Advances in Synthetic Biology of Fungi and Contributions to the Discovery of New Molecules DOI Creative Commons
Vito Valiante

ChemBioChem, Journal Year: 2023, Volume and Issue: 24(11)

Published: March 2, 2023

The sequencing of fungal genomes is becoming increasingly accessible, with a wealth data already available. In parallel, the prediction putative biosynthetic pathways responsible for synthesis potential new natural products also increasing. difficulty translating computational analyses into available compounds evident, slowing down process that was thought to be faster advent genomic era. Advances in gene techniques made it possible genetically modify wider range organisms, including fungi typically considered recalcitrant DNA manipulation. However, possibility screening many cluster activities high-throughput manner remains unfeasible. Nonetheless, some updates on synthetic biology could provide interesting insights help achieve this goal future.

Language: Английский

Predicting fungal secondary metabolite activity from biosynthetic gene cluster data using machine learning DOI Creative Commons
Olivia Riedling, Allison S. Walker, Antonis Rokas

et al.

Microbiology Spectrum, Journal Year: 2024, Volume and Issue: 12(2)

Published: Jan. 9, 2024

Fungal secondary metabolites (SMs) contribute to the diversity of fungal ecological communities, niches, and lifestyles. Many SMs have one or more medically industrially important activities (e.g., antifungal, antibacterial, antitumor). The genes necessary for SM biosynthesis are typically located right next each other in genome known as biosynthetic gene clusters (BGCs). However, whether bioactivity can be predicted from specific attributes BGCs remains an open question. We adapted machine learning models that bacterial BGC data with accuracies high 80% data. trained our predict cytotoxic/antitumor on two sets: (i) (data set comprised 314 BGCs) (ii) (314 (1,003 BGCs). found had balanced between 51% 68%, whereas training 56% 68%. low prediction accuracy bioactivities likely stems small size set; this lack data, coupled finding including did not substantially change currently limits application approaches studies. With >15,000 characterized SMs, millions putative genomes, increased demand novel drugs, efforts systematically link urgently needed.IMPORTANCEFungi key sources natural products iconic penicillin statins. DNA sequencing has revealed there pathways but chemical structures >99% produced by these remain unknown. used artificial intelligence diverse pathways. predictions were generally low, because only very few known. products, present study suggests is urgent need identify pathways, their bioactivities.

Language: Английский

Citations

10
Targeted Discovery of Glycosylated Natural Products by Tailoring Enzyme-Guided Genome Mining and MS-Based Metabolome Analysis DOI
Dawei Chen,

Zhijun Song,

Junjie Han

et al.

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(14), P. 9614 - 9622

Published: March 28, 2024

Glycosides make up a biomedically important class of secondary metabolites. Most naturally occurring glycosides were isolated from plants and bacteria; however, the chemical diversity glycosylated natural products in fungi remains largely unexplored. Herein, we present paradigm to specifically discover diverse bioactive by combining tailoring enzyme-guided genome mining with mass spectrometry (MS)-based metabolome analysis. Through

Language: Английский

Citations

9
Synthetic Biology Tools for Engineering Aspergillus oryzae DOI Creative Commons
Hui Yang,

Chaonan Song,

Chengwei Liu

et al.

Journal of Fungi, Journal Year: 2024, Volume and Issue: 10(1), P. 34 - 34

Published: Jan. 3, 2024

For more than a thousand years,

Language: Английский

Citations

6
Parallel Evolution of Asco- and Basidiomycete O-Prenyltransferases DOI

Tim Schäfer,

F Haun,

Markus Gressler

et al.

Journal of Natural Products, Journal Year: 2024, Volume and Issue: 87(3), P. 576 - 582

Published: Jan. 17, 2024

Prenyltransferases (PTs) are involved in the biosynthesis of a multitude pharmaceutically and agriculturally important plant, bacterial, fungal compounds. Although numerous prenylated compounds have been isolated from Basidiomycota (mushroom-forming fungi), knowledge PTs catalyzing transfer reactions this group fungi is scarce. Here, we report biochemical characterization an O- C-prenylating dimethylallyltryptophan synthase (DMATS)-like enzyme LpTyrPT scurfy deceiver Laccaria proxima. This PT transfers dimethylallyl moieties to l-tyrosine at para-O position l-tryptophan atom C-7 represents first basidiomycete described so far. Phylogenetic analysis revealed that evolved independently their ascomycete counterparts might represent evolutionary origin acting on phenolic secondary metabolism.

Language: Английский

Citations

6
Exploring the Diverse Landscape of Fungal Cytochrome P450‐Catalyzed Regio‐ and Stereoselective Dimerization of Diketopiperazines DOI Creative Commons
Chuanteng Ma, Wenxue Wang,

Kaijin Zhang

et al.

