Methodology for awakening the potential secondary metabolic capacity in actinomycetes

• Shun Saito and
• Midori A. Arai

Beilstein J. Org. Chem. 2024, 20, 753–766, doi:10.3762/bjoc.20.69

• secondary metabolism in actinomycetes. The technique known as “heterologous expression”, in which a biosynthetic gene cluster of a secondary metabolite is introduced into another organism, is a useful method for producing silent secondary metabolites (Figure 2a). For example, the cryptic trans

• ansaseomycins A (3) and B. A number of factors associated with the biosynthetic gene clusters of secondary metabolites regulate their expression; thus, controlling these factors can also be used to activate secondary metabolism (Figure 2b). For example, the production of some secondary metabolites in

• [46]. Finally, several studies have reported the modulation of secondary metabolic activation in actinomycetes using small molecules. For example, Ochi et al. proposed the “ribosome engineering” technique, in which actinomycetes are cultured with antibiotics to activate secondary metabolism by

Identification of the p-coumaric acid biosynthetic gene cluster in Kutzneria albida: insights into the diazotization-dependent deamination pathway

• Seiji Kawai,
• Akito Yamada,
• Yohei Katsuyama and
• Yasuo Ohnishi

Beilstein J. Org. Chem. 2024, 20, 1–11, doi:10.3762/bjoc.20.1

• [4]. To further understand the role of the ANS pathway in secondary metabolism, we recently identified the BGC for avenalumic acid (ava cluster, see the lower right corner of Figure 1B for its structure) by genome mining targeting the ANS pathway in Streptomyces sp. RI-77, and revealed its entire

• characterized in actinomycetes [27][28]. The Cma system may have some advantages over the general p-coumaric acid biosynthetic pathways when actinomycetes evolutionally develop the p-coumaric acid biosynthetic pathway in secondary metabolism. We identified CmaA6 as an ATP-dependent 3-ACA diazotase that showed a

Navigating and expanding the roadmap of natural product genome mining tools

• Friederike Biermann,
• Sebastian L. Wenski and
• Eric J. N. Helfrich

Beilstein J. Org. Chem. 2022, 18, 1656–1671, doi:10.3762/bjoc.18.178

• structures. Single gene duplication events are filtered out and all known BGCs are excluded in a similar fashion as in the gcBGC approach. The presence of prototypical tailoring enzymes ubiquitously distributed in secondary metabolism might serve as an additional line of evidence for a functional NP BGC

• : polytheonamide A (13) [76], closthioamide (14) [77], and biarylitide YYH (15) [33]. gcBGC prioritization process. The bar represents all identified gene clusters in one organism and is subdivided into primary (green) on the left and secondary metabolism (yellow) on the right. Gene clusters associated with

• primary or secondary metabolism (both ends of the spectrum) are identified using the strategies listed below the bar and subsequently excluded from further analysis. gcBGC aims at identifying as-of-yet overlooked BGCs that cannot be detected by state-of-the-art bioinformatic platforms, here referred to as

Tenacibactins K–M, cytotoxic siderophores from a coral-associated gliding bacterium of the genus Tenacibaculum

• Yasuhiro Igarashi,
• Yiwei Ge,
• Tao Zhou,
• Amit Raj Sharma,
• Enjuro Harunari,
• Naoya Oku and
• Agus Trianto

Beilstein J. Org. Chem. 2022, 18, 110–119, doi:10.3762/bjoc.18.12

• from 2.5 to 7.9 Mbp, biosynthetic gene clusters for siderophores, terpenes, and non-ribosomal peptides were identified by genome mining [39], suggesting a high capability of secondary metabolism in this genus. Further investigation is underway to disclose the actual diversity of metabolites from the

Unsaturated fatty acids and a prenylated tryptophan derivative from a rare actinomycete of the genus Couchioplanes

• Shun Saito,
• Kanji Indo,
• Naoya Oku,
• Hisayuki Komaki,
• Masashi Kawasaki and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2021, 17, 2939–2949, doi:10.3762/bjoc.17.203

• [35]. Further chemical exploration on the genus Couchioplanes will disclose its actual biosynthetic capacity in secondary metabolism. Experimental General experimental procedures Optical rotations were measured using a JASCO P-1030 polarimeter. UV spectra were recorded on a Shimadzu UV-1800 UV–vis

Natural products in the predatory defence of the filamentous fungal pathogen Aspergillus fumigatus

