Chemical structure of cichorinotoxin, a cyclic lipodepsipeptide that is produced by Pseudomonas cichorii and causes varnish spots on lettuce

• Hidekazu Komatsu,
• Takashi Shirakawa,
• Takeo Uchiyama and
• Tsutomu Hoshino

Beilstein J. Org. Chem. 2019, 15, 299–309, doi:10.3762/bjoc.15.27

• assign the D or L configurations for all the amino acids by the feeding experiments. However, we succeeded in proposing the complete stereochemistry of the molecule by careful analysis of the biosynthetic gene cluster (nonribosomal peptide synthetases, NRPS). These results will be reported in due course

Polyketide stereocontrol: a study in chemical biology

• Kira J. Weissman

Beilstein J. Org. Chem. 2017, 13, 348–371, doi:10.3762/bjoc.13.39

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

• generation GPAs in clinical use are all entirely derived from in vivo biosynthesis [1][2]. The biosynthesis of GPAs is based around the initial synthesis of the linear heptapeptide by a type-I non-ribosomal peptide synthetase (NRPS) [5][6] and its subsequent modification by cytochrome P450 monooxygenases [7

• by OxyE, which acts between OxyB and OxyA in the cyclisation cascade [27]. In vivo experiments also hinted towards the activity of the Oxy enzymes against the substrate peptides whilst they remain bound to the NRPS [29], and in vitro experiments performed with OxyB from the vancomycin biosynthesis

• NRPS machineries, known as the X-domain [16]. Characterisation of this domain has shown that it is a modified, catalytically inactive condensation-type domain and that this domain is capable of forming 1:1 complexes with the Oxy enzymes from GPA biosynthesis [16]. More importantly, with the exception

A non-canonical peptide synthetase adenylates 3-methyl-2-oxovaleric acid for auriculamide biosynthesis

• Daniel Braga,
• Dirk Hoffmeister and
• Markus Nett

Beilstein J. Org. Chem. 2016, 12, 2766–2770, doi:10.3762/bjoc.12.274

• were observed in cultures of H. aurantiacus 114-95T, providing initial evidence for the assumed secondary metabolome of this species [4][5][6]. Within the entire genus, 1 is only the second PKS/NRPS-derived molecule to be described, following the report on siphonazole (2, Figure 1) [7

• provide biochemical evidence for the participation of this unusual NRPS in the biosynthesis of 1. AulA is suggested to incorporate L-isoleucic acid (= 2-hydroxy-3-methylvaleric acid). The domain architecture indicates the substrate undergoes no other chemical modification besides a reductive step after

• requirements of the monomers to be recognised and incorporated to form the product [15][16]. In silico tools to identify the nonribosomal code, namely PKS/NRPS Analysis [17] and NRPSpredictor2 [18], are often accurate for the analysis of bacterial NRPSs. Yet, in our case, none retrieved any result after the

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

• enzymatic units that introduce nitrogen, we expanded the scope of this article to those products of polyketide synthase–non ribosomal peptide synthetase (NRPS) hybrid systems in which the polyketide portion strongly dominates the overall structure and in which the amino acid nitrogens are incorporated into

• characterised in the pederin (24) and the ambruticin (28) biosynthetic pathways (Scheme 3 and Scheme 4) [14][15]. PedPS7 is a monofunctional pyran synthase (PS) domain that was predicted to catalyse ring formation from an α,β-unsaturated intermediate in the biosynthesis of the PKS–NRPS hybrid product pederin

• –tautomerisation of the 3,5-dioxothioester formed by the final two elongation steps of the aureothin-PKS. Leupyrrins. The leupyrrins (leupyrrin A2 (80) is shown in Scheme 14) are remarkable hybrid natural products consisting of PKS, NRPS and isoprenoid-originating portions. They contain several heterocyclic

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

• biologically active PKS/NRPS-derived compound produced by the terrestrial S. cellulosum is the microtubule stabilizer epothilone B, of which the lactam analogue ixabepilone (6) is currently used together with capecitabine (7, Figure 3) in cancer therapy to improve the effectiveness of taxane-resistant

• that large genomes often correlate with the potential for prolific secondary metabolite production by revealing almost 8.6% of the genome to be possibly involved in the biosynthesis of secondary metabolites [36]. Mining this genome for the presence of PKS and NRPS genes exposed 18 biosynthetic clusters

• , with a predominance of hybrid PKS-NRPS systems [37]. M. xanthus strain DK1622 is responsible for the synthesis of metabolites like DKxanthene-534 (8, Figure 4), a pigment required for fruiting body formation and sporulation processes [37] and the siderophore myxochelin A (9), which belongs to a class

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

• synthetase (NRPS) system appears to be responsible for the assembly of the urea tripeptide building block 105. However, the non-proteinogenic amino acids need to be formed first. It has been proposed that L-arginine (106) undergoes 3-hydroxylation (giving 3-hydroxy-L-arginine (107)) and subsequent ring

