Sulfation and amidinohydrolysis in the biosynthesis of giant linear polyenes

• Hui Hong,
• Markiyan Samborskyy,
• Katsiaryna Usachova,
• Katharina Schnatz and
• Peter F. Leadlay

Beilstein J. Org. Chem. 2017, 13, 2408–2415, doi:10.3762/bjoc.13.238

• DSM4137 (formerly Streptomyces violaceusniger DSM4137) [6] and it co-occurs with the closely-related antifungal mediomycins A (1c) and B (1d, Scheme 1) in Streptomyces mediocidicus ATCC 23936 [7]. Mediomycins are also produced by Streptomyces blastmyceticus [8]. The genes for the assembly-line PKS for

• are summarised in Table S4 (Supporting Information File 1). Both gene clusters encode a giant modular PKS housing 27 extension modules, distributed across nine PKS subunits (Scheme 2). This is exactly the number of extension modules predicted on the basis of the known structures of 1a–d. Detailed

• comparison of our amino acid sequences for the Cle PKS [10] and the Med PKS with the sequence recently reported for the Med PKS of S. blastmyceticus [8] showed in each case a high degree of amino acid sequence identity across the entire PKS (≈96% identity) and essentially perfect conservation of sequence in

Strategies in megasynthase engineering – fatty acid synthases (FAS) as model proteins

• Manuel Fischer and
• Martin Grininger

Beilstein J. Org. Chem. 2017, 13, 1204–1211, doi:10.3762/bjoc.13.119

• Megasynthases are large multienzyme proteins that produce a plethora of important natural compounds by catalyzing the successive condensation and modification of precursor units. Within the class of megasynthases, polyketide synthases (PKS) are responsible for the production of a large spectrum of bioactive

• polyketides (PK), which have frequently found their way into therapeutic applications. Rational engineering approaches have been performed during the last 25 years that seek to employ the “assembly-line synthetic concept” of megasynthases in order to deliver new bioactive compounds. Here, we highlight PKS

• antineoplastic doxorubicin and by the antiparasitic avermectin (Figure 1a) [1]. PK are assembled from acyl-coenzyme A (acyl-CoA) units via a series of Claisen-type condensation reactions catalyzed by polyketide synthases (PKS) (Figure 1b). PKS occur as large multifunctional enzymes, termed megasynthases, which

Biosynthetic origin of butyrolactol A, an antifungal polyketide produced by a marine-derived Streptomyces

• Enjuro Harunari,
• Hisayuki Komaki and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2017, 13, 441–450, doi:10.3762/bjoc.13.47

• hydroxymalonyl-ACP formation in the zwittermicin biosynthesis (ZmaN, ZmaD, ZmaG, and ZmaE) (Figure 6) [24] are present in the downstream of the butyrolactol PKS cluster. Genes coding for O-methyltransferase homologues responsible for O-methylation of hydroxymalonyl-ACP were not found near the cluster

• the ACP as a starter or isobutyl-CoA is used as a starter and C-methylation takes place afterwards. The signature sequence region of the acyltransferase domain of the PKS starter loading module for butyrolactol biosynthesis (FAGHS) shares some amino acid residues with the known loading module of

• coding for C-methyltransferase are not present near the butyrolactol PKS genes. Further enzymatic studies are necessary to establish the order of the starter loading/C-methylation events. Conclusion In summary, we elucidated the biosynthetic origin of butyrolactol A (1) on the basis of the feeding

Polyketide stereocontrol: a study in chemical biology

• Kira J. Weissman

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

• (hence the name ‘modular PKS’ for this type of system), each of which carries out a single round of chain extension and chemical tailoring of the resulting intermediate. Each PKS module incorporates three functional domains necessary for chain growth (Figure 3): an acyl transferase (AT) which selects the

• positions in the polyketide chains. Building of the polyketide core is typically terminated by a thioesterase (TE) domain situated at the end of the final PKS multienzyme, which releases the product by hydrolysis or more usually macrolactonization, using an internal hydroxy nucleophile. This PKS-free

• intermediate (6-deoxyerythronolide B in the case of erythromycin biosynthesis, Figure 3) is then frequently modified by a series of so-called ‘post-PKS enzymes’ (e.g., methyl transferases, hydroxylases, and glycosyl transferases), to achieve its final bioactive form [10]. Nature has, in fact, evolved two

