Target Discovery of Dhilirane-Type Meroterpenoids by Biosynthesis Guidance and Tailoring Enzyme Catalysis DOI

Zhaolun Sun,

Mengyue Wu,

Boyuan Zhong

et al.

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(44), P. 30242 - 30251

Published: Oct. 25, 2024

Dhilirane-type meroterpenoids (DMs) featuring a 6/6/6/5/5 ring system represent rare group of fungal meroterpenoids. To date, merely 11 DMs have been isolated or derived, leaving their chemical diversity predominantly unexplored. Herein, we leverage an understanding biosynthesis to develop workflow for discovery by genome mining, metabolite analysis, and tailoring enzyme catalysis. Twenty-three new DMs, including seven unprecedented scaffolds, were consequently identified. An α-ketoglutarate (α-KG)-dependent oxygenase DhiD was found catalyze the stereodivergent contraction dhilirolide D form dhilirane skeleton; while cytochrome P450 DhiH reshaped structural establishing diverse C-C bonds oxidation. Crystallographic mutagenesis experiments provide molecular basis reaction its products. Notably, exhibits substrate-controlled catalytic versatility in expansion through contraction, hydroxylation, dehydrogenation, epoxidation, isomerization, epimerization, α-ketol cleavage. Bioassay results demonstrated that obtained exhibited anti-inflammatory insecticidal activities. Our work provides insight into nature's arsenal DM functional α-KG-dependent P450, which can be applied target diversification DM-type natural

Language: Английский

Supramolecular coordination cages as crystalline sponges through a symmetry mismatch strategy DOI
Wei He, Yi-Hsiang Yu, Kenta Iizuka

et al.

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

Published: March 5, 2025

Language: Английский

Citations

3
The chemistry and biology of fungal meroterpenoids (2009–2019) DOI
Minghua Jiang, Zhenger Wu,

Lan Liu

et al.

Organic & Biomolecular Chemistry, Journal Year: 2020, Volume and Issue: 19(8), P. 1644 - 1704

Published: Dec. 10, 2020

Fungal meroterpenoids are secondary metabolites from mixed terpene-biosynthetic origins. Their intriguing chemical structural diversification and complexity, potential bioactivities, pharmacological significance make them attractive targets in natural product chemistry, organic synthesis, biosynthesis. This review provides a systematic overview of the isolation, features, biological activities, fungal biodiversity 1585 novel 79 genera terrestrial marine-derived fungi including macrofungi, Basidiomycetes, 441 research papers 2009-2019. Based on nonterpenoid starting moiety their biosynthesis pathway, were classified into four categories (polyketide-terpenoid, indole-, shikimate-, miscellaneous-) with polyketide-terpenoids (mainly tetraketide-) shikimate-terpenoids as primary source. Basidiomycota produced 37.5% meroterpenoids, mostly shikimate-terpenoids. The Ganoderma, Penicillium, Aspergillus, Stachybotrys dominant producers. Moreover, about 56% display various pronounced cytotoxicity, enzyme inhibition, antibacterial, anti-inflammatory, antiviral, antifungal activities. It's exciting that several antroquinonol 4-acetyl B developed phase II clinically used drugs. We assume diversity therapeutic these will provide biologists medicinal chemists large promising sustainable treasure-trove for drug discovery.

Language: Английский

Citations

114
Charting the Evolution of Chemoenzymatic Strategies in the Syntheses of Complex Natural Products DOI
Carter N. Stout,

Nour Wasfy,

Fang Chen

et al.

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(33), P. 18161 - 18181

Published: Aug. 8, 2023

Bolstered by recent advances in bioinformatics, genetics, and enzyme engineering, the field of chemoenzymatic synthesis has enjoyed a rapid increase popularity utility. This Perspective explores integration enzymes into multistep chemical syntheses, highlighting unique potential biocatalytic transformations to streamline complex natural products. In particular, we identify four primary conceptual approaches illustrate each with number landmark case studies. Future opportunities challenges are also discussed.

Language: Английский

Citations

24
Chemistry of fungal meroterpenoid cyclases DOI
Lena Barra, Ikuro Abe

Natural Product Reports, Journal Year: 2020, Volume and Issue: 38(3), P. 566 - 585

Published: Oct. 1, 2020

Covering: up to July 2020Fungal meroterpenoid cyclases are a recently discovered emerging family of membrane-integrated, non-canonical terpene cyclases. They catalyze the conversion hybrid isoprenic precursors towards complex scaffolds and therefore great importance in structure diversification biosynthesis. The products these pathways exhibit intriguing molecular highly potent bioactivities, making them privileged structures from Nature attractive candidates for drug development or industrial applications. This review will provide comprehensive comparative view on fungal cyclases, their chemistries scaffold formation step polycyclic natural products.

Language: Английский

Citations

57
Two Cytochrome P450 Enzymes Form the Tricyclic Nested Skeleton of Meroterpenoids by Sequential Oxidative Reactions DOI

Erlan Yang,

Yongpeng Yao, Hao Su

et al.

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: unknown

Published: April 11, 2024

Meroterpenoid clavilactones feature a unique benzo-fused ten-membered carbocyclic ring unit with an α,β-epoxy-γ-lactone moiety, forming intriguing 10/5/3 tricyclic nested skeleton. These compounds are good inhibitors of the tyrosine kinase, attracting lot chemical synthesis studies. However, natural enzymes involved in formation skeleton remain unexplored. Here, we identified gene cluster responsible for biosynthesis clavilactone A basidiomycetous fungus Clitocybe clavipes. We showed that key cytochrome P450 monooxygenase ClaR catalyzes diradical coupling reaction between intramolecular hydroquinone and allyl moieties to form unit, followed by ClaT exquisitely stereoselectively assembles moiety biosynthesis. unprecedentedly acts as macrocyclase catalyze oxidative cyclization isopentenyl nonterpenoid macrocycle, multifunctional ten-electron oxidation accomplish clavilactones. Our findings establish foundation efficient production using synthetic biology approaches provide mechanistic insights into macrocycle fungal meroterpenoids.