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

• via horizontal gene transfer. Cystobactamids: The cystobactamids were recently isolated from a Cystobacter sp. and represent a novel class of NRPS-derived antimicrobial peptides [113]. Cystobactamids 919-1 and 919-2 (Figure 5) display an unusual aromatic scaffold composed of p-nitrobenzoic acid and

• NRPS or mixed NRPS/PKS clusters. This situation is hence quite similar to myxobacteria [56]. An unexpected finding, however, was the discovery of an enediyne PKS gene in H. aurantiacus 114-95T. Enediynes are highly potent antibiotics, causing DNA-strand scissions. Although an impressive number of 87

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

• 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

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

• -ribosomal peptides Non-ribosomal peptides often exhibit a high bioactivity and are biosynthesized by non-ribosomal peptide synthethases (NRPS) [33], which work RNA-independent and catalyze the assembly of both proteinogenic and non-proteinogenic amino acids in a modular fashion. Moreover, NRPSs can contain

• in all cases easily accessible for the unlabeled compound. In particular, advanced mass spectrometry techniques in combination with labeled amino acids catch a growing attention for the often challenging structure elucidation of NRPS products. To give insights into the assembled building blocks and

• the sum formula of the desired compound, either the traditional way of providing isotopically labeled amino acids to the NRPS can be used, or completely labeled media can be supplemented with non-labeled building blocks in an inverse feeding experiment [36]. The latter method is particularly

The myxocoumarins A and B from Stigmatella aurantiaca strain MYX-030

• Tobias A. M. Gulder,
• Snežana Neff,
• Traugott Schüz,
• Tammo Winkler,
• René Gees and
• Bettina Böhlendorf

Beilstein J. Org. Chem. 2013, 9, 2579–2585, doi:10.3762/bjoc.9.293

• interesting biological properties are the myxobacteria [9][10][11][12]. These organisms are especially talented in assembling PKS-, NRPS- and PKS/NRPS-hybrid products, often incorporating unusual biochemistry in the respective biosynthetic pathways [13][14][15]. The most well-known myxobacterial natural

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

• -aminosalicylate, antCD encode the hybrid NRPS/PKS machinery and antE and antM encode a crotonyl-CoA reductase and a discrete ketoreductase, respectively. The antB and antO genes encode tailoring enzymes and antA encodes an extracytoplasmic function (ECF) RNA polymerase σ factor named σAntA. The additional genes

• . Biosynthesis of the antimycin dilactone core Antimycins are produced by a hybrid non-ribosomal peptide synthetase (NRPS)/polyketide synthase (PKS) assembly line for which the complete biosynthetic pathway has been proposed [25][34] (Figure 3). The biosynthesis of antimycins involves the activities of fourteen

• reaction in phenylacetate catabolism [35] resulting in hydryoxylation of C-2 [33]. 3-Aminosalicylate serves as the starter unit and is presented to the NRPS, AntC. The AntC protein possesses two modules organised as follows: C1-A1-T1-C2-A2-KR-T2. The A1 domain activates and loads threonine onto T1

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

• B (52) as a model system [51][52][53][54][55]. It was hypothesized that the carbon backbone, which is connected to an amino acid, most likely originates from a polyketide synthase (PKS)/nonribosomal peptide synthetase (NRPS) hybrid machinery [56]. The discovery of a gene locus for a PKS-NRPS

• basis of the structural similarity between 208 and marinopyrrole A, another secondary metabolite derived from a marine Streptomyces species [156]. The common biosynthetic precursor 206 stems from a mixed nonribosomal peptide synthetase (NRPS)/polyketide synthase (PKS) pathway. The amino acid proline is

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

• previously identified and characterized compounds has become a serious impediment to the discovery of new bioactive natural products. Here, genetic knockout of an unusual non-ribosomal peptide synthetase (NRPS) C-PCP-C module, aziA2, is performed resulting in the accumulation of the secondary metabolite

• 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

• ]. The gene encodes a NRPS (non-ribosomal peptide synthetase, an enzyme involved in the biosynthesis of various peptide containing secondary metabolites) module of unusual domain architecture consisting of condensation, peptidyl carrier protein, and condensation domains (C-PCP-C), respectively. Gene

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

• nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) pathways and highlight the unique enzyme mechanisms that were elucidated or can be anticipated for the individual products. We further include ribosomal natural products and UV-absorbing pigments from cyanobacteria. Mechanistic insights

• obtained from the biochemical studies of cyanobacterial pathways can inspire the development of concepts for the design of bioactive compounds by synthetic-biology approaches in the future. Keywords: cyanobacteria; natural products; NRPS; PKS; ribosomal peptides; Introduction The role of cyanobacteria in

• in microorganisms Microbial natural products of the peptide class are produced by two types of biosynthetic pathways: By giant multi-domain enzymes, the nonribosomal peptide synthetases (NRPS) or by ribosomal synthesis and subsequent post-translational modification and processing. NRPS consist of