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

• microorganism as a promising source of natural products. Genes for nonribosomal peptide synthetases (NRPSs) were found to be preponderant, either solely or organised in combination with polyketide synthase (PKS) genes, representing four and five clusters, respectively. Two PKS and three putative bacteriocin

• 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

• ]. Retrobiosynthetic analysis allowed the identification of a 14,130 bp-gene cluster, now referred to as aul-cluster (Figure 2), which putatively encodes two NRPSs (AulA and AulB) and one PKS (AulC) possessing domains that collectively allow and plausibly explains the assembly of 1. A gene for a type-II thioesterase

Evidence for an iterative module in chain elongation on the azalomycin polyketide synthase

• Hui Hong,
• Yuhui Sun,
• Yongjun Zhou,
• Emily Stephens,
• Markiyan Samborskyy and
• Peter F. Leadlay

Beilstein J. Org. Chem. 2016, 12, 2164–2172, doi:10.3762/bjoc.12.206

• prompted efforts to manipulate PKS domains and modules into novel combinations, as a route to obtaining novel non-natural polyketide products [6][7], and facilitated the discovery of new biosynthetic gene clusters using whole-genome sequence analysis [8][9]. A number of assembly-line PKSs do not exactly

• [13]. In trans-AT PKSs, domains are often found in unconventional order, and modules may be split between different PKS multienzyme subunits. In both types of modular PKS, domains may be present but apparently not used, or expected domains may be missing [10][12]. Perhaps the most striking deviations

• from colinearity are those where the number of modules in the PKS does not correspond to the number of extension units found in the chemical product [10][12]. Strains subjected either to random mutagenesis or to a targetted block in post-PKS steps have been found to accumulate aberrant products of

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

• ]. Polyketides Polyketide natural products are biosynthesised by polyketide synthases (PKSs) of the types I–III. Type I PKS are multimodular megaenzyme complexes that produce linear, reduced polyketides in an assembly line process that uses acyl carrier proteins (ACP), ketosynthase (KS) and acyl transferase (AT

• ) domains as well as ketoreductase (KR), dehydratase (DH), enoyl reductase (ER) and thioesterase (TE) domains [6][8]. The PKS intermediates remain tethered to the megaenzyme via a thioester linkage during the whole process. Among these domains, only TE domains participate in cyclisation reactions as part of

• their standard catalytic repertoire (Scheme 1). They transacylate the thioester of a PKS-bound polyketide onto a nucleophile. If the nucleophile is water, this leads to carboxylic acids. The reactions of backbone hydroxy groups or amines consequently give lactones and lactams. TE domains mostly form

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

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

• 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

• enediyne clusters could be identified in sequencing projects over the past years, comparatively few loci were retrieved from microbes outside the actinobacteria [124]. This suggests an event of horizontal gene transfer (HGT) in H. aurantiacus 114-95T. Analysis of a large NRPS/PKS cluster in the same strain

Biosynthesis of α-pyrones

• Till F. Schäberle

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

• biosynthesis of these mostly polyketide-derived structures exist, thus it is assumed that the route towards α-pyrones has been developed several times in evolution. They can be built up by the catalytic activities of the different types of polyketide synthase (PKS) systems, and especially the final ring

• -pyrones [6]. Several derivatives exist, whereby aflatoxin B1 (61, Figure 16) represents the most poisonous compound. Usually these toxins are ingested, but 61 can also permeate through the skin. The aflatoxins are PKS-derived molecules which undergo an extreme rearrangement [66]. The cytotoxic effects of

• ellagitannin biosynthesis [73]. The ellagitannins can then be hydrolyzed to ellagic acid (22), and subsequently converted to urolithins (23–27). In microorganisms the PKS-derived origin was independently postulated for numerous compounds. The polyketide biosynthesis has much in common with fatty acid

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

• may not precisely follow the IUPAC rules. Review Polyketides Polyketide synthases (PKS) are multidomain enzymes that catalyze the formation of natural products via reaction steps similar to fatty acid biosynthesis, in which C2-units are fused in Claisen condensations and modified in an iterative or

• reductase [16], aflatoxin B1 (2) [17] and the potent antifungal agent amphotericin B (3) [18], which affects membrane integrity. The products of polyketide synthases (PKS) belong to the first secondary metabolites that were investigated using isotopically labeled compounds [19]. Feeding experiments using

