Activity assays of NnlA homologs suggest the natural product N-nitroglycine is degraded by diverse bacteria

• Kara A. Strickland,
• Brenda Martinez Rodriguez,
• Ashley A. Holland,
• Shelby Wagner,
• Michelle Luna-Alva,
• David E. Graham and
• Jonathan D. Caranto

Beilstein J. Org. Chem. 2024, 20, 830–840, doi:10.3762/bjoc.20.75

• . NNG is a non-proteinogenic amino acid, similar to other such N–N containing compounds such as piperazic acid and hydrazinoacetic acid [43]. These precursors are incorporated into larger NPs by non-ribosomal peptide synthases or polyketide synthases, and NNG may have a similar fate [44][45]. Another

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

• -acyltransferase polyketide synthase biosynthetic gene cluster sdl (80 kb) from Streptomyces sp. B59 was cloned and transferred into a heterologous host, Streptomyces albus J1074, resulting in the production of a class of polycyclic macrolide shuangdaolides A (1), B, and D and dumulmycin (2) [29]. Furthermore

• , genome mining of the marine actinomycete Streptomyces seoulensis A01 enabled the identification of a giant type I polyketide synthase gene cluster (asm) [30]. Heterologous expression of the cryptic asm cluster using a bacterial artificial chromosome vector in a heterologous host led to the production of

Substrate specificity of a ketosynthase domain involved in bacillaene biosynthesis

• Zhiyong Yin and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2024, 20, 734–740, doi:10.3762/bjoc.20.67

• second ketosynthase of the polyketide synthase BaeJ involved in bacillaene biosynthesis (BaeJ-KS2). For this purpose, both enantiomers of a 13C-labelled N-acetylcysteamine thioester (SNAC ester) surrogate of the proposed natural intermediate of BaeJ-KS2 were synthesised, including an enzymatic step with

• glutamate decarboxylase, and incubated with BaeJ-KS2. Substrate binding was demonstrated through 13C NMR analysis of the products against the background of various control experiments. Keywords: bacillaene; biosynthesis; enzyme mechanisms; isotopes; trans-AT polyketide synthases; Introduction Polyketides

• are a large class of natural products which often exhibit potent biological activities for their application in medicine, e.g., as antibiotics or immunosuppressants [1]. Despite their high structural variability all compounds from this class are commonly made through the action of polyketide synthases

Chemoenzymatic synthesis of macrocyclic peptides and polyketides via thioesterase-catalyzed macrocyclization

• Senze Qiao,
• Zhongyu Cheng and
• Fuzhuo Li

Beilstein J. Org. Chem. 2024, 20, 721–733, doi:10.3762/bjoc.20.66

• and multifunctional enzymatic assembly, nonribosomal peptide synthases (NRPS), polyketide synthases (PKS), and hybrid NRPS/PKS systems, which are organized into sets of functional domains known as modules and function through a similar mechanism [9][10][11][12]. Each NRPS module is composed of three

• terminal polyketide synthases (PKSs) in juvenimicin biosynthesis in 2017 [75], which presented a chance to accomplish the chemoenzymatic total syntheses of tylactone and the juvenimicins (Scheme 7). To generate an appropriately activated tylactone hexaketide intermediate 49, two key fragments, aldehyde 42

New variochelins from soil-isolated Variovorax sp. H002

• Jabal Rahmat Haedar,
• Aya Yoshimura and
• Toshiyuki Wakimoto

Beilstein J. Org. Chem. 2024, 20, 692–700, doi:10.3762/bjoc.20.63

• draft genome sequence of the H002 strain identified the variochelin biosynthetic gene cluster (var), which encodes PKS (polyketide synthase) and NRPS (non-ribosomal peptide synthetase) genes. Finally, the siderophores isolated in this study exhibited antibacterial activity against several bacteria

• in Supporting Information File 1). To investigate whether the identified var biosynthetic gene cluster is responsible for variochelin production, we substituted varG encoding the polyketide synthase (PKS) module with a chloramphenicol resistance (cmR) gene cassette, using homologous recombination

Production of non-natural 5-methylorsellinate-derived meroterpenoids in Aspergillus oryzae

