Chemical Evolution of Natural Product Structure

Journal of the American Chemical Society, Год журнала: 2022, Номер 144(8), С. 3314 - 3329

Опубликована: Фев. 21, 2022

Natural products are the result of Nature's exploration biologically relevant chemical space through evolution and an invaluable source bioactive small molecules for biology medicinal chemistry. Novel concepts discovery new compound classes based on natural product structure may enable wider space. The pseudo-natural concept merges relevance with efficient by means fragment-based development to inspire matter de novo combination fragments in unprecedented arrangements. novel scaffolds retain biological but not obtainable known biosynthetic pathways which can lead chemotypes that have unexpected or bioactivities. Herein, we cover workflow design development, highlight recent examples, discuss a cheminformatic analysis significant portion active synthetic compounds were found be products. We compare as human-made equivalent, i.e. structure.

Язык: Английский

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Cytochrome P450 enzymes in fungal natural product biosynthesis

Natural Product Reports, Год журнала: 2021, Номер 38(6), С. 1072 - 1099

Опубликована: Янв. 1, 2021

P450s play crucial roles in fungal natural product biosynthesis by mediating various common and uncommon reactions.

Язык: Английский

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Genome mining for unknown–unknown natural products

Nature Chemical Biology, Год журнала: 2023, Номер 19(5), С. 633 - 640

Опубликована: Янв. 26, 2023

Язык: Английский

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Current trends, limitations and future research in the fungi?

Fungal Diversity, Год журнала: 2024, Номер 125(1), С. 1 - 71

Опубликована: Март 20, 2024

Abstract The field of mycology has grown from an underappreciated subset botany, to a valuable, modern scientific discipline. As this study grown, there have been significant contributions science, technology, and industry, highlighting the value fungi in era. This paper looks at current research, along with existing limitations, suggests future areas where scientists can focus their efforts, mycology. We show how become important emerging diseases medical discuss trends potential drug novel compound discovery. explore phylogenomics, its potential, outcomes address question phylogenomics be applied fungal ecology. In addition, functional genomics studies are discussed importance unravelling intricate mechanisms underlying behaviour, interactions, adaptations, paving way for comprehensive understanding biology. look research building materials, they used as carbon sinks, biocircular economies. numbers always great interest often written about estimates varied greatly. Thus, we needs order obtain more reliable estimates. aspects machine learning (AI) it mycological research. Plant pathogens affecting food production systems on global scale, such, needed area, particularly disease detection. latest data High Throughput Sequencing if still gaining new knowledge same rate before. A review nanotechnology is provided addressed. Arbuscular Mycorrhizal Fungi addressed acknowledged. Fungal databases becoming important, therefore provide major databases. Edible medicinal huge medicines, especially Asia prospects discussed. Lifestyle changes (e.g., endophytes, pathogens, and/or saprobes) also extremely trend special issue Diversity.

Язык: Английский

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Developing fungal heterologous expression platforms to explore and improve the production of natural products from fungal biodiversity

Biotechnology Advances, Год журнала: 2021, Номер 54, С. 107866 - 107866

Опубликована: Ноя. 12, 2021

Natural products from fungi represent an important source of biologically active metabolites notably for therapeutic agent development. Genome sequencing revealed that the number biosynthetic gene clusters (BGCs) in is much larger than expected. Unfortunately, most them are silent or barely expressed under laboratory culture conditions. Moreover, many nature uncultivable cannot be genetically manipulated, restricting extraction and identification bioactive these species. Rapid exploration tremendous cryptic fungal BGCs necessitates development heterologous expression platforms, which will facilitate efficient production natural cell factories. Host selection, BGC assembly methods, promoters used expression, metabolic engineering strategies compartmentalization pathways key aspects consideration to develop such a microbial platform. In present review, we summarize current progress on above challenges promote research effort relevant fields.

Язык: Английский

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Deciphering chemical logic of fungal natural product biosynthesis through heterologous expression and genome mining

Natural Product Reports, Год журнала: 2022, Номер 40(1), С. 89 - 127

Опубликована: Сен. 20, 2022

Covering: 2010 to 2022Heterologous expression of natural product biosynthetic gene clusters (BGCs) has become a widely used tool for genome mining cryptic pathways, bottom-up investigation enzymes, and engineered biosynthesis new variants. In the field fungal products, heterologous complete pathway was first demonstrated in tenellin

Язык: Английский

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Terpene biosynthesis in marine sponge animals

Proceedings of the National Academy of Sciences, Год журнала: 2023, Номер 120(9)