• (1,2-13C2)acetate and (1-13C) or (2-13C)acetate are a convenient and simple source of information on intact acetate units, chain direction and modifications of PKS derived natural products. Sensu stricto, polyketides (i.e., polymers of the “ketide” group –CH2–CO–) are structurally made of malonyl-CoA

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

• , e.g., via 31 followed by double bond reduction may lead to piperideine 24, a precursor of the major liquid phase component 22. Alternatively, this compound might originate from the reduced PKS precursor 32 that is transformed via 33 into 24. Piperidine 22 is then obtained via imine reduction as

• biosynthesis of the streptopyridines. PKS: polyketide synthase; red: reduction; ta: transamination; ox: oxidation; elim: elimination. Volatile compounds identified in the headspace extract of Streptomyces strain FORM5. The amounts of the compounds are given as 0–2% (x), 2–8% (xx), >8% (xxx) relative to 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

• sequencing and bioinformatics analysis of Streptomyces sp. LZ35. This finding suggests the potential of LZ35 to produce 3-HBA-containing polyketides [4]. A gdmAI (encoding the first geldanamycin PKS module) deletion strain LZ35ΔgdmAI was constructed [3][5], as the production of geldanamycins was much higher

• employed in the polyketide chain extension. In addition, several post-PKS modifications are required to complete the biosynthesis of cuevaenes [4]. In this study, two pairs of geometrical isomers were reported. The difference between the geometrical isomers is the stereoconfiguration of the Δ4,5 double

• bond. A previous study indicated that the double-bond geometry is determined by the stereochemistry of Ketoreductase (KR)-catalyzed ketoreduction [9]. By multiple sequence alignment of modular PKS KR domains we identified an Asp residue in the KR5 domain of cuevaenes PKS (Supporting Information File 1

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

• position 12 in 1 is installed by the dehydratase of polyketide synthase (PKS) module 3 (BorDH3). Characteristic residues in the active site of the preceding ketoreductase point towards a 3D configuration of the BorDH3 precursor 3 [10][11]. Furthermore, we have shown in a previous study that BorDH3

• preferentially accepts the 2D,3D-configured precursor, if all four potential stereoisomers of 3-hydroxy-2-methyl-SNAc-pentanoate model substrates are presented [7]. A commonly accepted model suggests that DHs from PKS I systems catalyze the removal of water by syn-dehydration and that a 2D,3D-configured

• processes. Our aim was to assay the stereochemical course of the dehydratase of polyketide synthase (PKS) module 3 (BorDH3) in vitro. Therefore, the surrogate 5a for BorDH3 as well as reference molecules such as 6a and 6b and the corresponding methyl esters 7a and 7b, which resemble the potential assay

Preparation of new alkyne-modified ansamitocins by mutasynthesis

• Kirsten Harmrolfs,
• Lena Mancuso,
• Binia Drung,
• Florenz Sasse and
• Andreas Kirschning

Beilstein J. Org. Chem. 2014, 10, 535–543, doi:10.3762/bjoc.10.49

• (1, AHBA) is the starter building block of the PKS type I that is responsible for the biosynthesis of the ansamitocin backbone [22]. This PKS is a well studied megaenzyme complex and after the action of tailoring enzymes succeeding the PKS machinery ansamitocins 3–5 are formed [23][24][25][26][27

• ]. In the present case, 1 is loaded on the starter module of the polyketide synthase (Scheme 1). The last PKS module releases and cyclizes seco-proansamitocin, likely by an ansamycin amide synthase (gene asm9) [23][24][25][26][27], that generates the 19-membered macrocyclic lactam proansamitocin (2

• them to serve our purposes, when fully processed after being fed to the mutant strain of A. pretiosum blocked in the biosynthesis of the PKS starter unit AHBA (1). We found that several of these aminobenzoic acids, namely 10, 14 and 16–20 were either not loaded onto the PKS or not processed by the

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

• for the key role of late-stage hydroxylation at C-26 of the monensin molecule. Like other polyether ionophores, monensin is assembled by the polyketide biosynthetic pathway on a modular polyketide synthase (PKS) multienzyme [14]. A model has been proposed [14] for monensin biosynthesis in which an

