Confirmation of the stereochemistry of spiroviolene

• Yao Kong,
• Yuanning Liu,
• Kaibiao Wang,
• Tao Wang,
• Chen Wang,
• Ben Ai,
• Hongli Jia,
• Guohui Pan,
• Min Yin and
• Zhengren Xu

Beilstein J. Org. Chem. 2024, 20, 852–858, doi:10.3762/bjoc.20.77

• proposing a reasonable cyclization mechanism [5]. Spiroviolene (1, Figure 1) was identified by Dickschat and co-workers as a nascent cyclization product of spiroviolene synthase (SvS), the coding gene of which was cloned from Streptomyces violens NRRL ISP-5597 [6]. Its unique spiro-fused linear triquinane

• for GGPP production. Also, we have cloned the SvS-coding gene directly from Streptomyces violens CGMCC 4.1786 (= NRRL ISP-5597) into pET28a to give pET28a-svs. The resultant two plasmids were then co-transformed into commercially available E. coli BL21(DE3) for diterpene production. Spiroviolene could

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

• /bjoc.20.75 Abstract Linear nitramines (R–N(R′)NO2; R′ = H or alkyl) are toxic compounds, some with environmental relevance, while others are rare natural product nitramines. One of these natural product nitramines is N-nitroglycine (NNG), which is produced by some Streptomyces strains and exhibits

• , the physiological function of its substrate NNG. This compound is one of the few known nitramine natural products and the only one produced by bacteria instead of fungi [22]. Its only known natural sources are strains of Streptomyces bacteria [23][24]. The abundance and distribution of these NNG

• possibility is that NNG has several physiological functions and fates. For example, a natural product nitronate intermediate was recently shown to have two fates within Streptomyces achromogenes var. streptozoticus NRRL 3125 [46]. This nitronate intermediate was shown to be O-methylated to form O

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

• Dongxu Zhang,
• Wenyu Du,
• Xingming Pan,
• Xiaoxu Lin,
• Fang-Ru Li,
• Qingling Wang,
• Qian Yang,
• Hui-Min Xu and
• Liao-Bin Dong

Beilstein J. Org. Chem. 2024, 20, 815–822, doi:10.3762/bjoc.20.73

• biosynthetic pathways for DMTs have been primarily elucidated in fungi, with identified P450s only acting on the B ring. In this study, we isolated and characterized three bacterial DMTs, namely 3β-hydroxydrimenol (2), 2α-hydroxydrimenol (3), and 3-ketodrimenol (4), from Streptomyces clavuligerus. Through

• analogs. This discovery not only broadens the known chemical diversity of DMTs from bacteria, but also provides new insights into DMT biosynthesis in bacteria. Keywords: bacterial terpenoid; cytochrome P450s; drimane-type sesquiterpenoid; Streptomyces clavuligerus; terpenoid biosynthesis; Introduction

• associated with DMT biosynthesis have been identified in bacteria, the corresponding natural DMTs have not been discovered [17]. In this study, we isolated and characterized three drimenol congeners (2–4) from Streptomyces clavuligerus (Figure 2a). In the genome of S. clavuligerus, we identified a cav

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

• actinomycetes. Secondary metabolites produced by actinomycetes, representing a class of compounds with a diverse chemical space, have promising potential as sources of bioactive substances [10]. Due to his discovery of streptomycin from Streptomyces griseus, Waksman was awarded the Nobel Prize in Physiology and

• Medicine in 1952 [11]. Ōmura, who discovered avermectin from Streptomyces avermitilis, received the same award in 2015 [12]. While there are many such brilliant achievements, researchers are finding it increasingly difficult to isolate novel compounds from secondary metabolites produced by actinomycetes

• secondary metabolites from actinomycetes of the genus Streptomyces due to the prominence of species of this genus in surface soils and the difficulty of isolating members of other genera from natural environments. For this reason, actinomycetes other than those of the genus Streptomyces are referred to as

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

• understanding of the acidic lipopeptide structure–activity relationship (Scheme 4b). Surugamide B The cyclic octapeptides surugamides were isolated from several Streptomyces sp. and shown to be cathepsin B inhibitors [56][57][58]. According to a biosynthetic viewpoint, the corresponding modules consist of four