• Jia Tang,
• Yixiang Zhang and
• Yudai Matsuda

Beilstein J. Org. Chem. 2024, 20, 638–644, doi:10.3762/bjoc.20.56

• a general understanding of their biosynthesis [7][8]. Polyketide–terpenoid hybrids are among the largest families of meroterpenoids. Orsellinic acid, an aromatic polyketide, and its analogues have been commonly identified as polyketide components in fungal meroterpenoids. Notably, 3,5

• polyketide moiety, contributing to structural diversification [9][10]. By contrast, in the biosynthesis of meroterpenoids derived from orsellinic acid and 5-methylorsellinic acid (5-MOA), the prenylation reaction typically occurs at the non-substituted carbon atom and thus preserves the aromaticity of the

• polyketide portion [11][12][13][14]. One exception has been found in funiculolide biosynthesis, in which a 5-MOA-derived phthalide undergoes dearomatizing prenylation catalyzed by the UbiA-like prenyltransferase FncB (Figure 1B) [15]. In addition to prenyltransferases, transmembrane terpene cyclases play a

Recent developments in the engineered biosynthesis of fungal meroterpenoids

• Zhiyang Quan and
• Takayoshi Awakawa

Beilstein J. Org. Chem. 2024, 20, 578–588, doi:10.3762/bjoc.20.50

• structures, and are partially derived from terpenoids [1]. Many fungal meroterpenoids are composed of polyketide and terpenoid moieties. Examples of fungal meroterpenoids include mycophenolic acid (Figure 1, 1), which shows immunosuppressive activity and cell differentiation-inducing activity by inhibiting

• Aspergillus oryzae, will be also introduced. Review Standard reactions of fungal meroterpenoid biosynthesis The skeletal diversity within this group of compounds arises from polyketide synthesis, prenyl transfer, terpenoid cyclizations, and post-cyclization modifications [5]. In these reactions, terpenoid

• metabolic genes for ease of gene transfer and high substance production capabilities [10][11]. The expression of trt4 (polyketide synthase, PKS), trt2 (prenyltransferase, PT), trt5 (methyltransferase, MT), trt8 (flavin-dependent monooxygenase, FMO), and trt1 (meroterpenoid cyclase, CYC) in A. oryzae NSAR1

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

• reaction enabled us to perform a kinetic analysis of AvaA7, which confirmed that AvaA7 catalyzes the denitrification of 3-diazoavenalumic acid in avenalumic acid biosynthesis. This study deepened our understanding of the highly reducing type II polyketide synthase system as well as the diazotization

• biosynthetic pathway [13]. In this pathway, 3-amino-4-hydroxybenzoic acid (3,4-AHBA, 1), synthesized by AvaH and AvaI, is loaded onto AvaA3 (carrier protein) by AvaA1 (AMP-dependent ligase), resulting in 3,4-AHBA-AvaA3. A highly reducing type II polyketide synthase (PKS) system [15][16] (AvaA2, A4, A5, and A8

• by co-expressing with the sfp gene to obtain the holo-form of CmaA3 [21]. We tested whether CmaA1 and holo-CmaA3 are involved in the initial reaction in polyketide synthesis similar to AvaA1 and AvaA3; AvaA1 loads 3,4-AHBA (1) onto holo-AvaA3 using ATP in the biosynthetic pathway of avenalumic acid

Secondary metabolites of Diaporthe cameroonensis, isolated from the Cameroonian medicinal plant Trema guineensis

• Bel Youssouf G. Mountessou,
• Élodie Gisèle M. Anoumedem,
• Blondelle M. Kemkuignou,
• Yasmina Marin-Felix,
• Frank Surup,
• Marc Stadler and
• Simeon F. Kouam

Beilstein J. Org. Chem. 2023, 19, 1555–1561, doi:10.3762/bjoc.19.112

• polyketide 1, and an acetylated alternariol 2 were isolated, along with fifteen known secondary metabolites. Their structures were established by extensive NMR spectroscopy and mass spectrometry analyses, as well as by comparison with literature data of their analogs. Keywords: alternariol; Diaporthe

