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

• bacterial [28][35] and fungal [36][37] terpene cyclases. Results and Discussion Incubation of a recombinant terpene cyclase from Streptomyces viridochromogenes DSM 40736 (NCBI accession number WP_039931950) with farnesyl diphosphate (FPP) yielded a single product that was identified as α-amorphene (1

• relative of the enzyme from S. viridochromogenes is found in Streptomyces sp. NRRL S-481 (86% identity). Incubation of FPP with a recombinant terpene synthase from Roseiflexus castenholzii DSM 13941 (accession number WP_012119179) resulted in the formation of the sesquiterpene alcohol 2, previously

• established the structure of T-muurolol (2). The absolute configuration was determined as (1R,6S,7R,10R)-(+)-T-muurolol (2) from its optical rotary power ([α]D23 = +99.4 (c 1.10, CH2Cl2)). This is the same compound as was reported from a terpene cyclase from Streptomyces clavuligerus (accession number

Synthesis of the C8’-epimeric thymine pyranosyl amino acid core of amipurimycin

• Pramod R. Markad,
• Navanath Kumbhar and
• Dilip D. Dhavale

Beilstein J. Org. Chem. 2016, 12, 1765–1771, doi:10.3762/bjoc.12.165

• miharamycin that are known as antifungal agents [2]. Amipurimycin (1) isolated from Streptomyces novoguineensis sp. nov., displays antifungal activity against pyricularia oryzae – a causative agent in rice blast disease [3][4]. Goto and co-workers have proposed the primary structure of amipurimycin (1, Figure

Total synthesis of leopolic acid A, a natural 2,3-pyrrolidinedione with antimicrobial activity

• Atul A. Dhavan,
• Rahul D. Kaduskar,
• Loana Musso,
• Leonardo Scaglioni,
• Piera Anna Martino and
• Sabrina Dallavalle

Beilstein J. Org. Chem. 2016, 12, 1624–1628, doi:10.3762/bjoc.12.159

• ]. Chemical analysis of a terrestrial-derived Streptomyces sp. isolated from the rhizosphere of the plant Juniperus excelsa yielded a new metabolite, leopolic acid A (1, Figure 1) [2]. Leopolic acid has unprecedented structural features consisting of an aliphatic side chain attached to a 2,3-pyrrolidinedione

Biosynthesis of oxygen and nitrogen-containing heterocycles in polyketides

• Franziska Hemmerling and
• Frank Hahn

Beilstein J. Org. Chem. 2016, 12, 1512–1550, doi:10.3762/bjoc.12.148

• chapter 1.1.1, furan rings can also be biosynthesised via oxa-Michael additions. Nonactin. Nonactin (70) is the smallest homolog of the macrotetrolides, a family of cyclic polyethers that commonly have activity as ionophore antibiotics (Scheme 11a). It is produced by Streptomyces griseus subsp. griseus

• ETH A7796 as well as by Streptomyces fulvissimus and consists of four nonactic acid units, which are assembled in a head-to-tail fashion giving a C2-symmetric (−)-(+)-(−)-(+) macrocycle [53]. Nonactin (70) biosynthesis has been extensively studied and shows multiple unusual features. Genes of an ACP

• enzyme is proposed to convert both enantiomers, finally giving the nonactic acid monomers 69a and 69b. Priestley et al. showed that the cell lysate of a recombinant Streptomyces lividans strain overexpressing the nonS gene was able to convert the N-caprylcysteamine thioester (71b) into the respective

The EIMS fragmentation mechanisms of the sesquiterpenes corvol ethers A and B, epi-cubebol and isodauc-8-en-11-ol

• Patrick Rabe and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2016, 12, 1380–1394, doi:10.3762/bjoc.12.132

• bacterial terpene cyclases corvol ether synthase from Kitasatospora setae, the epi-cubebol synthase from Streptosporangium roseum, and the isodauc-8-en-11-ol synthase from Streptomyces venezuelae. The enzyme products were analysed by GC–MS and GC–QTOF MS2 and the obtained data were used to delineate the

