenzyme A ◽  
Primary Metabolites ◽  
Geranyl Diphosphate ◽  
Aromatic Polyketides

Abstract Natural products are also called secondary metabolites to distinguish them from the primary metabolites, i.e. those natural compounds like glucose, amino acids, etc. that are present in every living cell and are used and required in the essential life processes of cells. Natural products are classified according to their metabolic building blocks into alkaloids, fatty acids, polyketides, phenyl propanoids and aromatic polyketides, and terpenoids. The structural diversity of natural products is explored using the scaffold approach focusing on the characteristic carbon frameworks.  Aside from discussing specific alkaloids that are either pharmacologically (e.g. boldine, berberine, galantamine, etc.) or historically (caffeine, atropine, lobeline, etc.) important alkaloids, a single chart is presented which shows the typical scaffolds of the most important subclasses of alkaloids.  How certain classes of natural products are formed in nature from simple biochemical ‘building blocks’ are shown using graphical schemes. This has been done for a typical tetra-ketide (6-methylsalicylic acid) from acetyl coenzyme A, or in general to all the major subclasses of terpenes.   An important aspect of understanding the structural diversity of natural products is to recognize how some compounds can be visualized as key intermediates for enzyme mediated transformation to several other related structures.  This is seen in the case of how arachidonic acid can transform into prostaglandins, or geranyl diphosphate to various monoterpenes, or squalene epoxide to various pentacyclic triterpenes, or cholesterol transforming to sex hormones, bile acids and the cardioactive cardenolides and bufadienolides. These are presented in carefully designed schemes and charts that are appropriately placed in the relevant sections of the narrative texts.  The ecological functions and pharmacological properties of natural products are also presented showing wherever possible how the chemical scaffolds have led to developing drugs as well as commercial products like sweeteners.

scholarly journals Acyltransferases as Tools for Polyketide Synthase Engineering

Antibiotics ◽  
2018 ◽  
Vol 7 (3) ◽  
pp. 62 ◽  
Author(s):  
Ewa Musiol-Kroll ◽  
Wolfgang Wohlleben
Keyword(s):  
Natural Products ◽  
Rational Design ◽  
Polyketide Synthase ◽  
Antifungal Agents ◽  
Relevant Literature ◽  
Structural Diversity ◽  
Building Blocks ◽  
Assembly Lines ◽  
Acyl Carrier Proteins ◽  
Polyketide Biosynthesis

Polyketides belong to the most valuable natural products, including diverse bioactive compounds, such as antibiotics, anticancer drugs, antifungal agents, immunosuppressants and others. Their structures are assembled by polyketide synthases (PKSs). Modular PKSs are composed of modules, which involve sets of domains catalysing the stepwise polyketide biosynthesis. The acyltransferase (AT) domains and their “partners”, the acyl carrier proteins (ACPs), thereby play an essential role. The AT loads the building blocks onto the “substrate acceptor”, the ACP. Thus, the AT dictates which building blocks are incorporated into the polyketide structure. The precursor- and occasionally the ACP-specificity of the ATs differ across the polyketide pathways and therefore, the ATs contribute to the structural diversity within this group of complex natural products. Those features make the AT enzymes one of the most promising tools for manipulation of polyketide assembly lines and generation of new polyketide compounds. However, the AT-based PKS engineering is still not straightforward and thus, rational design of functional PKSs requires detailed understanding of the complex machineries. This review summarizes the attempts of PKS engineering by exploiting the AT attributes for the modification of polyketide structures. The article includes 253 references and covers the most relevant literature published until May 2018.

scholarly journals Exploring novel secondary metabolites from natural products using pre-processed mass spectral data

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Hyun Woo Kim ◽  
Seong Yeon Choi ◽  
Hyeon Seok Jang ◽  
Byeol Ryu ◽  
Sang Hyun Sung ◽  
...  
Keyword(s):  
Natural Products ◽  
Secondary Metabolites ◽  
Natural Product ◽  
Spectral Data ◽  
Structural Diversity ◽  
Natural Material ◽  
Natural Sources ◽  
Mass Spectral ◽  
Aerial Parts ◽  
Similar Chemical

