Bioinspired Synthesis of Microstegiol and Biosynthetically Related Skeleton-Rearranged Abietanes

Organic Letters, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 28, 2025

We report a bioinspired synthesis of microstegiol and biosynthetically related skeleton-rearranged abietane diterpenoids from commercially available carnosic acid. The strategy features Wagner-Meerwein type methyl migration followed by several cascade transformations, enabling the divergent five diterpenoids, including viridoquinone, prattinin A, saprorthoquinone, microstegiol, 1-deoxyviroxocin.

Language: Английский

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Discovery of bacterial terpenoids by genome mining

Methods in enzymology on CD-ROM/Methods in enzymology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

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Non-Canonical Type II Terpene Cyclases Deliver Rare Terpenoid Architectures

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: unknown

Published: March 17, 2025

Terpene cyclases (TCs) catalyze the generation of complex polycyclic terpenoids through elaborate mechanistic cascades. Very little is known about unusual type II TCs responsible for a large diverse family meroterpenoids as indole diterpenoids (IDTs). The radarins are insecticidal and cytotoxic IDTs that possess an core architecture which catalytic machinery unknown. Here, we interrogate genome Aspergillus fresenii to reveal biosynthetic delivering specific radarin scaffold. We demonstrate bespoke regioselective IDT epoxidase (RadM) acts at terminal olefin precursor 3′-geranylgeranylindole, providing access this distinct class architectures. Coexpression with noncanonical TC RadB led biosynthesis C, in skeletal rearrangement proceeds via rare alcoholic deprotonation ketone formation. Our modeling reveals catalysis by enabled unique His residue both proton donor acceptor. Intriguingly, coexpression RadM alternative A. cyclase gene, does not share His, revealed alternate partial cyclization 14,15-epoxy-3′-GGI, producing new decalin IDT. This work solves final piece puzzle full suite architectures, informs engineering efforts, expands repertoire impressive chemistry catalyzed TCs.

Language: Английский

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Deciphering a Distinct Biosynthetic Pathway for Meroterpenoids in Bacteria

Published: April 12, 2024

Meroterpenoids are hybrid natural products that arise from the integration of terpenoid and non-terpenoid biosynthetic pathways. While biosynthesis fungal meroterpenoids typically follows a well-established sequence prenylation, epoxidation, cyclization, pathways for bacterial perhydrophenanthrene remain poorly understood. In this study, we report construction an engineered metabolic pathway in Streptomyces production meroterpenoid, atolypene A (1). Our research reveals novel wherein structure is assembled through distinct divergent its counterparts. We demonstrate noncanonical class II terpene cyclase (TC) AtoE, E314 residue within characteristic E314TAE motif, functions as Brønsted acid, initiating cyclization by protonating epoxide. Additionally, bioinformatic analysis gene clusters (BGCs) contain AtoE-like TCs supports bacteria have potential to produce wide array meroterpenoids.

Language: Английский

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Discovery and biosynthesis of bacterial drimane-type sesquiterpenoids from Streptomyces clavuligerus

Beilstein Journal of Organic Chemistry, Journal Year: 2024, Volume and Issue: 20, P. 815 - 822

Published: April 16, 2024

Drimane-type sesquiterpenoids (DMTs) are characterized by a distinctive 6/6 bicyclic skeleton comprising the A and B rings. While DMTs commonly found in fungi plants, their presence bacteria has not been reported. Moreover, biosynthetic pathways for have primarily elucidated fungi, with identified P450s only acting on ring. In this study, we isolated three bacterial DMTs, namely 3β-hydroxydrimenol ( 2 ), 2α-hydroxydrimenol 3 3-ketodrimenol 4 from Streptomyces clavuligerus . Through genome mining heterologous expression, cav gene cluster responsible biosynthesis of – , along P450, CavA, introducing C-2 C-3 hydroxy groups. Furthermore, substrate scope CavA revealed its ability to hydroxylate drimenol analogs. This discovery broadens known chemical diversity bacteria, but also provides new insights into DMT bacteria.