• Jana M. Boysen,
• Nauman Saeed and
• Falk Hillmann

Beilstein J. Org. Chem. 2021, 17, 1814–1827, doi:10.3762/bjoc.17.124

• ; non-ribosomal peptides; polyketides; secondary metabolism; virulence; Introduction To thrive in their natural habitats all organisms from bacteria and fungi to plants and animals need access to sufficient nutritional sources and have to defend themselves against both, competitors and predators

• . aurantium), nematodes (e.g., Aphelenchus avenae) or arthropods like insects, mites and springtails (e.g., F. candida) [35][36][37][38][39]. However, the fungus may also act as a pathogen causing often lethal infections in immune-compromised patients, and thus its secondary metabolism was extensively studied

4-Hydroxy-3-methyl-2(1H)-quinolone, originally discovered from a Brassicaceae plant, produced by a soil bacterium of the genus Burkholderia sp.: determination of a preferred tautomer and antioxidant activity

• Dandan Li,
• Naoya Oku,
• Yukiko Shinozaki,
• Yoichi Kurokawa and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2020, 16, 1489–1494, doi:10.3762/bjoc.16.124

• secondary metabolism [15]. In the course of our continuing studies on bioactive metabolites of less studied bacterial taxa [16], Burkholderia sp. 3Y-MMP, isolated from soil by an exhaustive enrichment culture under Zn2+-load, was selected for a detailed chemical study, which resulted in the isolation of 4

A cyclopeptide and three oligomycin-class polyketides produced by an underexplored actinomycete of the genus Pseudosporangium

• Shun Saito,
• Kota Atsumi,
• Tao Zhou,
• Keisuke Fukaya,
• Daisuke Urabe,
• Naoya Oku,
• Md. Rokon Ul Karim,
• Hisayuki Komaki and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2020, 16, 1100–1110, doi:10.3762/bjoc.16.97

• species demonstrated that the distribution of secondary metabolite biosynthetic genes was not the same even in phylogenetically close species [11]. This finding became our starting point to explore the secondary metabolism in actinomycete genera from which no secondary metabolites were described. “Rare

Pigmentosins from Gibellula sp. as antibiofilm agents and a new glycosylated asperfuran from Cordyceps javanica

• Soleiman E. Helaly,
• Wilawan Kuephadungphan,
• Patima Phainuphong,
• Mahmoud A. A. Ibrahim,
• Kanoksri Tasanathai,
• Suchada Mongkolsamrit,
• Janet Jennifer Luangsa-ard,
• Souwalak Phongpaichit,
• Vatcharin Rukachaisirikul and
• Marc Stadler

Beilstein J. Org. Chem. 2019, 15, 2968–2981, doi:10.3762/bjoc.15.293

• them as promising candidates for alternative antibiofilm agents. We hope that our findings will also help to raise the general scientific interest in invertebrate-pathogenic fungi, and in particular in the taxonomy and secondary metabolism of the spider pathogens. Experimental General 1D and 2D NMR

Isolation of fungi using the diffusion chamber device FIND technology

• Benjamin Libor,
• Henrik Harms,
• Stefan Kehraus,
• Ekaterina Egereva,
• Max Crüsemann and
• Gabriele M. König

Beilstein J. Org. Chem. 2019, 15, 2191–2203, doi:10.3762/bjoc.15.216

• play a prominent role as lead structures in drug discovery [1]. Apart from bacteria, fungi are an impressive group of microorganisms in this respect, due to the high structural diversity of their rich secondary metabolism. Fungi are known as producers of many therapeutically important drugs, such as

Molecular basis for the plasticity of aromatic prenyltransferases in hapalindole biosynthesis

• Takayoshi Awakawa and
• Ikuro Abe

Beilstein J. Org. Chem. 2019, 15, 1545–1551, doi:10.3762/bjoc.15.157

• bioactive compounds, because the prenylated compounds exhibit better bioactivities due to their improved interactions with biological membranes [3]. The aromatic PTase superfamily involved in the secondary metabolism consists of the ABBA (α-β-β-α barrel)-type [4][5], the dimethylallyltryptophan synthase

Genomics-inspired discovery of massiliachelin, an agrochelin epimer from Massilia sp. NR 4-1

