scholarly journals Biosynthesis and molecular engineering of templated natural products

2016 ◽  
Vol 4 (4) ◽  
pp. 553-575 ◽  
Author(s):  
Ming Chen ◽  
Jingyu Liu ◽  
Panpan Duan ◽  
Mulin Li ◽  
Wen Liu
Keyword(s):  
Natural Products ◽  
Critical Role ◽  
Structural Complexity ◽  
Limited Range ◽  
Molecular Engineering ◽  
First Century ◽  
Design Development ◽  
Post Translational Modifications ◽  
Development And Utilization ◽  
Living Organisms

Abstract Bioactive small molecules that are produced by living organisms, often referred to as natural products (NPs), historically play a critical role in the context of both medicinal chemistry and chemical biology. How nature creates these chemical entities with stunning structural complexity and diversity using a limited range of simple substrates has not been fully understood. Focusing on two types of NPs that share a highly evolvable ‘template’-biosynthetic logic, we here provide specific examples to highlight the conceptual and technological leaps in NP biosynthesis and witness the area of progress since the beginning of the twenty-first century. The biosynthesis of polyketides, non-ribosomal peptides and their hybrids that share an assembly-line enzymology of modular multifunctional proteins exemplifies an extended ‘central dogma’ that correlates the genotype of catalysts with the chemotype of products; in parallel, post-translational modifications of ribosomally synthesized peptides involve a number of unusual biochemical mechanisms for molecular maturation. Understanding the biosynthetic processes of these templated NPs would largely facilitate the design, development and utilization of compatible biosynthetic machineries to address the challenge that often arises from structural complexity to the accessibility and efficiency of current chemical synthesis.

scholarly journals Control of Nucleophile Chemoselectivity in Cyanobactin YcaO Heterocyclases PatD and TruD

2021 ◽  
Author(s):  
Wenjia Gu ◽  
Yiwu Zheng ◽  
Taras Pogorelov ◽  
Satish K. Nair ◽  
Eric W. Schmidt
Keyword(s):  
Natural Products ◽  
Synthetic Biology ◽  
Post Translational Modifications ◽  
Pharmaceutical Development ◽  
The World ◽  
Academic Settings ◽  
Living Organisms

<div><div><div><p>YcaO proteins are ubiquitous in living organisms, where they perform crucial post-translational modifications of peptides and proteins. They are used extensively in biotechnology in companies and academic settings around the world. They also underlie some of the most important natural products in pharmaceutical development, such as thiopeptides (thiostrepton, etc.). Here, we solve one of the major outstanding mysteries behind YcaO proteins: how they exert precision selectivity of the nucleophile. The resulting findings have major implications in understanding the >30,000 YcaO proteins currently in sequencing databases and will be used widely for precision synthetic biology applications.</p></div></div></div>

scholarly journals Control of Nucleophile Chemoselectivity in Cyanobactin YcaO Heterocyclases PatD and TruD

2021 ◽  
Author(s):  
Wenjia Gu ◽  
Yiwu Zheng ◽  
Taras Pogorelov ◽  
Satish K. Nair ◽  
Eric W. Schmidt
Keyword(s):  
Natural Products ◽  
Synthetic Biology ◽  
Post Translational Modifications ◽  
Pharmaceutical Development ◽  
The World ◽  
Academic Settings ◽  
Living Organisms

<div><div><div><p>YcaO proteins are ubiquitous in living organisms, where they perform crucial post-translational modifications of peptides and proteins. They are used extensively in biotechnology in companies and academic settings around the world. They also underlie some of the most important natural products in pharmaceutical development, such as thiopeptides (thiostrepton, etc.). Here, we solve one of the major outstanding mysteries behind YcaO proteins: how they exert precision selectivity of the nucleophile. The resulting findings have major implications in understanding the >30,000 YcaO proteins currently in sequencing databases and will be used widely for precision synthetic biology applications.</p></div></div></div>

A Review on Important Histone Acetyltransferase (HAT) Enzymes as Targets for Cancer Therapy

2019 ◽  
Vol 15 (2) ◽  
pp. 120-130
Author(s):  
Mohammad Ghanbari ◽  
Reza Safaralizadeh ◽  
Kiyanoush Mohammadi
Keyword(s):  
Gene Expression ◽  
Histone Acetyltransferase ◽  
Critical Role ◽  
Cancer Treatments ◽  
Control Of Gene Expression ◽  
Post Translational Modifications ◽  
Therapeutic Drugs ◽  
The Status ◽  
Acetyl Group ◽  
Increase Gene Expression

At the present time, cancer is one of the most lethal diseases worldwide. There are various factors involved in the development of cancer, including genetic factors, lifestyle, nutrition, and so on. Recent studies have shown that epigenetic factors have a critical role in the initiation and development of tumors. The histone post-translational modifications (PTMs) such as acetylation, methylation, phosphorylation, and other PTMs are important mechanisms that regulate the status of chromatin structure and this regulation leads to the control of gene expression. The histone acetylation is conducted by histone acetyltransferase enzymes (HATs), which are involved in transferring an acetyl group to conserved lysine amino acids of histones and consequently increase gene expression. On the basis of similarity in catalytic domains of HATs, these enzymes are divided into different groups such as families of GNAT, MYST, P300/CBP, SRC/P160, and so on. These enzymes have effective roles in apoptosis, signaling pathways, metastasis, cell cycle, DNA repair and other related mechanisms deregulated in cancer. Abnormal activation of HATs leads to uncontrolled amplification of cells and incidence of malignancy signs. This indicates that HAT might be an important target for effective cancer treatments, and hence there would be a need for further studies and designing of therapeutic drugs on this basis. In this study, we have reviewed the important roles of HATs in different human malignancies.