• studies with (1(10)E,4E,6S,7R)-germacradien-6-ol synthase from Streptomyces pratensis and epi-isozizaene synthase from Streptomyces albus, that the enzymatically obtained products from the (13C1)FPP isotopomers are useful for detailed investigations on the EIMS fragmentation mechanisms of sesquiterpenes

• isodauc-8-en-11-ol made by terpene cyclases from Streptosporangium roseum [19][20] and from Streptomyces venezuelae [21]. Results and Discussion To investigate the EIMS fragmentation mechanisms for the two sesquiterpene ethers corvol ether A (1) and corvol ether B (2), and for the sesquiterpene alcohols

Muraymycin nucleoside-peptide antibiotics: uridine-derived natural products as lead structures for the development of novel antibacterial agents

• Daniel Wiegmann,
• Stefan Koppermann,
• Marius Wirth,
• Giuliana Niro,
• Kristin Leyerer and
• Christian Ducho

Beilstein J. Org. Chem. 2016, 12, 769–795, doi:10.3762/bjoc.12.77

• biosynthesis. This review will focus on muraymycins as a subclass of nucleoside antibiotics, covering their mode of action, synthetic approaches as well as SAR studies on several derivatives. Furthermore, first insights into the biosynthesis of these Streptomyces-produced secondary metabolites will be

• discussed. Review Structures of naturally occurring muraymycins The muraymycins were first isolated in 2002 from a broth of a Streptomyces sp. [22]. McDonald et al. discovered and characterised 19 naturally occurring muraymycins (Figure 1). These compounds belong to the family of nucleoside antibiotics

• peptidoglycan biosynthesis is given by Bugg et al. in two review articles [23][24] and by Ichikawa et al. in a recent review [25]. Representing the first discovered nucleoside antibiotics, the tunicamycins were isolated in 1971 from Streptomyces lysosuperficus nov. sp. by Takatsuki and Tamura et al. [26][27][28

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

• likely that corallopyronin is produced by myxobacteria to facilitate feeding on other bacteria. Althiomycin: The antibiotic althiomycin (Figure 4) had been initially discovered in cultures of Streptomyces althioticus [107], before it was also reported from strains of Myxococcus virescens, M. xanthus, and

Biosynthesis of α-pyrones

• Till F. Schäberle

Beilstein J. Org. Chem. 2016, 12, 571–588, doi:10.3762/bjoc.12.56

• was described, i.e., murayalactone (28) isolated from Streptomyces murayamaensis (Figure 5) [33]. 1.2 Monocyclic α-pyrones In addition to the aforementioned examples also the simplest α-pyrones show remarkable biological effects. Isolated from several fungi, e.g., Trichoderma viride, 6-pentyl-α-pyrone

• -pyran-2-one (47, Figure 10) [52]. Also antitumor activities of α-pyrones had been shown. Thus, pironetin (47, Figure 10) induced apoptosis in a dose- and time-dependent manner, and tubulin assembly was inhibited in vitro [53]. The natural product was isolated from Streptomyces sp. NK10958 [54], and its

• Streptomyces viridochromogenes NRRL B-1551, whereby the compounds had been detected in the supernatant of germinated spores, as well as in the supernatant of the submerged culture [59]. The excretion of these compounds prevents the germination of the spores too close to the parent culture. Germination of S

Natural products in synthesis and biosynthesis II

• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2016, 12, 413–414, doi:10.3762/bjoc.12.44

• Sciences) for the discovery of the terpenoid antimalaria drug artemisinin that is produced by the plant Artemisia annua [3], and to Satoshi Õmura and William C. Campbell for the discovery of avermectins isolated from the actinobacterium Streptomyces avermitilis at the famous Kitasato Institute and for 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