• ; endophytic fungi; hemiketal polyketide; Introduction Endophytic fungi are organisms that reside almost ubiquitously inside the fresh healthy tissue of plants, and they may increase the resistance of the host tropical trees to survive in extreme conditions [1]. As the global diversity of endophytic fungi is

• great structural variability such as polyketides, terpenoids, polyketide synthase–nonribosomal peptide synthetase (PKS–NRPS) alkaloids, and cytochalasins, which have been considered as taxonomic markers of the genus [7][8][9][10]. However, it is worthwhile to mention that the name Phomopsis should no

Asymmetric synthesis of a stereopentade fragment toward latrunculins

• Benjamin Joyeux,
• Antoine Gamet,
• Nicolas Casaretto and
• Bastien Nay

Beilstein J. Org. Chem. 2023, 19, 428–433, doi:10.3762/bjoc.19.32

• the natural products. Keywords: allylation; aldol reaction; latrunculins; stereocontrol; total synthesis; Introduction Latrunculins constitute a class of marine polyketide natural products isolated from Sponges like Negombata (= Latrunculia) magnifica [1][2]. They are characterized by the presence

1,4-Dithianes: attractive C2-building blocks for the synthesis of complex molecular architectures

• Bram Ryckaert,
• Ellen Demeyere,
• Frederick Degroote,
• Hilde Janssens and
• Johan M. Winne

Beilstein J. Org. Chem. 2023, 19, 115–132, doi:10.3762/bjoc.19.12

• erythromycin A [18], Woodward famously introduced thianes and ring-fused thianes (dithiodecalins) as building blocks for polyketide chain fragments, in order to be able to exploit their cyclohexane-like conformational behavior in the control of the relative stereochemistry along the polyketide backbone (Scheme

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

• -like pathways are canonical type I cis-acyltransferase polyketide synthases (PKSs) and type A non-ribosomal peptide synthetases (NRPSs) (Figure 2A) [25][26]. The substrate specificity of the specificity conferring domains in each module can be predicted from the sequences of adenylation (A) (for NRPS

• harbor non-canonical module architectures and cryptic domains [19][22]. As a result, the colinearity rule cannot be applied to predict trans-AT PKS-derived polyketide core structures [19]. Instead, it has been observed that the amino acid sequences of the ketosynthase domains in trans-AT PKSs correlate

• with their substrate specificity [27]. This correlation can be used for the prediction of trans-AT PKS-derived polyketide core structures and is referred to as the correlation rule [19]. All commonly occurring domains in assembly line-like NP biosynthetic pathways as well as their non-modular homologs

Synthesis of tryptophan-dehydrobutyrine diketopiperazine and biological activity of hangtaimycin and its co-metabolites

• Houchao Xu,
• Anne Wochele,
• Minghe Luo,
• Gregor Schnakenburg,
• Yuhui Sun,
• Heike Brötz-Oesterhelt and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2022, 18, 1159–1165, doi:10.3762/bjoc.18.120

• , People's Republic of China Institute of Inorganic Chemistry, University of Bonn, Gerhard-Domagk-Straße 1, 53121 Bonn, Germany 10.3762/bjoc.18.120 Abstract An improved synthesis for tryptophan-dehydrobutyrine diketopiperazine (TDD), a co-metabolite of the hybrid polyketide/non-ribosomal peptide

• -AT, [3][4]) polyketide synthase (PKS) and non-ribosomal peptide synthase (NRPS) [2] with a dehydrating bimodule [5][6] involved in the installation of the remaining Z-configured double bond within the polyketide backbone [7]. Furthermore, a cytochrome P450 monooxygenase was recently shown to be

Enzymes in biosynthesis

• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2022, 18, 1131–1132, doi:10.3762/bjoc.18.116

• proceed through multistep cationic cascade reactions and usually produce a polycyclic terpene hydrocarbon or alcohol with multiple stereogenic centers. While these transformations require only a single enzyme, polyketide and nonribosomal peptide biosyntheses are catalyzed by megasynthases that follow an

• assembly line logic, with individual domains for each single step [2]. Furthermore, the domains are organized into modules, each of which is responsible for the incorporation of one extender unit into the growing polyketide or peptide chain. With our knowledge today, the function of these large enzyme