Friends of Rose Canyon

2018 ◽  
Vol 95 (3) ◽  
pp. 2-20 ◽  
Author(s):  
Andrew Wiese
Keyword(s):  
Open Space ◽  
Critical Role ◽  
First Century ◽  
Grassroots Politics ◽  
History Of ◽  
University City ◽  
Participant Observer ◽  
The Rose

Place-based activism has played a critical role in the history of urban and environmental politics in California. This article explores the continuing significance of environmental place making to grassroots politics through a case study of Friends of Rose Canyon, an environmental group in San Diego. Based in the fast-growing University City neighborhood, Friends of Rose Canyon waged a long, successful campaign between 2002 and 2018 to prevent construction of a bridge in the Rose Canyon Open Space Park in their community. Using historical and participant observer methodologies, this study reveals how twenty-first-century California urbanites claimed and created meaningful local places and mobilized effective politics around them. It illuminates the critical role of individual activists; suggests practical, replicable strategies for community mobilization; and demonstrates the significant impact of local activism at the urban and metropolitan scales.

scholarly journals Palladium-Catalyzed Coupling Reactions on Functionalized 2-Trifluoromethyl-4-chromenone Scaffolds: Synthesis of Highly Functionalized Trifluoromethyl Heterocycles

Synthesis ◽  
2018 ◽  
Vol 51 (06) ◽  
pp. 1342-1352 ◽  
Author(s):  
Javier Izquierdo ◽  
Atul Jain ◽  
Sarki Abdulkadir ◽  
Gary Schiltz
Keyword(s):  
Natural Products ◽  
Organic Synthesis ◽  
Biological Activities ◽  
Structural Complexity ◽  
Biologically Active ◽  
Coupling Reactions ◽  
Trifluoromethyl Group ◽  
Palladium Catalyzed ◽  
Active Natural

The chromenone core is an ubiquitous group in biologically active natural products and has been extensively used in organic synthesis. Fluorine-derived compounds, including those with a trifluoromethyl group (CF3), have shown enhanced biological activities in numerous pharmaceuticals compared with their non-fluorinated analogues. 2-Trifluoromethylchromenones can be readily functionalized at the 8- and 7-positions, providing chromenones cores of high structural complexity, which are excellent precursors for numerous trifluoromethyl heterocycles.

scholarly journals NATURAL PRODUCTS: FROM TRADITIONAL MEDICINE TO LEAD COMPOUNDS FOR DRUG DEVELOPMENT IN THE 21ST CENTURY

2021 ◽  
pp. 97-104
Author(s):  
Beatriz de las Heras Polo
Keyword(s):  
Natural Products ◽  
Drug Discovery ◽  
High Throughput Screening ◽  
Structural Complexity ◽  
Cost Benefit ◽  
Bioactive Molecules ◽  
Computational Techniques ◽  
Design And Optimization ◽  
Technological Advances ◽  
Biological Tests

Natural products have historically contributed to drug discovery as a source of bioactive molecules, due to their great diversity and structural complexity. They have provided “lead” molecules for the development of drugs in different therapeutic areas, with a very prominent representation in the treatment of pain and inflammation, coagulation disorders, metabolic disorders, as well as in the treatment of cancer and infectious diseases. In recent decades there has been a paradigm shift in drug discovery strategies that has allowed the identification of new active natural products in therapeutic targets. Combinatorial Chemistry and biological tests (High Throughput Screening), together with the development of computational techniques, have contributed decisively to the design and optimization of libraries of natural product derivatives based on their biological activity. In parallel, technological advances in the field of Omics sciences and in data processing lead to a multidimensional approach in the drug discovery process. These powerful tools will allow the analysis of the pharmacological potential of natural products and their derivatives for the conversion of these molecules to active products with low toxicity. In the Precision Medicine era, natural products continue to be molecules with great potential in pharmaceutical development, since, unlike other therapeutic strategies, they have a favorable cost-benefit ratio, which will allow their future use in this discipline.

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.