• the solitary digger wasp European beewolf (Philanthus triangulum), catch and paralyze honeybees and use the insect prey as food source for their larvae. To protect the offspring, beewolves cultivate the endosymbiont ”Candidatus Streptomyces philanthi” in antennal glands. By inoculation of the soil of

• . Using symbiont pairing bioassays and chemical analysis one of the major isolates Streptomyces thermosacchari was shown to produce the fungicide mycangimycin (12), which inhibits the growth of the antagonist O. minus. Mycangimycin is an unusual carboxylic acid derivative with an endoperoxide unit and a

• conjugated heptaene moiety [86][87]. Subsequent chemical analysis of another Streptomyces strain associated with the southern pine beetle led to the discovery of two new members of polyketide-derived polycyclic tetramate macrolactams named frontalamides A (13) and B (14) (Figure 5) [88][89], which also

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

• mechanism. An interesting feeding experiment was performed for the elucidation of both absolute configuration and biosynthesis of the polyketid alkaloid coelimycin P1 (8, Scheme 2). The compound was isolated from Streptomyces coelicolor M145 after genetically engineered increase of the metabolic flux and is

• polyketide products. Emphasizing the same principle, the biosynthesis of trioxacarcin A (9, Scheme 3), a complex aromatic natural product originally isolated from Streptomyces bottropensis DO-45 and showing remarkable antibacterial and antitumor properties [25], was investigated using isotopically labeled

• . on the anthraquinone crysophanol, for which different folding modes in fungi (F type folding) and in bacteria (S type, “Streptomyces” type) were found by isotopic labeling experiments for one and the same compound [30]. As an additional concluding remark of this chapter, the role of isotopic labeling

A novel and widespread class of ketosynthase is responsible for the head-to-head condensation of two acyl moieties in bacterial pyrone biosynthesis

• Darko Kresovic,
• Florence Schempp,
• Zakaria Cheikh-Ali and
• Helge B. Bode

Beilstein J. Org. Chem. 2015, 11, 1412–1417, doi:10.3762/bjoc.11.152

• . The biosynthetic importance of the second group including PpyS homologues from Burkholderia, Legionella, Nocardia, Microcystis and Streptomyces needs to be determined in future work. In contrary, MxnB and CorB are located within the FabH clade, showing that not only the reaction mechanism of these two

A new and convenient synthetic way to 2-substituted thieno[2,3-b]indoles

• Roman A. Irgashev,
• Arseny A. Karmatsky,
• Gennady L. Rusinov and
• Valery N. Charushin

Beilstein J. Org. Chem. 2015, 11, 1000–1007, doi:10.3762/bjoc.11.112

• of Streptomyces albogriseolus and characterized by Kanbe et al. [2][3], has shown to exhibit a plant-growth-regulation activity (Figure 1). Furthermore, it has been reported that some thienoindoles are therapeutically agents for treating diseases of the central nervous system [4], potential

(2R,1'S,2'R)- and (2S,1'S,2'R)-3-[2-Mono(di,tri)fluoromethylcyclopropyl]alanines and their incorporation into hormaomycin analogues

• Armin de Meijere,
• Sergei I. Kozhushkov,
• Dmitrii S. Yufit,
• Christian Grosse,
• Marcel Kaiser and
• Vitaly A. Raev

Beilstein J. Org. Chem. 2014, 10, 2844–2857, doi:10.3762/bjoc.10.302

• isolated from a Streptomyces griseoflavus (strain W-384) fermentation broth by Zähner et al. in Tübingen, Germany and structurally identified by Zeeck et al. in Göttingen, Germany in 1989–1990 [3][4]. Once the absolute configuration of all the previously unassigned stereogenic centers in the

Sacrolide A, a new antimicrobial and cytotoxic oxylipin macrolide from the edible cyanobacterium Aphanothece sacrum