• biocatalytic cyclization, a crucial feature for the chemoenzymatic synthesis of macrolides and PKS/NRPS hybrids. The pikromycins Methymycin (20) and pikromycin (21) are 12- and 14-membered macrolide antibiotics both isolated from Streptomyces venezuelae ATCC15439. The Kang lab reported the total synthesis of

• macrolactonization, leading to the formation of tylactone (39) in 69% yield. Furthermore, the Streptomyces strain S. venezuelae DHS316 [76] performed an in vivo glycosylation resulting in M-4365 G1 (50) in 15 linear steps and 4.6% overall yield from commercial resources. With regio- and stereoselective C–H

A myo-inositol dehydrogenase involved in aminocyclitol biosynthesis of hygromycin A

• Michael O. Akintubosun and
• Melanie A. Higgins

Beilstein J. Org. Chem. 2024, 20, 589–596, doi:10.3762/bjoc.20.51

• was discovered in the 1950s and is produced by the soil bacterium Streptomyces hygroscopicus [1]. It has broad spectrum antibiotic activity, antitreponemal activity against the pathogen that causes swine dysentery, and selective activity against the spirochete that causes Lyme disease [1][2][3]. It

• Cloning, expression, and purification Streptomyces leeuwenhoekii NRRL B-24963 [28] was used as a template to amplify the hyg17 (GenBank CQR59633) with the primers 5’-GTTAGCCATATGACGGTCGCCGTCGTGGGC-3’ and 5’-GTAATGCTCGAGCGGCGCCACCGGCACCGA-3’. hyg17 was cloned into pTip-QC1 [10] using NdeI and XhoI

A new analog of dihydroxybenzoic acid from Saccharopolyspora sp. KR21-0001

• Rattiya Janthanom,
• Yuta Kikuchi,
• Hiroki Kanto,
• Tomoyasu Hirose,
• Arisu Tahara,
• Takahiro Ishii,
• Arinthip Thamchaipenet and
• Yuki Inahashi

Beilstein J. Org. Chem. 2024, 20, 497–503, doi:10.3762/bjoc.20.44

• actinomycetes, with 70% from Streptomyces and the rest from rare actinomycetes (non-Streptomyces) [5]. Rare actinomycetes are defined as actinomycete strains with low isolation rates when compared with the isolation of Streptomyces [6]. Currently, the discovery of new natural compounds is focusing on rare

• Rare actinomycetes are excellent sources of novel bioactive compounds, since they are less explored for secondary metabolites than the more common strains of Streptomyces [19][20]. The compounds from this group often have unique structures that may exhibit novel biological activities and could be

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

• on an ava cluster-related BGC in Kutzneria albida JCM 3240. We showed that this BGC is involved in p-coumaric acid biosynthesis by heterologous expression in Streptomyces albus J1074 and several in vitro biochemical experiments using recombinant proteins. CmaA6 was shown to catalyze the diazotization

• . E. coli S17-1 was used for conjugation. Streptomyces albus J1074 was used for heterologous expression. Kutzneria albida JCM 3240 was purchased from the Japan Collection of Microorganisms. Enzymes used for DNA manipulation, including polymerase and restriction enzymes, were purchased from TaKaRa Bio

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

• isolated from Streptomyces [30] and whose antimicrobial activity is probably related to the glutarimide moiety. In compound 1, the lack of this moiety, in addition to the fact that it has been isolated as a racemate could not lead to any beneficial property. As for compound 2, it is a diacetylated

Functions of enzyme domains in 2-methylisoborneol biosynthesis and enzymatic synthesis of non-natural analogs

• Binbin Gu,
• Lin-Fu Liang and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2023, 19, 1452–1459, doi:10.3762/bjoc.19.104

• diphosphate synthase (FPPS) and 2MIBS from Streptomyces coelicolor [26] (Scheme 1B). Crystal structures of both enzymes have been obtained [27][28] and allowed for a deep structure-based investigation of 2MIBS through site-directed mutagenesis [29]. The predicted amino acid sequences of 2MIBS homologs from

Functional characterisation of twelve terpene synthases from actinobacteria

• Anuj K. Chhalodia,
• Houchao Xu,
• Georges B. Tabekoueng,
• Binbin Gu,
• Kizerbo A. Taizoumbe,
• Lukas Lauterbach and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2023, 19, 1386–1398, doi:10.3762/bjoc.19.100