• monensin PKS (MonAI-MonAVIII) assembles the carbon skeleton of monensin A from five acetate, one butyrate and seven propionate units. The butyrate unit may be substituted by a further propionate unit, producing monensin B, which bears a methyl instead of an ethyl group at C-16. It appears that oxidative

• cyclisation is not initiated before the full-length chain is produced, and that the initial product of the PKS is a linear enzyme-bound (E,E,E)-triene, “premonensin” (2) [19]. The monensin PKS does not have a conventional C-terminal thioesterase domain that would catalyse polyketide chain release, and instead

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

• , followed by condensation of 3-aminosalicylate and threonine promoted by C1. The A2 domain activates and loads pyruvate onto T2. Pyruvate is subsequently stereospecifically reduced by the KR domain and condensed with threonine by C2. The PKS, AntD posseses one module composed of the domains KS-AT-ACP-TE

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

• 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

• . 3-Methoxy-5-methyl-1-naphthoic acid was detected in trace amounts (suggesting that the metabolite is released in solution from the PKS and not directly transferred to that of a subsequent NRPS module) and complete abolishment of the azinomycins was observed. The production of the naphthoic acid

Quantification of N-acetylcysteamine activated methylmalonate incorporation into polyketide biosynthesis

• Stephan Klopries,
• Uschi Sundermann and
• Frank Schulz

Beilstein J. Org. Chem. 2013, 9, 664–674, doi:10.3762/bjoc.9.75

• widespread application in current medicine and agriculture. Polyketide synthases (PKS), giant multienzyme complexes, play a pivotal role in their biosynthesis. PKS generate molecular complexity and diversity through a number of stepwise condensations in analogy to fatty acid synthases but with optional and

• ]. Current experiments to generate biosynthetic polyketide diversity focus on different aspects of the biosynthetic reaction cascade. Mainly by genetic replacement or deletion of various fragments of PKS, alterations in chain length [9][10][11], redox pattern [12][13][14], stereochemistry [15][16][17], and

• pattern are highly sought after [4][17][21][22][23][24][25][26]. Different strategies can be pursued to introduce non-native extender units into the PKS machinery. They rely on the replacement of an acyltransferase domain of a given PKS module with another domain possessing different substrate specificity

Unprecedented deoxygenation at C-7 of the ansamitocin core during mutasynthetic biotransformations

• Tobias Knobloch,
• Gerald Dräger,
• Wera Collisi,
• Florenz Sasse and
• Andreas Kirschning

Beilstein J. Org. Chem. 2012, 8, 861–869, doi:10.3762/bjoc.8.96

• ansamitocin producer [13][14][15][16][17], and Streptomyces hygroscopicus, the geldanamycin producer [18][19]. These engineered strains are unable to biosynthesize 3-amino-5-hydroxybenzoic acid (1) [20], the common starter unit for both polyketide synthases (PKS) (Scheme 1). These assembly-line-type

• multienzymes are responsible for setting up the complete carbon backbone of both ansamycin antibiotics [21][22][23][24]. More precisely, the biosynthesis of ansamitocins relies on a type I modular polyketide synthase (PKS), with 3-amino-5-hydroxybenzoic acid (1, AHBA) [20] as the starter unit followed by chain

• extension by one “glycolate”, three propionate and three acetate units. The last PKS module holds seco-proansamitocin, which is released and cyclized, presumably by an ansamycin amide synthase (Asm9) [21][22][23][24], to yield the 19-membered macrocyclic lactam proansamitocin (2). Proansamitocin (2) is

Phytoalexins of the Pyrinae: Biphenyls and dibenzofurans

• Cornelia Chizzali and
• Ludger Beerhues

Beilstein J. Org. Chem. 2012, 8, 613–620, doi:10.3762/bjoc.8.68

• ]. Biosynthesis of biphenyls and dibenzofurans The key enzyme of the biosynthetic pathway is biphenyl synthase (BIS) [22]. This type-III polyketide synthase (PKS) catalyzes the iterative condensation of benzoyl-CoA with three acetyl units from the decarboxylation of malonyl-CoA to form a linear tetraketide

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

• combined with transport across the plasma membrane [12] (Figure 2). Macrolides in microorganisms are produced by modular type polyketide synthases (PKS) resembling NRPS with respect to their modular nature. In contrast to the peptide-synthesizing enzymes, different types of carboxylic acids are activated