• Naoya Oku,
• Miyako Matsumoto,
• Kohsuke Yonejima,
• Keijiroh Tansei and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2014, 10, 1808–1816, doi:10.3762/bjoc.10.190

• . Antimicrobial testing against four Gram-positive bacteria (Bacillus subtilis, Micrococcus luteus, Staphylococcus aureus, and Streptomyces lividans), one Gram-negative bacterium (Escherichia coli), two yeasts (Candida albicans and Saccharomyces cerevisiae), and two fungi (Aspergillus oryzae and Penicillum

• the growth of Gram-positive bacteria (Micrococcus luteus, Streptomyces lividans, Staphylococcus aureus, Bacillus subtilis), a yeast (Saccharomyces cerevisiae) and a fungus (Penicillium chrysogenum) (Table 2). Moreover, 1 was cytotoxic to 3Y1 rat fibroblasts (GI50 4.5 μM). Under microscopic observation

• strains were grown on agar media (Staphylococcus aureus FDA209P JC-1, Micrococcus luteus ATCC9341, Escherichia coli NIHJ JC-2, Saccharomyces cerevisiae S100, and Candida albicans A9540) or in Sabouraud broth (Penicillum chrysogenum NBRC4626, Streptomyces lividans TK23) overnight and then diluted with

Multicomponent reactions in nucleoside chemistry

• Mariola Koszytkowska-Stawińska and
• Włodzimierz Buchowicz

Beilstein J. Org. Chem. 2014, 10, 1706–1732, doi:10.3762/bjoc.10.179

• hydantoins attracted a considerable attention because of their importance in medicine and industry [116][117]. N-Nucleoside analogs with (thio)hydatantoin scaffold as a nucleobase mimic were also extensively investigated [118]. (+)-Hydantocidin (Scheme 43), isolated from Streptomyces hygroscopicus, is a

Chemistry of polyhalogenated nitrobutadienes, 14: Efficient synthesis of functionalized (Z)-2-allylidenethiazolidin-4-ones

• Viktor A. Zapol’skii,
• Jan C. Namyslo,
• Mimoza Gjikaj and
• Dieter E. Kaufmann

Beilstein J. Org. Chem. 2014, 10, 1638–1644, doi:10.3762/bjoc.10.170

• focus on their anticancer [29][30][31] and anti-HIV potential [30][32]. Several 4-thiazolidinone derivatives such as ralitoline (anticonvulsant), etozoline (antihypertensive), pioglitazone (hypoglycemic) and thiazolidomycin (activity against streptomyces species) are already in the market [33]. Beyond

Streptopyridines, volatile pyridine alkaloids produced by Streptomyces sp. FORM5

• Ulrike Groenhagen,
• Michael Maczka,
• Jeroen S. Dickschat and
• Stefan Schulz

Beilstein J. Org. Chem. 2014, 10, 1421–1432, doi:10.3762/bjoc.10.146

• Ulrike Groenhagen Michael Maczka Jeroen S. Dickschat Stefan Schulz Institut für Organische Chemie, Technische Universität Braunschweig, Hagenring 30, 38106 Braunschweig, Germany 10.3762/bjoc.10.146 Abstract Streptomyces sp. FORM5 is a bacterium that is known to produce the antibiotic streptazolin

• [2] such as methyl pyrrole-2-carboxylate, emitted by Stackebrandtia nassauensis, or 2-acetylpyrrole from Saccharopolyspora erythraea, volatile alkaloids are rarely produced by actinomycetes. We became interested in the strain Streptomyces sp. FORM5 to elucidate whether volatile formation is linked to

• aqueous phase. In our study the volatile bouquet of the actinomycete Streptomyces sp. FORM5 was investigated and several new 2-alkylated pyridines were identified using the closed-loop stripping analysis (CLSA) [7] headspace technique followed by GC–MS analysis and synthesis of the target compounds for

Selective allylic hydroxylation of acyclic terpenoids by CYP154E1 from Thermobifida fusca YX