• . The first discovered example from this class is the fusicoccadiene (4) synthase from Phomopsis amygdali [8], and even triterpenes such as macrophomene (5) can be generated by these bifunctional enzymes [9]. After cloning of the gene for pentalenene (6) synthase from Streptomyces exfoliatus [10], many

• , revealing that the functions of still many terpene synthase homologs are unknown. Some of the largest branches in this tree represent the homologs of epi-isozizaene synthase from Streptomyces coelicolor [24], caryolan-1-ol synthase from Streptomyces griseus [25], selina-4(15),7(11)-diene synthase from

• Streptomyces pristinaespiralis [26], spiroviolene synthase from Streptomyces violens [27], micromonocyclol synthase from Micromonospora marina [28], α-amorphene synthase from Streptomyces viridochromogenes [29][30], epi-cubenol synthase from S. griseus [31], germacrene A synthase from M. marina [32], and 7-epi

Strategies to access the [5-8] bicyclic core encountered in the sesquiterpene, diterpene and sesterterpene series

• Cécile Alleman,
• Charlène Gadais,
• Laurent Legentil and
• François-Hugues Porée

Beilstein J. Org. Chem. 2023, 19, 245–281, doi:10.3762/bjoc.19.23

Germacrene B – a central intermediate in sesquiterpene biosynthesis

• Houchao Xu and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2023, 19, 186–203, doi:10.3762/bjoc.19.18

• germacrene C synthase from Lycopersicon esculentum [32], the (+)-germacrene D synthase from Zingiber officinalis (17.1%) [33], the avermitilol synthase from Streptomyces avermitilis (5%) [34], and VoTPS1 from Valeriana officinalis [35]. For the bacterial selinadiene synthase (SdS) from Streptomyces

• of the δ-selinene synthase (ag4) from Abies grandis [66] and a product of several terpene synthases from C. sativa (CsTPS7, CsTPS8 and CsTPS22) [67], while 10 is the main product of the bacterial selinadiene synthase from Streptomyces pristinaespiralis [36][68]. It has recently been shown by a

Digyalipopeptide A, an antiparasitic cyclic peptide from the Ghanaian Bacillus sp. strain DE2B

• Adwoa P. Nartey,
• Aboagye K. Dofuor,
• Kofi B. A. Owusu,
• Anil S. Camas,
• Hai Deng,
• Marcel Jaspars and
• Kwaku Kyeremeh

Beilstein J. Org. Chem. 2022, 18, 1763–1771, doi:10.3762/bjoc.18.185

• the group have instilled fear in the scientists that may wish to investigate their potential. This has rendered the genera much less studied when compared to their Streptomyces counterparts in terms of bioprospecting for novel drug scaffolds. However, a substantial number of Bacillus species have

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

• sequences of the model actinomycete Streptomyces coelicolor A3(2) [1] and the producer of the antiparasitic drug avermectin, Streptomyces avermitilis [2], were published. These index cases marked the transition from the pre- to the post-genomic era in microbial natural product (NP) research [3]. The

• overcome the rediscovery problem frequently encountered using traditional approaches. Contrary to earlier estimations that were based on bioactivity-guided discovery strategies, mining microbial genomes revealed a much higher biosynthetic potential than initially anticipated [14]. Streptomyces

• typically used for BGC identification, thus showing the potential of the approach (Figure 3) [84]. CGA aims at scaling this approach and comparing all sequenced strains of one genus (e.g., Streptomyces) to find non-syntenic blocks that might code for NP BGCs. Comparable to the genome-wide characterization

Solid-phase total synthesis and structural confirmation of antimicrobial longicatenamide A

• Takumi Matsumoto,
• Takefumi Kuranaga,
• Yuto Taniguchi,
• Weicheng Wang and
• Hideaki Kakeya

Beilstein J. Org. Chem. 2022, 18, 1560–1566, doi:10.3762/bjoc.18.166

• .18.166 Abstract Longicatenamides A–D are cyclic hexapeptides isolated from the combined culture of Streptomyces sp. KUSC_F05 and Tsukamurella pulmonis TP-B0596. Because these peptides are not detected in the monoculture broth of the actinomycete, they are key tools for understanding chemical