Language: Английский

Citations

7
Advanced crystallography for structure determination of natural products DOI Creative Commons
Jian‐Guo Song, Wen‐Cai Ye, Ying Wang

et al.

Natural Product Reports, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Four cutting-edge crystallography strategies for structure elucidation of natural products that are difficult to crystallize or in nanocrystalline form.

Language: Английский

Citations

1
Total Synthesis of DMOA-Derived Meroterpenoids: Achieving Selectivity in the Synthesis of (+)-Berkeleyacetal D and (+)-Peniciacetal I DOI
Jianpeng Zhang,

Xiaotong Luo,

Jingfu Zhang

et al.

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

Published: Feb. 4, 2025

The synthesis of complex natural products requires efficient control over chemoselectivity, stereoselectivity, and regioselectivity. Berkeleyacetals, a subfamily 3,5-dimethylorsellinic acid (DMOA)-derived meroterpenoids, pose substantial synthetic challenges due to their densely functionalized highly oxidized architectures, which have constrained efforts. Here, we present the first total this class DMOA-derived specifically (+)-berkeleyacetal D (+)-peniciacetal I. Our approach features chemoselective deprotonation followed by an intramolecular single-electron transfer (SET) from enolate alkyl bromide, enabling construction 2,3-dihydrofuran ring in berkeleyacetal D. Additional selective transformations include endo-selective Diels–Alder reaction, methylations semihydrogenation [3]dendralene, solvent-controlled diastereoselective epoxidation. Beyond providing route these congested products, our study offers mechanistic insights into achieving selectivity assembly architecturally demanding molecules.

Language: Английский

Citations

1
A Chiral-Pool-Based Strategy to Access trans-syn-Fused Drimane Meroterpenoids: Chemoenzymatic Total Syntheses of Polysin, N-Acetyl-polyveoline and the Chrodrimanins DOI
Fuzhuo Li, Hans Renata

Journal of the American Chemical Society, Journal Year: 2021, Volume and Issue: 143(43), P. 18280 - 18286

Published: Oct. 20, 2021

trans-syn-Fused drimane meroterpenoids are unique natural products that arise from contra-thermodynamic polycyclizations of their polyene precursors. Herein we report the first total syntheses four trans-syn-fused meroterpenoids, namely polysin, N-acetyl-polyveoline, chrodrimanin C, and verruculide A, in 7–18 steps sclareolide. The unit is accessed through an efficient acid-mediated C9 epimerization Subsequent applications enzymatic C–H oxidation contemporary annulation methodologies install requisite C3 hydroxyl group enable rapid generation structural complexity to provide concise access these products.

Language: Английский

Citations

36
Enantioselective Total Synthesis of Hyperforin and Pyrohyperforin DOI

Yunpeng Ji,

Benke Hong,

Ivan Franzoni

et al.

Angewandte Chemie International Edition, Journal Year: 2022, Volume and Issue: 61(16)

Published: Feb. 7, 2022

Capitalizing on the late-stage diversification of an essential 1,3-diene intermediate, we describe herein a 9-step enantioselective total synthesis (+)-hyperforin and (+)-pyrohyperforin, starting from commercially available allylacetone. Our convergent features series critical reactions: 1) deconjugative α-alkylation α,β-unsaturated acid using chiral lithium amides as noncovalent stereodirecting auxiliaries; 2) HfCl4 -mediated carbonyl α-tert-alkylation to forge intricate bicyclo[3.3.1]nonane framework; 3) abiotic cascade pyran formation; 4) selective 1,4-semihydrogenation polyenes. During course our synthesis, also identified 1,2-cyclopropanediol overbred intermediate which was responsible for precursor formation through controlled fragmentation.

Language: Английский

Citations

20
Unified, Asymmetric Total Synthesis of the Asnovolins and Related Spiromeroterpenoids: A Fragment Coupling Approach DOI
Feng Yang, John A. Porco

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(28), P. 12970 - 12978

Published: July 6, 2022

3,5-Dimethylorsellinic acid (DMOA)-derived spiromeroterpenoids are a unique natural product family with attractive structures, unconventional stereochemistry, and potent biological activities. Herein, we report the first asymmetric total syntheses of asnovolins, DMOA-derived spiromeroterpenoids. The spirocyclic skeleton was efficiently assembled through sterically hindered bis-neopentyl 1,2-addition coupling/oxidative Michael addition sequence. unusual axial C12-methyl stereochemistry established via metal hydrogen atom transfer (MHAT) reduction involving chair-to-boat conformational change. mechanism HAT process studied both deuterium labeling computational studies. Attempted late-stage alkene isomerization an exocyclic enone proved to be challenging resulted in hetero-Diels–Alder dimerization, which ultimately led development alternative desaturation/coupling Endgame core modifications including orthogonal desaturation, Sc(III)-promoted regioselective Baeyer–Villiger oxidation, Meerwein–Ponndorf–Verley enabled collective five asnovolin-related products. This study demonstrates utility anionic fragment coupling assemble congested molecular framework provides foundation for synthesis spiromeroterpenoid congeners higher oxidation states

Language: Английский

Citations

20