• Anna M. Bogazkaya,
• Clemens J. von Bühler,
• Sebastian Kriening,
• Alexandrine Busch,
• Alexander Seifert,
• Jürgen Pleiss,
• Sabine Laschat and
• Vlada B. Urlacher

Beilstein J. Org. Chem. 2014, 10, 1347–1353, doi:10.3762/bjoc.10.137

• only allylic alcohols. Immediate heme surroundings shown for the nearest relative of CYP154E1 with available crystal structure (CYP154A1, from Streptomyces coelicolor, PDB entry 1ODO). The residue in position 5 after the conserved ExxR motif (V286 in CYP154E1, green) reaches close to the heme centre

Heronapyrrole D: A case of co-inspiration of natural product biosynthesis, total synthesis and biodiscovery

• Jens Schmidt,
• Zeinab Khalil,
• Robert J. Capon and
• Christian B. W. Stark

Beilstein J. Org. Chem. 2014, 10, 1228–1232, doi:10.3762/bjoc.10.121

• /bjoc.10.121 Abstract The heronapyrroles A–C have first been isolated from a marine-derived Streptomyces sp. (CMB-0423) in 2010. Structurally, these natural products feature an unusual nitropyrrole system to which a partially oxidized farnesyl chain is attached. The varying degree of oxidation of the

• : biomimetic synthesis; biosynthesis; heronapyrroles; microbial biodiscovery; natural products; nitropyrroloterpenes; Introduction Heronapyrroles A–C (Figure 1) were first reported in 2010 by Capon et al. from a marine-derived Streptomyces sp. (CMB-M0423) obtained from a shallow water sand sample collected

• initiate a cyclization cascade [1][3][8] that would provide the bis-tetrahydrofuran heronapyrrole C (Scheme 1), via a mechanism that closely resembles polyether antibiotic biosynthesis [12][13][14][15][16][17]. This biosynthetic hypothesis raises the possibility that Streptomyces sp. (CMB-M0423) may

Cuevaenes C–E: Three new triene carboxylic derivatives from Streptomyces sp. LZ35ΔgdmAI

• Jing-Jing Deng,
• Chun-Hua Lu,
• Yao-Yao Li,
• Shan-Ren Li and
• Yue-Mao Shen

Beilstein J. Org. Chem. 2014, 10, 858–862, doi:10.3762/bjoc.10.82

• isomers – cuevaenes A (1) and C (3) as well as cuevaenes D (4) and E (5) – and cuevaene B (2) were isolated from gdmAI-disrupted Streptomyces sp. LZ35. The constitution of cuevaene C (3) was found to be identical to cuevaene A (1) by means of NMR spectroscopy and high resolution mass spectrometry. However

• ; geometrical isomer; natural products; Streptomyces sp. LZ35; Introduction Cuevaenes are polyketides containing 3-hydroxybenzoic acid (3-HBA). Only 4 naturally occurring cuevaenes are described. Cuevaenes A and B were isolated from Streptomyces sp. HKI 0180 fifteen years ago and display moderate antibacterial

• activity against Gram-positive bacteria [1]. JBIR-23 and JBIR-24, novel anti-malignant pleural mesothelioma (MPM) agents, were isolated from Streptomyces sp. AK-AB27 six years ago [2]. All of these natural products have a tricyclic core and a polyene side chain with an enolmethyl ether inside. This type of

Intermediates in monensin biosynthesis: A late step in biosynthesis of the polyether ionophore monensin is crucial for the integrity of cation binding

• Wolfgang Hüttel,
• Jonathan B. Spencer and
• Peter F. Leadlay

Beilstein J. Org. Chem. 2014, 10, 361–368, doi:10.3762/bjoc.10.34

• steps in monensin biosynthesis, namely hydroxylation catalysed by the P450 monooxygenase MonD and O-methylation catalysed by the methyl-transferase MonE. The corresponding genes were deleted in-frame in a monensin-overproducing strain of Streptomyces cinnamonensis. The mutants produced the expected