• Jan Diettrich,
• Hirokazu Kage and
• Markus Nett

Beilstein J. Org. Chem. 2019, 15, 1298–1303, doi:10.3762/bjoc.15.128

• ]. In this study, we analyzed the β-proteobacterium Massilia sp. NR 4-1, which had been isolated from a soil sample collected under a nutmeg tree [6]. Although, this strain had already been identified as producer of the antibiotic violacein [6], still not much is known about its secondary metabolism or

Phylogenomic analyses and distribution of terpene synthases among Streptomyces

• Lara Martín-Sánchez,
• Kumar Saurabh Singh,
• Mariana Avalos,
• Gilles P. van Wezel,
• Jeroen S. Dickschat and
• Paolina Garbeva

Beilstein J. Org. Chem. 2019, 15, 1181–1193, doi:10.3762/bjoc.15.115

• transfers of terpene synthase genes in Streptomyces, but could also point to secondary metabolite genes as being less conserved than housekeeping (primary metabolism) genes. Rapid evolution of secondary metabolism can lead to new natural products with advanced ecological functions in specific ecological

New terpenoids from the fermentation broth of the edible mushroom Cyclocybe aegerita

• Frank Surup,
• Florian Hennicke,
• Nadine Sella,
• Maria Stroot,
• Steffen Bernecker,
• Sebastian Pfütze,
• Marc Stadler and
• Martin Rühl

Beilstein J. Org. Chem. 2019, 15, 1000–1007, doi:10.3762/bjoc.15.98

• liquid culture and could eventually serve as hosts for heterologous production of secondary metabolites derived from other Basidiomycota that are more difficult or even impossible to culture. With these goals in mind, we have initiated extensive studies of the secondary metabolism of the aforementioned

Two new 2-alkylquinolones, inhibitory to the fish skin ulcer pathogen Tenacibaculum maritimum, produced by a rhizobacterium of the genus Burkholderia sp.

• Dandan Li,
• Naoya Oku,
• Atsumi Hasada,
• Masafumi Shimizu and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2018, 14, 1446–1451, doi:10.3762/bjoc.14.122

• Burkholderia produce many more secondary metabolites than reported, as this group was previously classified into the genus Pseudomonas [8]. In fact, the high capacity of Burkholderia in secondary metabolism is demonstrated by the presence of unique functionalities, such as monocyclic 3-pyrazolone [9], α

• -aminoacrylonitrile, and thioimidazolinone [10], all of which are not preceded in metabolites from other taxa. The large genome size of Burkholderia also suggests a high capacity for secondary metabolism. According to the NCBI genome database (https://www.ncbi.nlm.nih.gov/genome/browse#!/prokaryotes/), the genome

Volatiles from three genome sequenced fungi from the genus Aspergillus

• Jeroen S. Dickschat,
• Ersin Celik and
• Nelson L. Brock

Beilstein J. Org. Chem. 2018, 14, 900–910, doi:10.3762/bjoc.14.77

• rich secondary metabolism with 807 compounds from 675 species that were recently summarised in the Aspergillus secondary metabolome database [14]. However, only a few studies about volatile natural products from Aspergillus are available [15][16][17][18][19][20][21][22]. Here we report on the volatiles

Biosynthetic origin of butyrolactol A, an antifungal polyketide produced by a marine-derived Streptomyces

• Enjuro Harunari,
• Hisayuki Komaki and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2017, 13, 441–450, doi:10.3762/bjoc.13.47

• diverse secondary metabolites with pharmaceutically useful bioactivities. Importantly, members of the genus Streptomyces have been the main source of drug discovery programs due to their high capacity in secondary metabolism including polyketides, peptides, terpenoids, alkaloids, and amino acid

Biochemical and structural characterisation of the second oxidative crosslinking step during the biosynthesis of the glycopeptide antibiotic A47934

• Veronika Ulrich,
• Clara Brieke and
• Max J. Cryle

Beilstein J. Org. Chem. 2016, 12, 2849–2864, doi:10.3762/bjoc.12.284

• of under 2.0 Å (Table 3). Other P450 enzymes with high structural similarity to StaF are those from secondary metabolism and involve oxidative functionalisation of large substrates, such as pravastatin (CYP105AS, PDB ID: 4OQS) [42], oleandomycin (OleP, PDB ID: 4XE3) [43], mycinamicin (MycG, PDB ID

Mechanistic investigations on six bacterial terpene cyclases

• Patrick Rabe,
• Thomas Schmitz and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2016, 12, 1839–1850, doi:10.3762/bjoc.12.173

