Explainable deep learning and virtual evolution identifies antimicrobial peptides with activity against multidrug-resistant human pathogens

Nature Microbiology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 17, 2025

Language: Английский

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High-efficient production of mushroom polyketide compounds in a platform host Aspergillus oryzae

Microbial Cell Factories, Journal Year: 2023, Volume and Issue: 22(1)

Published: March 30, 2023

Abstract Background Orsellinic acid (2,4-dihydroxy-6-methylbenzoic acid, OA) and its structural analog o -Orsellinaldehyde, have become widely used intermediates in clinical drugs synthesis. Although the research on biosynthesis of such compounds has made significant progress, due to lack suitable hosts, there is still far from industrial production based synthetic biology. Results With help genome mining, we found a polyketide synthase (PKS, HerA) Hericium erinaceus , which shares 60% amino sequence homology with ArmB Armillaria mellea an identified PKS capable synthesizing OA. To characterize function HerA, cloned herA heterologously expressed it Aspergillus oryzae successfully detected Subsequently, introduction incomplete (Pks5) Ustilago maydis containing only three domains (AMP-ACP-R), was into -containing A. resulted -Orsellinaldehyde. Considering economic value OA then optimized yield these . The screening showed that when maltose as carbon source, yields -Orsellinaldehyde were 57.68 mg/L 15.71 respectively, while 340.41 mg/Kg 84.79 respectively rice medium for 10 days. Conclusions Herein, genes basidiomycetes using heterologous host. As fungus ascomycetes, not correctly splices multiple introns, but also efficiently produces their metabolites. This study highlights excellent host fungal natural products, potential efficient chassis basidiomycete secondary metabolites Graphical

Language: Английский

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Harnessing the potential: advances in cyanobacterial natural product research and biotechnology

Natural Product Reports, Journal Year: 2023, Volume and Issue: 41(3), P. 347 - 369

Published: Dec. 13, 2023

Covering: 2000 to 2023Cyanobacteria produce a variety of bioactive natural products that can pose threat humans and animals as environmental toxins, but also have potential for or inspire pharmaceutical use. As oxygenic phototrophs, cyanobacteria furthermore hold great promise sustainable biotechnology. Yet, the necessary tools exploiting their biotechnological so far been established only few model strains cyanobacteria, while large untapped biosynthetic resources are hidden in slow-growing cyanobacterial genera difficult access by genetic techniques. In recent years, several approaches developed circumvent bottlenecks product research. Here, we summarize current progress has made unlocking characterizing cryptic metabolic pathways using integrated omics techniques, orphan gene cluster activation, use original producers, heterologous expression chemo-enzymatic We mainly highlighting genomic mining concepts strategies towards high-titer production from last 10 years discuss need further research developments this field.

Language: Английский

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Combinatorial biosynthesis for the engineering of novel fungal natural products

Communications Chemistry, Journal Year: 2024, Volume and Issue: 7(1)

Published: April 18, 2024

Abstract Natural products are small molecules synthesized by fungi, bacteria and plants, which historically have had a profound effect on human health quality of life. These natural evolved over millions years resulting in specific biological functions that may be interest for pharmaceutical, agricultural, or nutraceutical use. Often need to structurally modified make them suitable applications. Combinatorial biosynthesis is method alter the composition enzymes needed synthesize product diversified molecules. In this review we discuss different approaches combinatorial via engineering fungal biosynthetic pathways. We highlight knowledge gained from these studies provide examples new-to-nature bioactive molecules, including using combinations non-fungal enzymes.

