Cyclic Sesquiterpene–Flavanone [4+2] Hybrids, Syzygioblanes A–C, Found in an Indonesian Traditional Medicine, “Jampu Salo” (Syzygium oblanceolatum) DOI

N. Koga,

Yohei Saito, Katsunori Miyake

et al.

Organic Letters, Journal Year: 2024, Volume and Issue: 26(20), P. 4302 - 4307

Published: May 10, 2024

A plant used in an Indonesian traditional herbal medicine as a diabetes treatment and known locally "Jampu Salo" was collected on Sulawesi Island, Indonesia. It identified Syzygium oblanceolatum (C. B. Rob.) Merr. (Myrtaceae) found for the first time Sulawesi; it previously reported only eastern Philippines Borneo. phytochemical study of S. led to isolation three unprecedented meroterpenoids, syzygioblanes A–C (1–3, respectively). These compounds might be biosynthesized through [4+2] cycloaddition various germacrane-based cyclic sesquiterpenoids with flavone desmethoxymatteucinol form spiro skeleton. The unique complex structures were elucidated by microcrystal electron diffraction analysis addition general analytical techniques such high-resolution mass spectrometry, nuclear magnetic resonance methods, infrared spectroscopy. Synchrotron X-ray calculations electronic circular dichroism spectra helped determine absolute configurations. newly isolated exhibited collateral sensitivity more strongly inhibit growth multidrug resistant tumor cell line compared chemosensitive line.

Language: Английский

Strategies for Engineering Natural Product Biosynthesis in Fungi DOI Creative Commons
Elizabeth Skellam

Trends in biotechnology, Journal Year: 2018, Volume and Issue: 37(4), P. 416 - 427

Published: Oct. 10, 2018

Fungi are a prolific source of bioactive compounds, some which have been developed as essential medicines and life-enhancing drugs. Genome sequencing has revealed that fungi the potential to produce considerably more natural products (NPs) than typically observed in laboratory. Recently, there significant advances identification, understanding, engineering fungal biosynthetic gene clusters (BGCs). This review briefly describes examples NP biosynthesis at global, pathway, enzyme level using vivo vitro approaches refers range scale heterologous expression systems available, developments combinatorial biosynthesis, progress understanding how BGCs regulated, applications these novel enzymes biocatalysts.

Language: Английский

Citations

78
Genome Mining of Alkaloidal Terpenoids from a Hybrid Terpene and Nonribosomal Peptide Biosynthetic Pathway DOI
Danielle A. Yee,

Thomas B. Kakule,

Wei Cheng

et al.

Journal of the American Chemical Society, Journal Year: 2019, Volume and Issue: 142(2), P. 710 - 714

Published: Dec. 28, 2019

Biosynthetic pathways containing multiple core enzymes have potential to produce structurally complex natural products. Here we mined a fungal gene cluster that contains two predicted terpene cyclases (TCs) and nonribosomal peptide synthetase (NRPS). We showed the flv pathway produces flavunoidine 1, an alkaloidal terpenoid. The of 1 is tetracyclic, cage-like, oxygenated sesquiterpene connected dimethylcadaverine via C–N bond acylated with 5,5-dimethyl-l-pipecolate. roles all are established on basis metabolite analysis from heterologous expression.

Language: Английский

Citations

60
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

56
Harnessing ortho-Quinone Methides in Natural Product Biosynthesis and Biocatalysis DOI
Trevor N. Purdy, Bradley S. Moore, April L. Lukowski

et al.

Journal of Natural Products, Journal Year: 2022, Volume and Issue: 85(3), P. 688 - 701

Published: Feb. 2, 2022

The implementation of ortho-quinone methide (o-QM) intermediates in complex molecule assembly represents a remarkably efficient strategy designed by Nature and utilized synthetic chemists. o-QMs have been taken advantage biomimetic syntheses for decades, yet relatively few examples o-QM-generating enzymes natural product biosynthetic pathways reported. that discovered thus far exhibit tremendous potential biocatalytic applications, enabling the selective production desirable compounds are otherwise intractable or inherently difficult to achieve traditional methods. Characterization this machinery has shine light on new capable similar chemistry diverse substrates, expanding our knowledge Nature's catalytic repertoire. presently known include flavin-dependent oxidases, hetero-Diels–Alderases, S-adenosyl-l-methionine-dependent pericyclases, α-ketoglutarate-dependent nonheme iron enzymes. In review, we discuss their enzymatic mechanisms as biocatalysts constructing molecules such cannabinoids.

