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

• gene clusters, among them three NRPS, two PKS, three NRPS/PKS and four ribosomal peptides (see Table 1). Apart from homologies to geosmin (100%), aurafuron (71%) and paneibactin (50%) biosynthetic genes, the gene clusters display a large degree of novelty. Recently, the biosynthetic gene cluster of

• the producing strain SWB007. The results revealed a PKS III gene cluster adjacent to a halogenase sequence (unpublished data). Upon sequencing, primers for these genes were designed. Given the genetic proximity among the E. salina isolates, strains SWB004, SWB005 and SWB006 were screened with the PKS

• synthesis of NRPS, PKS and hybrid NRPS-PKS products (see Table 1). Apart from the geosmin biosynthesis genes, no gene cluster or fragment thereof shares an identity higher than 33% to any known gene cluster in the MiBIG database [64]. It should be noted that since this is a draft genome sequence, the actual

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 So far, there are only limited insights into muraymycin biosynthesis. The biosynthetic gene cluster for the formation of muraymycins in Streptomyces sp. NRRL 30471 has been identified by Chen, Deng et al. in 2011 [118]. The sequence analysis revealed the cluster to contain 33 open reading frames

• (ORFs) with 26 of them being involved in muraymycin formation. Based on their elucidation of the gene cluster and sequence homologies, Chen, Deng et al. proposed an outline pathway for muraymycin biosynthesis (Scheme 10). According to this biosynthetic proposal, uridine (1) is enzymatically oxidised to

• dioxygenase Mur16 to catalyse β-hydroxylations of two structurally distinct amino acid substrates, i.e., L-arginine (106) and thioester-activated L-leucine 112. As pointed out, there is a lack of experimental insights into muraymycin biosynthesis beyond the elucidation of its gene cluster. However, Van Lanen

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

• reaction [109][110]. The althiomycin biosynthetic gene cluster was recently identified in M. xanthus DK897 by a combination of retrobiosynthetic analysis and gene inactivation [111]. Two open reading frames (ORFs) encoding for a nonribosomal peptide synthetase (NRPS) and a NRPS/polyketide synthase (PKS

• cystobactamid biosynthesis gene cluster led to the identification of a gene encoding a putative resistance factor. This discovery was the starting point for resolving the molecular target of these antibiotics. Subsequent assays confirmed that the cystobactamids act as bacterial DNA gyrase inhibitors [113

• metabolites from the H. aurantiacus type strain 114-95T led to the discovery of auriculamide (22) [127]. This natural product is composed of a 2-hydroxy-3-methylvalerate and a 2-amino-1-(3-chloro-4-hydroxyphenyl)pentan-3-one residue. A retrobiosynthetic analysis allowed the assignment of the gene cluster

Biosynthesis of α-pyrones

• Till F. Schäberle

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

• lactonization at the ACP-bound terminus yields the pyrone ring. As an example the enterocin (76, Figure 19) biosynthesis will be regarded (Figure 20). In the marine bacterium Streptomyces maritimus a gene cluster corresponding to enterocin (enc) biosynthesis was identified [81]. The minimal enc PKS, EncABC, is

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

• molecular analysis of the biosynthetic gene cluster of pederin (3) [49][50][51][52]. Beetle larvae hatching from pederin-containing eggs were less prone to predation by wolf spiders than pederin-free larvae, indicating the ecological significance of this secondary metabolite [53]. The biosynthetic gene

• displayed negative effects on the growth of the antagonistic fungus O. minus. By genetic analysis and manipulation of the producing Streptomyces strain the respective biosynthetic gene cluster could be identified. It encodes a hybrid polyketide synthase–non-ribosomal peptide synthase (PKS–NRPS), and

• cluster analysis also revealed that pederin is formed by an enzyme belonging to a functionally and evolutionarily novel group termed trans-acyltransferase PKSs (trans-AT PKSs) [24][52]. The structurally related compound diaphorin (4) was later found in a study of the defensive symbiosis between the Asian