AbstractMany natural product chemists are working to identify a wide variety of novel secondary metabolites from natural materials and are eager to avoid repeatedly discovering known compounds. Here, we developed liquid chromatography/mass spectrometry (LC/MS) data-processing protocols for assessing high-throughput spectral data from natural sources and scoring the novelty of unknown metabolites from natural products. This approach automatically produces representative MS spectra (RMSs) corresponding to single secondary metabolites in natural sources. In this study, we used the RMSs of Agrimonia pilosa roots and aerial parts as models to reveal the structural similarities of their secondary metabolites and identify novel compounds, as well as isolation of three types of nine new compounds including three pilosanidin- and four pilosanol-type molecules and two 3-hydroxy-3-methylglutaryl (HMG)-conjugated chromones. Furthermore, we devised a new scoring system, the Fresh Compound Index (FCI), which grades the novelty of single secondary metabolites from a natural material using an in-house database constructed from 466 representative medicinal plants from East Asian countries. We expect that the FCIs of RMSs in a sample will help natural product chemists to discover other compounds of interest with similar chemical scaffolds or novel compounds and will provide insights relevant to the structural diversity and novelty of secondary metabolites in natural products.

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 Generation of Unusual Aromatic Polyketides by Incorporation of Phenylamine Analogues into a C-Ring-Cleaved Angucyclinone

Molecules ◽  
2021 ◽  
Vol 26 (7) ◽  
pp. 1959
Author(s):  
Hua Xiao ◽  
Guiyang Wang ◽  
Zhengdong Wang ◽  
Yi Kuang ◽  
Juan Song ◽  
...  
Keyword(s):  
Natural Products ◽  
Biological Activities ◽  
Structural Diversity ◽  
Related Factor ◽  
Nuclear Factor ◽  
Streptomyces Sp ◽  
Mild Conditions ◽  
Aromatic Polyketides ◽  
Marine Streptomyces ◽  
New Compounds

Angucyclinones are aromatic polyketides that possess impressive structural diversity and significant biological activities. The structural diversity of these natural products is attributed to various enzymatic or nonenzymatic modifications on their tetracyclic benz(a)anthracene skeleton. Previously, we discovered an unusual phenylamine-incorporated angucyclinone (1) from a marine Streptomyces sp. PKU-MA00218, and identified that it was produced from the nonenzymatic conversion of a C-ring-cleaved angucyclinone (2) with phenylamine. In this study, we tested the nonenzymatic conversion of 2 with more phenylamine analogues, to expand the utility of this feasible conversion in unusual angucyclinones generation. The (3-ethynyl)phenylamine and disubstituted analogues including (3,4-dimethyl)phenylamine, (3,4-methylenedioxy)phenylamine, and (4-bromo-3-methyl)phenylamine were used in the conversion of 2, which was isolated from the fermentation of Streptomyces sp. PKU-MA00218. All four phenylamine analogues were incorporated into 2 efficiently under mild conditions, generating new compounds 3–6. The activation of 3–6 on nuclear factor erythroid 2-related factor 2 (Nrf2) transcription were tested, which showed that 4 possessing a dimethyl-substitution gave most potent activity. These results evidenced that disubstitutions on phenylamine can be roughly tolerated in the nonenzymatic reactions with 2, suggesting extended applications of more disubstituted phenylamines incorporation to generate new bioactive angucyclinones in the future.

scholarly journals The Structural Diversity of Marine Microbial Secondary Metabolites Based on Co-Culture Strategy: 2009–2019