• the combined-culture strategy and new labeling reagents has led to the detection and structural determination of several unprecedented secondary metabolites [5][6][7]. Longicatenamides A–D (1–4, Figure 1) are cyclic hexapeptides isolated from the combined-culture of Streptomyces sp. KUSC_F05 and T

• developed [4]. Among the isolated longicatenamides, compound 1 exhibits weak but preferential antimicrobial activity against Bacillus subtilis. Because peptides 1–4 are not detected in the monoculture broth of Streptomyces sp. KUSC_F05, they are key tools for understanding chemical communication in the

Preparation of an advanced intermediate for the synthesis of leustroducsins and phoslactomycins by heterocycloaddition

• Anaïs Rousseau,
• Guillaume Vincent and
• Cyrille Kouklovsky

Beilstein J. Org. Chem. 2022, 18, 1385–1395, doi:10.3762/bjoc.18.143

• phoslactomycins 2a–f are a family of closely related natural products extracted from Streptomyces platensis (leustroducsins) or Streptomyces nigresens (phoslactomycins) [1][2][3][4]. The main difference within this large family is the presence of an additional ester substituent on the terminal cyclohexane ring

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

• hangtaimycin, starting from ʟ-tryptophan is presented. Comparison to TDD isolated from the hangtaimycin producer Streptomyces spectabilis confirmed its S configuration. The X-ray structure of the racemate shows an interesting dimerisation through hydrogen bridges. The results from bioactivity testings of

• hangtaimycin, TDD and the hangtaimycin degradation product HTM222 are given. Keywords: antibiotics; enantioselective synthesis; peptides; racemisation; Streptomyces; Introduction Hangtaimycin (1, Scheme 1) was first isolated from Streptomyces spectabilis and shown to possess weak antimicrobial activity

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

• . However, our understanding of the dimerization enzymes involved in this biotransformation is still limited compared to the numerous reported dimeric natural products. Here, we report the characterization of three new isoflavone dimers from Streptomyces cattleya cultured on an isoflavone-containing agar

• catalyzed by isoflavone synthases [21]. The sporadic distribution of this isoflavone synthase limits the discovery of isoflavones in the plant kingdom [22], and the enzymes catalyzing isoflavone dimerization, to our knowledge, remain uncharacterized. In this study, we report the discovery of a Streptomyces

• cytochrome P450 enzyme that catalyzes dimerization of plant isoflavones. By untargeted metabolomics, we isolated three new isoflavone dimers, namely cattleyaisoflavones A–C (1–3), from Streptomyces cattleya cultured in soy flour-containing media. We then identified a P450 enzyme, CYP158C1, which is able to

New azodyrecins identified by a genome mining-directed reactivity-based screening

• Atina Rizkiya Choirunnisa,
• Kuga Arima,
• Yo Abe,
• Noritaka Kagaya,
• Kei Kudo,
• Hikaru Suenaga,
• Junko Hashimoto,
• Manabu Fujie,
• Noriyuki Satoh,
• Kazuo Shin-ya,
• Kenichi Matsuda and
• Toshiyuki Wakimoto

Beilstein J. Org. Chem. 2022, 18, 1017–1025, doi:10.3762/bjoc.18.102

• . Azodyrecins D–G, four new analogs of aliphatic azoxides, were identified from two Streptomyces species by a reactivity-based screening that targets azoxy bonds. A biological activity evaluation demonstrated that the double bond in the alkyl side chain is important for the cytotoxicity of azodyrecins. An in

• of their biosynthetic mechanisms. Keywords: biosynthesis; methyltransferase; natural azoxides; reactivity-based screening; Streptomyces; Introduction Azoxy natural products are a rare yet intriguing class of natural products with various beneficial biological properties, such as antibacterial

• the N-acyl intermediate for azoxy bonds, suggesting that a genetic region containing both genes could be a potential biosynthetic gene cluster of aliphatic azoxy natural products. Results and Discussion Reactivity-based isolation of azodyrecins from two Streptomyces strains During our efforts toward

Isolation and biosynthesis of daturamycins from Streptomyces sp. KIB-H1544

• Yin Chen,
• Jinqiu Ren,
• Ruimin Yang,
• Jie Li,
• Sheng-Xiong Huang and
• Yijun Yan