• ploughed earth. Only recent research revealed that terpenes are in fact widespread in bacteria, in particular in actinomycetes and a few other taxa that are actively engaged in secondary metabolism [7][8][9]. Since a couple of years the rapidly evolved genome sequencing techniques allow for a mining of

Cyclisation mechanisms in the biosynthesis of ribosomally synthesised and post-translationally modified peptides

• Andrew W. Truman

Beilstein J. Org. Chem. 2016, 12, 1250–1268, doi:10.3762/bjoc.12.120

• the identification of homologous bacterial flavoproteins (Dfp) that catalyse the decarboxylation of 4’-phospho-N-pantothenoylcysteine to 4’-phosphopantetheine, which is essential for coenzyme A biosynthesis [68] (Figure 5B). This demonstrates how the mechanistic analysis of secondary metabolism can

Marine-derived myxobacteria of the suborder Nannocystineae: An underexplored source of structurally intriguing and biologically active metabolites

• Antonio Dávila-Céspedes,
• Peter Hufendiek,
• Max Crüsemann,
• Till F. Schäberle and
• Gabriele M. König

Beilstein J. Org. Chem. 2016, 12, 969–984, doi:10.3762/bjoc.12.96

• genome mining. Thus, knowledge derived from bioinformatic analysis of microbial genomes paved the way to gain detailed insights into bacterial secondary metabolism. Since then, in silico methods for genome mining have enormously advanced and effective experimental approaches for connecting genomic and

• homology to known biosynthetic genes. Compared to Myxococcus xanthus DK1622, the so far sequenced strains dedicate a similar or even larger portion of their genome of up to 10% to secondary metabolism. These “cryptic” or “silent” gene clusters may be addressed with different strategies [73], e.g., the

Antibiotics from predatory bacteria

• Juliane Korp,
• María S. Vela Gurovic and
• Markus Nett

Beilstein J. Org. Chem. 2016, 12, 594–607, doi:10.3762/bjoc.12.58

• possess impressive capacities for natural product biosynthesis. Here, we will present the results from recent chemical investigations of this bacterial group, compare the biosynthetic potential with that of non-predatory bacteria and discuss the link between predation and secondary metabolism. Keywords

• DK1622 chromosome with antiSMASH indicated the presence of 24 gene clusters, which are involved in the secondary metabolism (Table 2). Until now, six loci have been associated with isolated natural products on the basis of biosynthetic precedence and extensive metabolome analyses (Figure 1) [56][57

• regulators of secondary metabolism via DNA–protein pull-down assays [84]. Knock-out studies revealed that both EBPs are necessary for the formation of intact fruiting body and sporulation. DKxanthene biosynthesis was strongly influenced by HsfA and MXAN4899, respectively, which is in good agreement with the

Natural products from microbes associated with insects

• Christine Beemelmanns,
• Huijuan Guo,
• Maja Rischer and
• Michael Poulsen

Beilstein J. Org. Chem. 2016, 12, 314–327, doi:10.3762/bjoc.12.34

• light on the ecology and evolution of defensive associations. Keywords: biosynthesis; chemical ecology; natural products; secondary metabolism; structure elucidation; symbiosis; Introduction Although natural products represent the most consistently successful drug leads [1][2], many pharmaceutical

Recent highlights in biosynthesis research using stable isotopes

• Jan Rinkel and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2015, 11, 2493–2508, doi:10.3762/bjoc.11.271

• agreement with the detection of (ring-2H5)benzoic acid in culture extracts from labeling experiments with (ring-2H5)Phe. This interconversion of two proteinogenic amino acids in the biosynthesis of an NRPS compound from secondary metabolism is unprecedented and its discovery was strongly supported by the

• labeling experiments were used by Andexer et al. to elucidate the mechanism of chorismatases [74]. Biochemically, chorismate (68) plays an important role at the border of primary and secondary metabolism for many natural products made from aromatic building blocks [75]. Chorismatases were, e.g., found to

Tanzawaic acids I–L: Four new polyketides from Penicillium sp. IBWF104-06

• Louis P. Sandjo,
• Eckhard Thines,
• Till Opatz and
• Anja Schüffler

Beilstein J. Org. Chem. 2014, 10, 251–258, doi:10.3762/bjoc.10.20

• secondary metabolism of fungal species for the identification of novel lead structures for agrochemical and pharmaceutical research, we isolated a fungal strain from a soil sample. The culture filtrate extract of this organism was found to inhibit the conidial germination in the rice blast fungus