Marine Drugs ◽  
2020 ◽  
Vol 18 (9) ◽  
pp. 449
Author(s):  
Jianwei Chen ◽  
Panqiao Zhang ◽  
Xinyi Ye ◽  
Bin Wei ◽  
Mahmoud Emam ◽  
...  
Keyword(s):  
Natural Products ◽  
Secondary Metabolites ◽  
Biological Activities ◽  
Structural Diversity ◽  
Marine Microorganisms ◽  
Future Prospects ◽  
Marine Microbes ◽  
Cultivation Strategy ◽  
Culture Strategy ◽  
Bioactive Natural Product

Marine microorganisms have drawn great attention as novel bioactive natural product sources, particularly in the drug discovery area. Using different strategies, marine microbes have the ability to produce a wide variety of molecules. One of these strategies is the co-culturing of marine microbes; if two or more microorganisms are aseptically cultured together in a solid or liquid medium in a certain environment, their competition or synergetic relationship can activate the silent biosynthetic genes to produce cryptic natural products which do not exist in monocultures of the partner microbes. In recent years, the co-cultivation strategy of marine microbes has made more novel natural products with various biological activities. This review focuses on the significant and excellent examples covering sources, types, structures and bioactivities of secondary metabolites based on co-cultures of marine-derived microorganisms from 2009 to 2019. A detailed discussion on future prospects and current challenges in the field of co-culture is also provided on behalf of the authors’ own views of development tendencies.

scholarly journals Engineering the acyltransferase substrate specificity of assembly line polyketide synthases

2013 ◽  
Vol 10 (85) ◽  
pp. 20130297 ◽  
Author(s):  
Briana J. Dunn ◽  
Chaitan Khosla
Keyword(s):  
Natural Products ◽  
Substrate Specificity ◽  
Assembly Line ◽  
Current Knowledge ◽  
Structural Diversity ◽  
Structural Data ◽  
Building Blocks ◽  
Polyketide Synthases ◽  
Biologically Active ◽  
Recent Developments

Polyketide natural products act as a broad range of therapeutics, including antibiotics, immunosuppressants and anti-cancer agents. This therapeutic diversity stems from the structural diversity of these small molecules, many of which are produced in an assembly line manner by modular polyketide synthases. The acyltransferase (AT) domains of these megasynthases are responsible for selection and incorporation of simple monomeric building blocks, and are thus responsible for a large amount of the resulting polyketide structural diversity. The substrate specificity of these domains is often targeted for engineering in the generation of novel, therapeutically active natural products. This review outlines recent developments that can be used in the successful engineering of these domains, including AT sequence and structural data, mechanistic insights and the production of a diverse pool of extender units. It also provides an overview of previous AT domain engineering attempts, and concludes with proposed engineering approaches that take advantage of current knowledge. These approaches may lead to successful production of biologically active ‘unnatural’ natural products.

Formation of Carbon-Oxygen Bond Mediated by Hypervalent Iodine Reagents Under Metal-free Conditions

2020 ◽  
Vol 17 ◽  
Author(s):  
Ayesha Jalil ◽  
Yaxin O Yang ◽  
Zhendong Chen ◽  
Rongxuan Jia ◽  
Tianhao Bi ◽  
...  
Keyword(s):  
Natural Products ◽  
Bond Formation ◽  
Building Blocks ◽  
Review Article ◽  
Hypervalent Iodine ◽  
Metal Free ◽  
Bioactive Natural Products ◽  
The Past ◽  
Oxygen Bond ◽  
Privileged Scaffolds

: Hypervalent iodine reagents are a class of non-metallic oxidants have been widely used in the construction of several sorts of bond formations. This surging interest in hypervalent iodine reagents is essentially due to their very useful oxidizing properties, combined with their benign environmental character and commercial availability from the past few decades ago. Furthermore, these hypervalent iodine reagents have been used in the construction of many significant building blocks and privileged scaffolds of bioactive natural products. The purpose of writing this review article is to explore all the transformations in which carbon-oxygen bond formation occurred by using hypervalent iodine reagents under metal-free conditions

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