Beilstein J. Org. Chem. 2022, 18, 1009–1016, doi:10.3762/bjoc.18.101

• Chinese Academy of Sciences, Beijing 100049, China 10.3762/bjoc.18.101 Abstract Two novel diarylcyclopentenones daturamycin A and B (1 and 2), and one new p-terphenyl daturamycin C (3), along with three known congeners (4–6), were isolated from a rhizosphere soil-derived Streptomyces sp. KIB-H1544. The

• daturamycins was identified through gene knockout and biochemical characterization experiments and the biosynthetic pathway of daturamycins was proposed. Keywords: biosynthesis; diarylcyclopentenone; polyporic acid synthetase; p-terphenyl; Streptomyces; Introduction Natural products containing a terphenyl

• Streptomyces species [1][2][3][4]. Meanwhile, these types of compounds exhibit a broad spectrum of bioactivities, including antitumor [5][6], antibacterial [7][8], antioxidant [9][10][11][12], immunosuppressive [13], and antithrombotic activities [14]. The biosynthesis of the p-terphenyls has been studied

Understanding the competing pathways leading to hydropyrene and isoelisabethatriene

• Shani Zev,
• Marion Ringel,
• Ronja Driller,
• Bernhard Loll,
• Thomas Brück and
• Dan T. Major

Beilstein J. Org. Chem. 2022, 18, 972–978, doi:10.3762/bjoc.18.97

• and downstream functionalizing enzymes, like P450s, together produce more than 80,000 known terpenes and terpenoids [1][2][3]. Hydropyrene synthase (HpS) from Streptomyces clavuligerus generates a mixture of diterpenes named hydropyrene (HP) (52%) and diterpenoid named hydropyrenol (HPol) (26%) as its

Efficient production of clerodane and ent-kaurane diterpenes through truncated artificial pathways in Escherichia coli

• Fang-Ru Li,
• Xiaoxu Lin,
• Qian Yang,
• Ning-Hua Tan and
• Liao-Bin Dong

Beilstein J. Org. Chem. 2022, 18, 881–888, doi:10.3762/bjoc.18.89

• , as well as two possible producers (Streptomyces sp. San01 and Kitasatospora sp. CB02891) after a survey of the existing genome sequence databases, however, we discovered a strain, Kitasatosporia griseola DSM 43859, without a genome sequence disclosed, from the strain library of CGMCC. Using the

• ent-CPP into the target tetracyclic skeleton, ent-kaurene (Figure 2). In this study, the ent-CPP synthase (eCDPS) gene was cloned from Streptomyces sp. NRRL S-1813, which was an alternative ent-kaurenol-derived antibiotic platensimycin producer [33][34][35], while the ent-kaurene synthase (BjKS) gene

The stereochemical course of 2-methylisoborneol biosynthesis

• Binbin Gu,
• Anwei Hou and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2022, 18, 818–824, doi:10.3762/bjoc.18.82

• 2-methylisoborneol from (S)-2-Me-LPP may be explained by isomerization to 2-Me-GPP and then to (R)-2-Me-LPP. Keywords: biosynthesis; enantioselective synthesis; enzyme mechanisms; gas chromatography; terpenoids; Introduction After its first discovery from Streptomyces [1][2], it has been

• recognized that many soil bacteria including various genera from the actinobacteria [3][4][5][6][7] and myxobacteria [8] produce the volatile musty odour compound 2-methylisoborneol (1). The compound is also found in marine Streptomyces strains [9] and aquatic cyanobacteria that can cause drinking water

• ]. Recent research on its chemical ecology demonstrated that arthropodes are attracted by compound 1 which helps in the dispersion of Streptomyces spores [20]. The absolute configuration of (–)-1 has been established through a synthesis from (+)-camphor [21]. The biosynthesis of compound 1 was initially

Synthesis and late stage modifications of Cyl derivatives

• Phil Servatius and
• Uli Kazmaier

Beilstein J. Org. Chem. 2022, 18, 174–181, doi:10.3762/bjoc.18.19

• naturally occurring HDAC inhibitors are known to date [12]. Acyclic molecules like, e.g., trichostatin A (TSA, Figure 1) were among the first isolated HDAC inhibitors. Isolated in 1976 from Streptomyces hygroscopicus by Tsuji et al. [13], TSA played an important role in rationalizing the mode of action of