A Streptomyces P450 enzyme dimerizes isoflavones from plants

• Run-Zhou Liu,
• Shanchong Chen and
• Lihan Zhang

Beilstein J. Org. Chem. 2022, 18, 1107–1115, doi:10.3762/bjoc.18.113

• [1][10][11][12][13][14]. In plants and fungi, laccases and cytochrome P450 monooxygenases play pivotal roles in the biaryl bond formation of various polyketide dimers [10][15][16]. In contrast, in bacteria, P450 enzymes are the dominant catalysts, but no laccases have been reported for dimerization

• clustered into the CYP158 clade that reportedly catalyzes dimerization of type III polyketide synthase (T3PKS) products, such as naphthols. Considering the similar biosynthetic pathway of isoflavones shared, this enzyme was expressed in E. coli and purified for in vitro biochemical assay together with four

• . Interestingly, we found that CYP158C1 clusters together with a T3PKS gene in the S. cattleya genome, which is similar to the biflaviolin [30] and naringenin [31] biosynthetic gene clusters. The native function of these type-III polyketide synthase products is believed to be involved in the protection of the

Bioinspired tetraamino-bisthiourea chiral macrocycles in catalyzing decarboxylative Mannich reactions

• Hao Guo,
• Yu-Fei Ao,
• De-Xian Wang and
• Qi-Qiang Wang

Beilstein J. Org. Chem. 2022, 18, 486–496, doi:10.3762/bjoc.18.51

• cavity could resemble the circumstance of the catalytic triad of Polyketide synthases (PKSs) [40][41][42] (Figure 1). On the other hand, the organocatalytic asymmetric decarboxylative addition reactions of MAHTs to imines provide an efficient means for accessing valuable chiral β-amino esters [43][44][45

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

• metabolites of Pseudosporangium sp. RD062863, a strain available at the culture collection of the Biological Resource Center, National Institute of Technology and Evaluation (NBRC) [20], and discovered a novel cyclopeptide pseudosporamide along with three new oligomycin-class polyketide [21]. In addition, the

• metabolite with a methyl-branched C9 unsaturated acyl chain [31]. Moreover, salinipyrones, produced by a Salinispora strain, were shown to be biosynthetic byproducts of the rosamicin polyketide synthase [32]. Though not a result from Micromonosporaceae, another example of truncated polyketides is citreodiol

• , a similarly methyl-branched unsaturated fatty acid ester, which is produced by type I polyketide synthase in a Streptomyces strain by a heterologous expression experiment [33]. These facts suggest that 1–5 could be byproducts from the biosynthesis of larger polyketides, but further investigation is

Nomimicins B–D, new tetronate-class polyketides from a marine-derived actinomycete of the genus Actinomadura

• Zhiwei Zhang,
• Tao Zhou,
• Taehui Yang,
• Keisuke Fukaya,
• Enjuro Harunari,
• Shun Saito,
• Katsuhisa Yamada,
• Chiaki Imada,
• Daisuke Urabe and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2021, 17, 2194–2202, doi:10.3762/bjoc.17.141

• cytotoxicity against P388 murine leukemia cells with IC50 values of 33 and 89 μM, respectively. Keywords: Actinomadura; nomimicin; polyketide; spirotetronate; Introduction Actinomycetes are a valuable source of bioactive compounds, accounting for approximately two thirds of all known antibiotics, and more

• collection sites [12]. Furthermore, we found that the DSW of Sagami Bay (Pacific Ocean side of Honshu Island, Japan) contained more unknown actinomycete species than other sea areas, which eventually led to the discovery of akazamicin, a new cytotoxic aromatic polyketide from Nonomuraea [13] and akazaoxime

• , nomimicin A (4) [15]. From the extract of the fermentation broth cultured in A11M medium, an additional new tetronate polyketide, nomimicin D (3), was isolated (Figure 1). Nomimicin B (1) was obtained as a colorless amorphous solid. The molecular formula was determined to be C30H40O8, based on the

On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets

• Renato L. Carvalho,
• Amanda S. de Miranda,
• Mateus P. Nunes,
• Roberto S. Gomes,
• Guilherme A. M. Jardim and
• Eufrânio N. da Silva Júnior