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

• the product of a polyketide biosynthetic gene cluster [24]. To test whether N-acetylcysteine could be a biosynthetic precursor of the unusual 1,5-oxathiocane structure, feeding experiments using both (2S)- and (2R)-N-((2H3)acetyl)cysteine were performed. The deuterium atoms of both precursors were

• , the first structurally characterized bacterial diterpene cyclase [66]. After identification of the biosynthetic gene cluster, a mechanism involving a deprotonation–reprotonation sequence and two 1,2-hydride shifts was proposed [67]. However, a simple feeding experiment performed with a S. albus

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

• polyketide synthase gene cluster has not been identified yet. The streptazones are relatively small compounds suggesting that they may be volatile enough to find them in the headspace above bacterial cultures, although the presence of hydrogen bond donor and acceptor sites hints to good solubility in the

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

• triene structural moiety is rarely found in natural products. Streptomyces sp. LZ35 was isolated from the intertidal soil collected at Jimei, Xiamen, China [3]. An orphan type I polyketide synthase gene cluster that contains a putative chorismatase/3-hydroxybenzoate synthase gene was identified by genome

• as compound 1 [8]. Recently, we have reported the identification and characterization of the biosynthetic gene cluster of cuevaenes from Streptomyces sp. LZ35. Cuevaenes are 3-HBA-containing type I polyketides. An aromatic starter unit (3-HBA converted from chorismate) and six extender units are

Synthesis of complex intermediates for the study of a dehydratase from borrelidin biosynthesis

• Frank Hahn,
• Nadine Kandziora,
• Steffen Friedrich and
• Peter F. Leadlay

Beilstein J. Org. Chem. 2014, 10, 634–640, doi:10.3762/bjoc.10.55

• biosynthesis, we became interested in the formation of the (12Z,14E)-diene [7]. Z-configured double bonds are much rarer in polyketides than their E-configured counterparts, and their biosynthesis has not been thoroughly investigated yet [7][8][9]. Gene cluster analysis suggested that the double bond at

• precursor should lead to an E-configured BorDH3 product [10]. However, in the case of borrelidin this is in contradiction to the structure of the natural product in which a Z-configured double bond is present at position 12. In the borrelidin gene cluster, there is no obvious gene coding for an isomerase

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

• a transferase (MonKSX) transfers the chain to a discrete acyl carrier protein (MonACPX) [20], both of these proteins being encoded within the monensin gene cluster [16]. The flavin-dependent epoxidase MonCI then catalyses three stereospecific epoxidations to give the tri-epoxide 3, which then

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

• 10.3762/bjoc.9.290 Abstract Antimycins (>40 members) were discovered nearly 65 years ago but the discovery of the gene cluster encoding antimycin biosynthesis in 2011 has facilitated rapid progress in understanding the unusual biosynthetic pathway. Antimycin A is widely used as a piscicide in the catfish

• over-produced in cancer cells that are resistant to apoptosis-inducing chemotherapy agents, so antimycins have great potential as anticancer drugs used in combination with existing chemotherapeutics. Here we review what is known about antimycins, the regulation of the ant gene cluster and the unusual

• species is likely to grow rapidly with the advent of genome mining approaches, which start by identifying promising specialised metabolite gene clusters in whole genome sequences and then inducing their expression through chemical or genetic manipulation of the gene cluster in the native or a heterologous

The chemistry of isoindole natural products

• Klaus Speck and
• Thomas Magauer

Beilstein J. Org. Chem. 2013, 9, 2048–2078, doi:10.3762/bjoc.9.243

• -dideoxyribopyranose (218) is found in 217. The structure of the aglycone 214 is related to tetracenomycins, a family of tetracyclic aromatic polyketides, which are produced by several Streptomyces species [159]. Biosynthetic investigations revealed a striking similarity of the gene cluster responsible for the

Activation of cryptic metabolite production through gene disruption: Dimethyl furan-2,4-dicarboxylate produced by Streptomyces sahachiroi

• Dinesh Simkhada,
• Huitu Zhang,
• Shogo Mori,
• Howard Williams and
• Coran M. H. Watanabe