• tailoring step as well as polyether formation. Keywords: antibiotics; biosynthesis; natural products; polyketides; Streptomyces; synthetic biology; Introduction Monensin A (1) from Streptomyces cinnamonensis is one of the most prominent and best-studied of the polyether class of complex polyketides, an

• (5) and (d) the overlay of 5 (blue) with sodium monensin (1) (green). The proposed pathway for monensin biosynthesis in Streptomyces cinnamonensis. The polyketide synthase (PKS) initially produces an enzyme-bound triene, which is transferred to a discrete acylcarrier protein (ACPX) to give 2. After

[²H₂₆]-1-epi-Cubenol, a completely deuterated natural product from Streptomyces griseus

• Christian A. Citron and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2013, 9, 2841–2845, doi:10.3762/bjoc.9.319

• Streptomyces griseus. This compound represents the first completely deuterated terpene obtained by fermentation. Despite a few previous reports in the literature the operability of this approach to fully deuterated compounds is still surprising, because the strong kinetic isotope effect of deuterium is known

• to slow down all metabolic processes in living organisms. Potential applications of completely labelled compounds from natural sources in structure elucidation, biosynthetic or pharmacokinetic investigations are discussed. Keywords: biosynthesis; deuterium; labelling; natural products; Streptomyces

• ; terpenes; Introduction The actinomycete Streptomyces griseus is a producer of three terpenes, 2-methylisoborneol (2-MIB, 1), (+)-caryolan-1-ol (2), and (+)-1-epi-cubenol (3, Figure 1). The biosynthesis of 2 and 3 requires the action of well characterized terpene cyclases [1][2], while the biosynthesis of

Halogenated volatiles from the fungus Geniculosporium and the actinomycete Streptomyces chartreusis

• Tao Wang,
• Patrick Rabe,
• Christian A. Citron and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2013, 9, 2767–2777, doi:10.3762/bjoc.9.311

• brominated or even iodinated volatiles are even more rare. Surprisingly, headspace extracts from Streptomyces chartreusis contained methyl 2-iodobenzoate, a new natural product that adds to the small family of iodinated natural products. Keywords: constitutional isomerism; GC-MS; natural products

• haloperoxidases [19]. Here we report on the identification of two chlorinated volatile compounds from the fungus Geniculosporium and a iodinated volatile from Streptomyces chartreusis. Results and Discussion Chlorinated volatiles from Geniculosporium The volatiles emitted by agar plate cultures of the fungus

• ) [25] or the trichlorinated phenols 20–22 (Figure 5) [26]. The biological function of 4b and 10b in Geniculosporium is unknown, but the antibiotic activity of the related compound drosophilin A towards bacteria is well known [27]. A iodinated volatile from Streptomyces chartreusis During the course of

The regulation and biosynthesis of antimycins

• Ryan F. Seipke and
• Matthew I. Hutchings

Beilstein J. Org. Chem. 2013, 9, 2556–2563, doi:10.3762/bjoc.9.290

• biosynthetic pathway. Keywords: antimycins; gene regulation; genome mining; natural products; Streptomyces; Review It is estimated that around 60% of all known antibiotics are derived from secondary metabolites made by filamentous actinomycete bacteria, most notably Streptomyces species [1]. Streptomyces

• neighbouring microbes [3]. In recent years genome sequencing has revealed that each Streptomyces species encodes many more specialised metabolites than it makes in laboratory culture, leading to new efforts to activate these so-called “silent pathways.” The number of known antibiotics made by Streptomyces

• host. This approach has already been used to identify novel chemical scaffolds of antibiotics produced by well-studied Streptomyces species [4][5][6] and to identify the biosynthetic gene clusters for commercially important antibiotics [7][8][9][10][11]. The latter allows cloning, optimisation and