Beilstein J. Org. Chem. 2021, 17, 1849–1938, doi:10.3762/bjoc.17.126

• White’s oxidation method as the final step in the first total synthesis of gracilioether F (75) [157], a natural polyketide with an unusual tricyclic core and five contiguous stereocenters, part of the family of gracilioethers 71–74 (Scheme 26A) extracted from the marine sponge Plakinastrella mamillaris

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

• , comparable to how Trichoderma virens protects cotton seedlings from its pathogen Pythium ultimum [122]. Trypacidin The spore-born toxin trypacidin (8) is a polyketide that belongs to an anthraquinone-derived class of secondary metabolites (Figure 4) [107]. In A. fumigatus, the trypacidin biosynthetic cluster

• of its biosynthesis are well established: the 19 kb gene cluster contains 6 genes and lies downstream of the conidiation pathway. The polyketide synthase PksP combines the starter units acetyl-CoA and malonyl-CoA into the heptaketide naphthopyrone YWA1 (11). The hydrolytic activity of Ayg1 shortens

Prins cyclization-mediated stereoselective synthesis of tetrahydropyrans and dihydropyrans: an inspection of twenty years

• Asha Budakoti,
• Pradip Kumar Mondal,
• Prachi Verma and
• Jagadish Khamrai

Beilstein J. Org. Chem. 2021, 17, 932–963, doi:10.3762/bjoc.17.77

• with DTBP for the synthesis of polyketide SCH 351448 [43], as shown in Scheme 14. Hart and Bennett have also examined the trifluroacetic acid-catalyzed Prins cyclization of acetal 71 to afford 72 along with side-chain-exchanged product 73 (Scheme 15) [44]. This method was utilized for the synthesis of

¹⁹F NMR as a tool in chemical biology

• Diana Gimenez,
• Aoife Phelan,
• Cormac D. Murphy and
• Steven L. Cobb

Beilstein J. Org. Chem. 2021, 17, 293–318, doi:10.3762/bjoc.17.28

Total synthesis of decarboxyaltenusin

• Lucas Warmuth,
• Aaron Weiß,
• Marco Reinhardt,
• Anna Meschkov,
• Ute Schepers and
• Joachim Podlech

Beilstein J. Org. Chem. 2021, 17, 224–228, doi:10.3762/bjoc.17.22

• compound due to the reduced accessibility of the precursors and since no experimental details have been published for the transformation. To continue our efforts in the total synthesis of mycotoxins [8][9][10][11][12][13][14][15][16][17][18] and to provide larger amounts of the polyketide 1 sufficient for

Nocarimidazoles C and D, antimicrobial alkanoylimidazoles from a coral-derived actinomycete Kocuria sp.: application of ¹J_C,H coupling constants for the unequivocal determination of substituted imidazoles and stereochemical diversity of anteisoalkyl chains in microbial metabolites

• Md. Rokon Ul Karim,
• Enjuro Harunari,
• Amit Raj Sharma,
• Naoya Oku,
• Kazuaki Akasaka,
• Daisuke Urabe,
• Mada Triandala Sibero and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2020, 16, 2719–2727, doi:10.3762/bjoc.16.222

• genomic information suggests the presence of biosynthetic genes for nonribosomal peptide synthetase and type III polyketide synthase in some Kocuria strains [18], which leaves a hope for new secondary metabolites. At present, only a few limited structural types of metabolites, including polyamine-derived

Syntheses of spliceostatins and thailanstatins: a review

• William A. Donaldson

Beilstein J. Org. Chem. 2020, 16, 1991–2006, doi:10.3762/bjoc.16.166

• with their complex structure, a number of total syntheses have been reported. This review will compare the synthetic strategies reported through the end of 2019. Keywords: antiproliferative; polyketide natural products; tetrahydropyrans; total synthesis; Introduction The spliceostatins/thailanstatins

• (Figure 1) are a family of linear peptide/polyketide natural products isolated from the bacteria Burkholderia sp. FERM BP-3421 [1][2][3] (originally identified as Pseudomonas sp. No 2663) and Burkholderia sp. MSMB 43 [4][5]. These compounds are of interest due to their ability to bind to a subunit of the