Beilstein J. Org. Chem. 2013, 9, 1768–1773, doi:10.3762/bjoc.9.205

• kb) [6][7]. Direct manipulation, “induced” biosynthetic activation, of a sequenced cluster has also met with some success. The Aspergillus nidulans genome was mined for cryptic orphan gene clusters from which a single, unexpressed PKS-NRPS hybrid was identified. The expression of the gene cluster was

• precursors of the orphan pathway are fed to the organism and used to screen extracts of the fermentation broth, to identify metabolites containing the labeled precursors [9][10]. Here, we have carried out a functional knockout of aziA2 within the azinomycin gene cluster of Streptomyces sahachiroi [11][12

• implicated a pyruvate aldolase and methyltransferase containing gene cluster as well as potential polyketide gene clusters containing methyltransferase genes, which will be evaluated in due course through genetic knockout experiments of the ΔaziA2 mutant strain. Disruption of the aziA2 gene gave

Isotopically labeled sulfur compounds and synthetic selenium and tellurium analogues to study sulfur metabolism in marine bacteria

• Nelson L. Brock,
• Christian A. Citron,
• Claudia Zell,
• Martine Berger,
• Irene Wagner-Döbler,
• Jörn Petersen,
• Thorsten Brinkhoff,
• Meinhard Simon and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2013, 9, 942–950, doi:10.3762/bjoc.9.108

• pathways, as a dmd-gene cluster for the demethylation pathway is located on a 262 kb plasmid and a gene for the lyase DddP is encoded on its chromosome. Isotopically labeled [2H6]DMSP was efficiently incorporated into methanethiol-derived sulfur volatiles like dimethyl disulfide (1), dimethyl trisulfide (2

Mutational analysis of a phenazine biosynthetic gene cluster in Streptomyces anulatus 9663

• Orwah Saleh,
• Katrin Flinspach,
• Lucia Westrich,
• Andreas Kulik,
• Bertolt Gust,
• Hans-Peter Fiedler and
• Lutz Heide

Beilstein J. Org. Chem. 2012, 8, 501–513, doi:10.3762/bjoc.8.57

• , 72076 Tübingen, Germany 10.3762/bjoc.8.57 Abstract The biosynthetic gene cluster for endophenazines, i.e., prenylated phenazines from Streptomyces anulatus 9663, was heterologously expressed in several engineered host strains derived from Streptomyces coelicolor M145. The highest production levels were

• group of endophenazine A forming an amide bond to the α-amino group of L-Gln. Gene inactivation experiments in the gene cluster proved that ppzM codes for a phenazine N-methyltransferase. The gene ppzV apparently represents a new type of TetR-family regulator, specifically controlling the prenylation in

• the first investigation of the regulatory genes of phenazine biosynthesis in Streptomyces. Keywords: phenazine; gene cluster; gene inactivation; Introduction Phenazine natural products have important biological activities comprising antibacterial, antifungal, antitumor, antimalarial, antioxidant and

Natural product biosyntheses in cyanobacteria: A treasure trove of unique enzymes

• Jan-Christoph Kehr,
• Douglas Gatte Picchi and
• Elke Dittmann

Beilstein J. Org. Chem. 2011, 7, 1622–1635, doi:10.3762/bjoc.7.191

• inhibit proteases. A signature of the group is the conserved ureido linkage connecting the side-chain amino acid to D-lysine. The corresponding NRPS gene cluster was first analyzed in the strain Anabaena sp. 90 and revealed a new mechanism underlying production of diverse variants by the same strain: Two

• neurotoxins produced by cyanobacteria. A gene cluster for the alkaloid was first described for the strain Oscillatoria sp. PCC 6506 [36]. Analysis of the gene cluster and feeding studies suggested a biosynthetic scheme starting from L-proline and involving three polyketide synthases, with (S)-1-pyrolline-5

• cassette that is expected to be involved in β-branching of polyketides [52]. NRPS and PKS pathways in terrestrial cyanobacteria Nostopeptolide The nostopeptolide gene cluster was the first NRPS/PKS type gene cluster described for a terrestrial cyanobacterial strain, namely Nostoc sp. GSV 224 [53