Advanced Science, Journal Year: 2024, Volume and Issue: 11(26)

Published: April 30, 2024

Abstract Dimeric indole‐containing diketopiperazines (di‐DKPs) are a diverse group of natural products produced through cytochrome P450‐catalyzed C–C or C–N coupling reactions. The regio‐ and stereoselectivity these reactions plays significant role in the structural diversity di‐DKPs. Despite their pivotal role, mechanisms governing selectivity fungi not fully understood. Employing bioinformatics analysis heterologous expression experiments, five undescribed P450 enzymes (AmiP450, AcrP450, AtP450, AcP450, AtuP450) responsible for stereoselective dimerization (DKPs) identified. function P450s is consistent with phylogenetic analysis, highlighting dominant controlling modes. Combinatorial biosynthesis‐based pathway reconstitution non‐native gene clusters expands chemical space fungal di‐DKPs reveals that regioselectivity influenced by substrate. Furthermore, multiple sequence alignment molecular docking demonstrate C‐terminal variable region near substrate tunnel entrance AtuP450 crucial its regioselectivity. These findings only reveal secret but also deepen understanding catalytic specificity involved

Language: Английский

Citations

5
Characterization of the depsidone gene cluster reveals etherification, decarboxylation and multiple halogenations as tailoring steps in depsidone assembly DOI Creative Commons
Jiafan Yang,

Zhenbin Zhou,

Yingying Chen

et al.

Acta Pharmaceutica Sinica B, Journal Year: 2023, Volume and Issue: 13(9), P. 3919 - 3929

Published: June 1, 2023

Depsides and depsidones have attracted attention for biosynthetic studies due to their broad biological activities structural diversity. Previous structure‒activity relationships indicated that triple halogenated display the best anti-pathogenic activity. However, gene cluster tailoring steps responsible depsidone nornidulin (3) remain enigmatic. In this study, we disclosed complete pathway of through in vivo disruption, heterologous expression vitro biochemical experiments. We demonstrated an unusual depside skeleton biosynthesis process mediated by both highly-reducing polyketide synthase non-reducing synthase, which is distinct from common biosynthesis. This was subsequently modified two in-cluster enzymes DepG DepF ether bond formation decarboxylation, respectively. addition, decarboxylase exhibited substrate promiscuity different scaffold substrates. Finally, interestingly, discovered a halogenase encoded remotely cluster, catalyzes triple-halogenation produce active end product (3). These discoveries provide new insights further understanding derivatives.

Language: Английский

Citations

11
Complexity of fungal polyketide biosynthesis and function DOI Creative Commons

María C. Stroe,

Jia Gao,

Michael Pitz

et al.

Molecular Microbiology, Journal Year: 2023, Volume and Issue: 121(1), P. 18 - 25

Published: Nov. 13, 2023

Abstract Where does one draw the line between primary and secondary metabolism? The answer depends on perspective. Microbial metabolites (SMs) were at first believed not to be very important for producers because they are dispensable growth under laboratory conditions. However, such compounds become in natural niches of organisms, some prime importance humanity. Polyketides an group SMs with aflatoxin as a well‐known well‐characterized example. In Aspergillus spp., all 34 afl genes encoding enzymes biosynthesis located close vicinity chromosome III so‐called gene cluster. This led assumption that most required polyketide organized clusters. Recent research, however, revealed enormous complexity different polyketides, ranging from individual synthases cluster producing several compounds, or clusters additional scattered genome production compound. Research last decade furthermore huge potential SM hidden fungal genomes, methods developed wake up sleeping genes. analysis organismic interactions starts reveal ecological functions polyketides fungi.

Language: Английский

Citations

11
A Cytochrome P450 Catalyzes Oxidative Coupling Formation of Insecticidal Dimeric Indole Piperazine Alkaloids DOI
He Qian, Huaran Zhang, Yi Zou

et al.

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(22)

Published: March 26, 2024

Abstract Cytochrome P450 (CYP450)‐catalyzed oxidative coupling is an efficient strategy for using simple building blocks to construct complex structural scaffolds of natural products. Among them, heterodimeric between two different monomers relatively scarce, and the corresponding CYP450s are largely undiscovered. In this study, we discovered a fungal CYP450 (CpsD) its associated cps cluster from 37208 Pfam PF00067 family member database subsequently identified group new skeleton indole piperazine alkaloids (campesines A−G) by combination genome mining heterologous synthesis. Importantly, CpsD mainly catalyzes intermolecular heterocoupling generate unexpected 6/5/6/6/6/6/5/6 eight‐ring scaffold through formation one C−C bond C−N bonds, illuminating first dimerase role in The proposed catalytic mechanism was deeply investigated diversified substrate derivatization. Moreover, dimeric campesine G shows good insecticidal activity against global honeybee pest Galleria mellonella . Our study representative example discovering monomeric microbial resources, expands our knowledge supports further development newly engineered compounds as potential biopesticides.

Language: Английский

Citations

4
Developing filamentous fungal chassis for natural product production DOI
Jie Fan, Peng‐Lin Wei, Yuanyuan Li

et al.

Bioresource Technology, Journal Year: 2024, Volume and Issue: unknown, P. 131703 - 131703

Published: Oct. 1, 2024

Language: Английский

Citations

4
Discovery and Characterization of a Fungal N-acetylglucosamine Transferase in the Biosynthesis of Furanone Glycosides DOI

Yongchun Zhu,

Xianyan Zhang, Chuanteng Ma

et al.

Journal of Natural Products, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 30, 2025

Malfilamentosides are a class of fungal secondary metabolites characterized by glycosylated furanone scaffold; however, the enzyme that catalyzes O-glycosylation core with N-acetylglucosamine (GlcNAc) has not yet been identified. In this study, we discovered and identified biosynthetic gene cluster malfilamentosides. vivo in vitro investigations revealed glycosyltransferase, MftB, scaffold GlcNAc. Furthermore, MftB exhibits broad promiscuity toward glycosyl donors acceptors, highlighting its potential glycoside production.

Language: Английский

Citations

0