Опубликована: Фев. 21, 2023

Sea sponges are the largest marine source of small-molecule natural products described to date. Sponge-derived molecules, such as chemotherapeutic eribulin, calcium-channel blocker manoalide, and antimalarial compound kalihinol A, renowned for their impressive medicinal, chemical, biological properties. Sponges contain microbiomes that control production many isolated from these invertebrates. In fact, all genomic studies date investigating metabolic origins sponge-derived small molecules concluded microbes—not sponge animal host—are biosynthetic producers. However, early cell-sorting suggested host may play a role particularly in terpenoid molecules. To investigate genetic underpinnings biosynthesis, we sequenced metagenome transcriptome an isonitrile sesquiterpenoid-containing order Bubarida. Using bioinformatic searches biochemical validation, identified group type I terpene synthases (TSs) this multiple other species, first enzyme class characterized holobiome. The Bubarida TS-associated contigs consist intron-containing genes homologous feature GC percentage coverage consistent with eukaryotic sequences. We TS homologs five different species geographically distant locations, thereby suggesting broad distribution amongst sponges. This work sheds light on secondary metabolite speaks possibility sponge-specific originate host.

Язык: Английский

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Discovery and Characterization of Pyridoxal 5′-Phosphate-Dependent Cycloleucine Synthases

Journal of the American Chemical Society, Год журнала: 2024, Номер 146(21), С. 14672 - 14684

Опубликована: Май 14, 2024

Pyridoxal 5′-phosphate (PLP)-dependent enzymes are the most versatile biocatalysts for synthesizing nonproteinogenic amino acids. α,α-Disubstituted quaternary acids, such as 1-aminocyclopentane-1-carboxylic acid (cycloleucine), useful building blocks pharmaceuticals. In this study, starting with biosynthesis of fusarilin A, we discovered a family PLP-dependent that can facilitate tandem carbon–carbon forming steps to catalyze an overall [3 + 2]-annulation. first step, cycloleucine synthases use SAM latent electrophile and in situ-generated enamine nucleophile γ-substitution. Whereas previously characterized γ-replacement protonate resulting α-carbon release acyclic acid, additional, intramolecular aldol or Mannich reaction nucleophilic form substituted cyclopentane. Overall, net 2]-annulation lead 2-hydroxy 2-aminocycloleucine products. These studies further expand biocatalytic scope enzymes.

Язык: Английский

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Enzymatic combinatorial synthesis of E-64 and related cysteine protease inhibitors

Nature Chemical Biology, Год журнала: 2025, Номер unknown

Опубликована: Май 9, 2025

Abstract E-64 is an irreversible cysteine protease inhibitor prominently used in chemical biology and drug discovery. Here we uncover a nonribosomal peptide synthetase-independent biosynthetic pathway for E-64, which widely conserved fungi. The starts with epoxidation of fumaric acid to the warhead (2 S ,3 )- trans -epoxysuccinic Fe(II)/α-ketoglutarate-dependent oxygenase, followed by successive condensation l -amino adenosine triphosphate grasp enzyme amine fungal example amide bond synthetase. Both bond-forming enzymes display notable biocatalytic potential, including scalability, stereoselectivity toward broader substrate scopes forming bonds. Biocatalytic cascade these generated library inhibitors, leading more potent cathepsin inhibitors. Additionally, one-pot reactions enabled preparative synthesis clinically relevant Our work highlights importance investigation discovery potential synthesizing small-molecule libraries.

Язык: Английский

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Discovery and Biocatalytic Application of a PLP-Dependent Amino Acid γ-Substitution Enzyme That Catalyzes C–C Bond Formation

Journal of the American Chemical Society, Год журнала: 2020, Номер 142(23), С. 10506 - 10515

Опубликована: Май 20, 2020

Pyridoxal phosphate (PLP)-dependent enzymes can catalyze transformations of l-amino acids at α, β, and γ positions. These are frequently involved in the biosynthesis nonproteinogenic amino as building blocks natural products attractive biocatalysts. Here, we report discovery a two-step enzymatic synthesis (2S,6S)-6-methyl pipecolate 1, from biosynthetic pathway citrinadin. The key enzyme CndF is PLP-dependent catalyzes (S)-2-amino-6-oxoheptanoate 3 that equilibrium with cyclic Schiff base. second CndE stereoselective imine reductase gives 1. Biochemical characterization showed this performs γ-elimination O-acetyl-l-homoserine to generate vinylglycine ketimine, which subjected nucleophilic attack by acetoacetate form new Cγ-Cδ bond complete γ-substitution reaction. displays promiscuity toward different β-keto carboxylate esters. With use an Aspergillus strain expressing CndE, feeding various alkyl-β-keto esters led 6-substituted l-pipecolates. expands repertoire reactions be catalyzed enzymes.

Язык: Английский

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