Fungal Production and Manipulation of Plant Hormones

2018 ◽  
Vol 25 (2) ◽  
pp. 253-267 ◽  
Author(s):  
Sandra Fonseca ◽  
Dhanya Radhakrishnan ◽  
Kalika Prasad ◽  
Andrea Chini
Keyword(s):  
Stress Responses ◽  
Current Knowledge ◽  
Critical Role ◽  
Plant Defence ◽  
Pathogenic Fungi ◽  
Plant Responses ◽  
Defensive Strategies ◽  
Hormone Balance ◽  
Living Organisms

Living organisms are part of a highly interconnected web of interactions, characterised by species nurturing, competing, parasitizing and preying on one another. Plants have evolved cooperative as well as defensive strategies to interact with neighbour organisms. Among these, the plant-fungus associations are very diverse, ranging from pathogenic to mutualistic. Our current knowledge of plant-fungus interactions suggests a sophisticated coevolution to ensure dynamic plant responses to evolving fungal mutualistic/pathogenic strategies. The plant-fungus communication relies on a rich chemical language. To manipulate the plant defence mechanisms, fungi produce and secrete several classes of biomolecules, whose modeof- action is largely unknown. Upon perception of the fungi, plants produce phytohormones and a battery of secondary metabolites that serve as defence mechanism against invaders or to promote mutualistic associations. These mutualistic chemical signals can be co-opted by pathogenic fungi for their own benefit. Among the plant molecules regulating plant-fungus interaction, phytohormones play a critical role since they modulate various aspects of plant development, defences and stress responses. Intriguingly, fungi can also produce phytohormones, although the actual role of fungalproduced phytohormones in plant-fungus interactions is poorly understood. Here, we discuss the recent advances in fungal production of phytohormone, their putative role as endogenous fungal signals and how fungi manipulate plant hormone balance to their benefits.

scholarly journals A noncanonical vacuolar sugar transferase required for biosynthesis of antimicrobial defense compounds in oat

2019 ◽  
Vol 116 (52) ◽  
pp. 27105-27114 ◽  
Author(s):  
Anastasia Orme ◽  
Thomas Louveau ◽  
Michael J. Stephenson ◽  
Ingo Appelhagen ◽  
Rachel Melton ◽  
...  
Keyword(s):  
Natural Products ◽  
Agronomic Traits ◽  
Glycosyl Hydrolase ◽  
Critical Role ◽  
Large Family ◽  
Biosynthetic Gene Cluster ◽  
Uridine Diphosphate ◽  
Sugar Chain ◽  
Defense Compounds ◽  
Antimicrobial Defense

Plants produce an array of natural products with important ecological functions. These compounds are often decorated with oligosaccharide groups that influence bioactivity, but the biosynthesis of such sugar chains is not well understood. Triterpene glycosides (saponins) are a large family of plant natural products that determine important agronomic traits, as exemplified by avenacins, antimicrobial defense compounds produced by oats. Avenacins have a branched trisaccharide moiety consisting ofl-arabinose linked to 2d-glucose molecules that is critical for antifungal activity. Plant natural product glycosylation is usually performed by uridine diphosphate-dependent glycosyltransferases (UGTs). We previously characterized the arabinosyltransferase that initiates the avenacin sugar chain; however, the enzymes that add the 2 remainingd-glucose molecules have remained elusive. Here we characterize the enzymes that catalyze these last 2 glucosylation steps. AsUGT91G16 is a classical cytosolic UGT that adds a 1,2-linkedd-glucose molecule tol-arabinose. Unexpectedly, the enzyme that adds the final 1,4-linkedd-glucose (AsTG1) is not a UGT, but rather a sugar transferase belonging to Glycosyl Hydrolase family 1 (GH1). Unlike classical UGTs, AsTG1 is vacuolar. Analysis of oat mutants reveals thatAsTG1corresponds toSad3, a previously uncharacterized locus shown by mutation to be required for avenacin biosynthesis.AsTG1andAsUGT91G16form part of the avenacin biosynthetic gene cluster. Our demonstration that a vacuolar transglucosidase family member plays a critical role in triterpene biosynthesis highlights the importance of considering other classes of carbohydrate-active enzymes in addition to UGTs as candidates when elucidating pathways for the biosynthesis of glycosylated natural products in plants.

scholarly journals Divergent synthesis of complex diterpenes through a hybrid oxidative approach

Science ◽  
2020 ◽  
Vol 369 (6505) ◽  
pp. 799-806 ◽  
Author(s):  
Xiao Zhang ◽  
Emma King-Smith ◽  
Liao-Bin Dong ◽  
Li-Cheng Yang ◽  
Jeffrey D. Rudolf ◽  
...  
Keyword(s):  
Natural Products ◽  
De Novo ◽  
Biological Activities ◽  
Structural Complexity ◽  
Enzymatic Oxidation ◽  
Chemical Tools ◽  
Skeletal Rearrangements ◽  
Skeletal Diversity

Polycyclic diterpenes exhibit many important biological activities, but de novo synthetic access to these molecules is highly challenging because of their structural complexity. Semisynthetic access has also been limited by the lack of chemical tools for scaffold modifications. We report a chemoenzymatic platform to access highly oxidized diterpenes by a hybrid oxidative approach that strategically combines chemical and enzymatic oxidation methods. This approach allows for selective oxidations of previously inaccessible sites on the parent carbocycles and enables abiotic skeletal rearrangements to additional underlying architectures. We synthesized a total of nine complex natural products with rich oxygenation patterns and skeletal diversity in 10 steps or less from ent-steviol.

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