Language: Английский

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Exploring and expanding the natural chemical space of bacterial diterpenes

Published: Aug. 30, 2024

Terpenoids are the largest family of natural products but relatively rare in bacteria. Genome mining reveals wide- spread prevalence terpene synthases, enzymes responsible for constructing hydrocarbon skeletons, Using an engineered E. coli diterpene production system, we screened 334 diverse synthases from 8 phyla, 17 classes, and 83 genera bacteria found that 125 (37%) were active as synthases. Isolation structural elucidation 28 bacterial diterpenes 31 TSs revealed three new skeletons previously unseen nature, known other organisms (e.g., coral, sponge, algae) with unknown biosynthetic pathways, fungi, plants) have not been seen bacteria, stereochemical isomers diterpenes. This study will lead to novel products, advances terpenoid biosynthesis roles these products.

Language: Английский

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Cyclo-farnesyl Diphosphate-Dependent Prenylation in Fungi

Organic Letters, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 23, 2024

A conserved two-gene cassette in fungi was discovered by genome mining, which encodes a UbiA family intramembrane prenyltansferase (VviA) and haloacid dehalogenase-like hydrolase terpene cyclase (VviB), respectively. series of

Language: Английский

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Prospecting Pharmacologically Active Biocompounds from the Amazon Rainforest: In Vitro Approaches, Mechanisms of Action Based on Chemical Structure, and Perspectives on Human Therapeutic Use

Pharmaceuticals, Journal Year: 2024, Volume and Issue: 17(11), P. 1449 - 1449

Published: Oct. 30, 2024

The Amazon rainforest is an important reservoir of biodiversity, offering vast potential for the discovery new bioactive compounds from plants. In vitro studies allow investigation biological processes and interventions in a controlled manner, making them fundamental pharmacological biotechnological research. These approaches are faster less costly than vivo studies, providing standardized conditions that enhance reproducibility precision data. However, methods have limitations, including inability to fully replicate complexity living organism absence complete physiological context. Translating results models not always straightforward, due differences pharmacokinetics interactions. this context, aim literature review assess advantages disadvantages search drugs Amazon, identifying challenges limitations associated with these comparing testing. Thus, bioprospecting involves evaluating plant extracts through bioassays investigate pharmacological, antimicrobial, anticancer activities. Phenolic terpenes frequently identified as main agents, exhibiting antioxidant, anti-inflammatory, antineoplastic Chemical characterization, molecular modifications, development delivery systems, such nanoparticles, highlighted improve therapeutic efficacy. Therefore, offers great drugs; however, significant challenges, standardization extraction need clinical trials, must be overcome become viable medications.

Language: Английский

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Between scents and sterols: Cyclization of labdane-related diterpenes as model systems for enzymatic control of carbocation cascades

Journal of Biological Chemistry, Journal Year: 2024, Volume and Issue: unknown, P. 108142 - 108142

Published: Dec. 1, 2024

The citrus scent arises from the volatile monoterpene limonene, whose cyclic nature can be viewed as a miniaturized form of poly-cyclic sterol triterpenoids. In particular, these rings are all formed poly-isoprenyl precursors via carbocation cascades. However, relevant reactions initiated by distinct mechanisms, either lysis/ionization an allylic diphosphate ester bond, in limonene synthases, or protonation terminal olefin epoxide, lanosterol synthases. Labdane-related diterpenoids unique their utilization both types reactions. With over 7,000 such natural products known, this pair clearly generates privileged scaffolds, hydrocarbon backbones which biological activity is readily derived. Moreover, enzymes serve model systems for terpene cyclization more generally. Indeed, investigation enzymatic structure-function relationships has highlighted importance catalytic base positioning within active site cavity specifying product outcome. Conversely, comparison to cyclases other terpenoid suggests new directions discovery and/or engineering those labdane-related diterpenoid biosynthesis.

Language: Английский

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Deciphering magnesium binding site and structure-function insights in a class II sesquiterpene cyclase

Methods in enzymology on CD-ROM/Methods in enzymology, Journal Year: 2024, Volume and Issue: unknown, P. 25 - 57

Published: Jan. 1, 2024

Language: Английский

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