Language: Английский

Citations

31
Tandem intermolecular [4 + 2] cycloadditions are catalysed by glycosylated enzymes for natural product biosynthesis DOI
Jia-Wang Liu,

Jiayan Lu,

Chen Zhang

et al.

Nature Chemistry, Journal Year: 2023, Volume and Issue: 15(8), P. 1083 - 1090

Published: June 26, 2023

Language: Английский

Citations

20
Engineered and total biosynthesis of fungal specialized metabolites DOI
Russell J. Cox

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

Published: Jan. 3, 2024

Language: Английский

Citations

8
Discovery of fungal onoceroid triterpenoids through domainless enzyme-targeted global genome mining DOI Creative Commons
Jia Tang, Yudai Matsuda

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

Citations

7
Diterpene Biosynthesis in Actinomycetes: Studies on Cattleyene Synthase and Phomopsene Synthase DOI

Jan Rinkel,

Simon T. Steiner, Jeroen S. Dickschat

et al.

Angewandte Chemie International Edition, Journal Year: 2019, Volume and Issue: 58(27), P. 9230 - 9233

Published: May 1, 2019

Three diterpene synthases from actinomycetes have been studied. The first enzyme Streptomyces cattleya produced the novel compound cattleyene. other two enzymes Nocardia testacea and rhamnosiphila were identified as phomopsene synthases. cyclisation mechanism of cattleyene synthase EIMS fragmentation its product extensively studied by incubation experiments with isotopically labelled precursors. Oxidative transformations expanded chemical space these unique diterpenes.

Language: Английский

Citations

47
Synthetic Biology Driven Biosynthesis of Unnatural Tropolone Sesquiterpenoids DOI Creative Commons
Carsten Schotte, Lei Li, Daniel Wibberg

et al.

Angewandte Chemie International Edition, Journal Year: 2020, Volume and Issue: 59(52), P. 23870 - 23878

Published: Sept. 17, 2020

Tropolone sesquiterpenoids (TS) are an intriguing family of biologically active fungal meroterpenoids that arise through a unique intermolecular hetero Diels-Alder (hDA) reaction between humulene and tropolones. Here, we report on the combinatorial biosynthesis series unprecedented analogs TS pycnidione 1 xenovulene A 2. In systematic synthetic biology driven approach, recombined genes from three biosynthetic gene clusters (pycnidione 1, 2 eupenifeldin 3) in host Aspergillus oryzae NSAR1. Rational design reconstituted pathways granted control over number hDA reactions taking place, chemical nature fused polyketide moiety (tropolono- vs. monobenzo-pyranyl) degree hydroxylation. Formation unexpected monobenzopyranyl was investigated using isotope-feeding studies to reveal new highly unusual oxidative ring contraction rearrangement.

Language: Английский

Citations

45
Secondary metabolite biosynthetic diversity in the fungal family Hypoxylaceae and Xylaria hypoxylon DOI Creative Commons
Eric Kuhnert, Jorge C. Navarro-Muñoz, Kevin Becker

et al.

Studies in Mycology, Journal Year: 2021, Volume and Issue: 99(1), P. 100118 - 100118

Published: June 1, 2021

To date little is known about the genetic background that drives production and diversification of secondary metabolites in Hypoxylaceae . With recent availability high-quality genome sequences for 13 representative species one relative ( Xylaria hypoxylon ) we attempted to survey diversity biosynthetic pathways these organisms investigate their true potential as metabolite producers. Manual search strategies based on accumulated knowledge biosynthesis fungi enabled us identify 783 across 14 studied species, majority which were arranged gene clusters (BGC). The similarity BGCs was analysed with BiG-SCAPE engine organised into 375 cluster families (GCF). Only ten GCFs conserved all indicating speciation accompanied by changes metabolism. From compounds produced family members some can be directly correlated identified highlighted herein azaphilone, dihydroxynaphthalene, tropolone, cytochalasan, terrequinone, terphenyl brasilane giving insights evolution those compound classes. Vice versa , products various predicted through homology analysis from other shown ergot alkaloid, trigazaphilone, curvupallide, viridicatumtoxin swainsonine BGCs. However, had no obvious links or well-studied fungi. These findings highlight number strongly underrepresents a tremendous unidentified still hidden. Moreover, increasing numbers genomes further becoming available, likelihood revealing new encode new, potentially useful will significantly improve. Reaching better understanding biology producers, development methods manipulation, crucial access treasures.

Language: Английский

Citations

35