Language: Английский

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Discovery of fungal onoceroid triterpenoids through domainless enzyme-targeted global genome mining

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: May 21, 2024

Abstract Genomics-guided methodologies have revolutionized the discovery of natural products. However, a major challenge in field genome mining is determining how to selectively extract biosynthetic gene clusters (BGCs) for untapped products from numerous available sequences. In this study, we developed fungal tool that extracts BGCs encoding enzymes lack detectable protein domain (i.e., domainless enzymes) and are not recognized as proteins by existing bioinformatic tools. We searched homologue Pyr4-family terpene cyclases, which representative examples apparently enzymes, approximately 2000 genomes discovered several with unique features. The subsequent characterization selected led onoceroid triterpenoids unprecedented synthases. Furthermore, addition onoceroids, previously unreported sesquiterpene hydroquinone, biosynthesis involves cyclase, was obtained. Our has broad applicability can serve beneficial platform accessing diverse, unexploited

Language: Английский

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Recent advances in genome mining and synthetic biology for discovery and biosynthesis of natural products

Critical Reviews in Biotechnology, Journal Year: 2024, Volume and Issue: unknown, P. 1 - 21

Published: Aug. 12, 2024

Natural products have long served as critical raw materials in chemical and pharmaceutical manufacturing, primarily which can provide superior scaffolds or intermediates for drug discovery development. Over the last century, natural contributed to more than a third of therapeutic production. However, traditional methods producing drugs from become less efficient expensive over past few decades. The combined utilization genome mining synthetic biology based on sequencing, bioinformatics tools, big data analytics, genetic engineering, metabolic systems promises counter this trend. Here, we reviewed recent (2020–2023) examples used resolve challenges production products, such variety, poor efficiency, low yield. Additionally, emerging design principles, building strategies its application prospects NPs synthesis also been discussed.

Language: Английский

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Engineered and total biosynthesis of fungal specialized metabolites

Nature Reviews Chemistry, Journal Year: 2024, Volume and Issue: 8(1), P. 61 - 78

Published: Jan. 3, 2024

Language: Английский

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Characterization and structural analysis of a versatile aromatic prenyltransferase for imidazole-containing diketopiperazines

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 2, 2025

Prenylation modifications of natural products play essential roles in chemical diversity and bioactivities, but imidazole modification prenyltransferases are not well investigated. Here, we discover a dimethylallyl tryptophan synthase family prenyltransferase, AuraA, that catalyzes the rare dimethylallylation on moiety biosynthesis aurantiamine. Biochemical assays validate AuraA could accept both cyclo-(L-Val-L-His) cyclo-(L-Val-DH-His) as substrates, while prenylation modes completely different, yielding C2-regular C5-reverse products, respectively. Cryo-electron microscopy analysis its two ternary complex structures reveal distinct for receptor binding, demonstrating tolerance altered orientations highly similar receptors. The mutation experiments further demonstrate promiscuity towards imidazole-C-dimethylallylation. In this work, also characterize case mutant-catalyzed moiety, offering available structural insights into utilization engineering prenyltransferases. authors

Language: Английский

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Discovery and heterologous biosynthesis of glycosylated polyketide luteodienoside A reveals unprecedented glucinol-mediated product offloading by a fungal carnitine O-acyltransferase domain

Chemical Science, Journal Year: 2024, Volume and Issue: 15(9), P. 3349 - 3356

Published: Jan. 1, 2024

Luteodienoside A is a novel glycosylated polyketide produced by the Australian fungus Aspergillus luteorubrus MST-FP2246, consisting of an unusual 1-O-β-d-glucopyranosyl-myo-inositol (glucinol) ester 3-hydroxy-2,2,4-trimethylocta-4,6-dienoic acid. Mining genome A. identified putative gene cluster for luteodienoside biosynthesis (ltb), harbouring highly reducing synthase (HR-PKS, LtbA) fused at its C-terminus to carnitine O-acyltransferase (cAT) domain. Heterologous pathway reconstitution in nidulans, substrate feeding assays and truncation confirmed identity ltb demonstrated that cAT domain essential offloading from upstream HR-PKS. Unlike previously characterised domains, LtbA uses glucinol as release product Furthermore, PKS methyltransferase (MT) capable catalysing gem-dimethylation acid intermediate, without requiring reversible recapture This study expands repertoire modifications known be catalysed domains highlights potential mining fungal genomes this subclass PKSs discover new structurally diverse secondary metabolites.

Language: Английский

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Recent advances of activation techniques-based discovery of new compounds from marine fungi

Fitoterapia, Journal Year: 2023, Volume and Issue: 167, P. 105503 - 105503

Published: April 8, 2023

Language: Английский

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