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

• ]. 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

• polyketide synthase in A. pretiosum and thus no formation of new ansamitocin derivatives was encountered in these cases. In contrast, benzoic acid 11 provided Br-F-ansamitocin derivatives 21a–d after being fed to a growing culture of the mutant strain as judged by HRMS (Scheme 4). The retention times in LC

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

• 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

• with the polyketide in thioester linkage to a discrete acyl carrier protein (MonACPX) [20], and therefore the terminal carboxylate is not available as an alternative ligand for the bound cation until all the tailoring steps have been accomplished and the mature antibiotic is released by thioesterase

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

• . 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

Synthesis of the spiroketal core of integramycin

• Evgeny. V. Prusov

Beilstein J. Org. Chem. 2013, 9, 2446–2450, doi:10.3762/bjoc.9.282

• ; hydrozirconation; natural products; spiroketals; total synthesis; Findings Integramycin is a polyketide natural product isolated from Actinoplanes sp. by the Singh group at Merck [1] (Figure 1). The compound was found to inhibit HIV-1 integrase coupled strand transfer reactions with IC50 values of 3 and 4 μM

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

• isopentyl pyrophosphate (IPP, 166), and orsellinic acid (168), which is derived from a fungal iterative type I polyketide pathway [142], are connected to give 169. This substrate is already poised for a polyene cyclization cascade, which only has to be triggered via activation of the epoxide. After the

• contain the same prenylated polyketide core imply a direct biosynthetic relationship [147]. The reaction of 192 with an equivalent of ammonia gives a cyclic iminohemiaminal, which first tautomerizes to the hydroxy isoindole and then to the isoindolinone 193. This biosynthetic transformation was also used

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

• compound as dimethyl furan-2,4-dicarboxylate, which has been previously observed in microbial head-space or vapor phase extracts and its structure determined through chemical synthesis [15]. The biosynthetic origin of dimethyl furan-2,4-dicarboxylate could be polyketide derived where the furan ring system

• 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

New tridecapeptides of the theonellapeptolide family from the Indonesian sponge Theonella swinhoei

• Annamaria Sinisi,
• Barbara Calcinai,
• Carlo Cerrano,
• Henny A. Dien,
• Angela Zampella,
• Claudio D’Amore,
• Barbara Renga,
• Stefano Fiorucci and
• Orazio Taglialatela-Scafati

Beilstein J. Org. Chem. 2013, 9, 1643–1651, doi:10.3762/bjoc.9.188

• reference compound in the class of actin interacting cell growth inhibitors [5]), polyene derivatives (as aurantosides [6]), and polypeptides/depsipeptides. The biosynthesis of several secondary metabolites of Theonella has been ascribed to symbiotic microorganisms, as in the case of the polyketide onnamide

• , Indonesia), which proved to be rich in aurantosides [6] and 4-methylene steroids [18], while polyketide macrolides and peptide-based derivatives were extremely rare if not absent. Remarkably, the chemical analysis of a different specimen of T. swinhoei, collected in the same area as the previous one

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

• Polyketides are biosynthesized through consecutive decarboxylative Claisen condensations between a carboxylic acid and differently substituted malonic acid thioesters, both tethered to the giant polyketide synthase enzymes. Individual malonic acid derivatives are typically required to be activated as coenzyme

• A-thioesters prior to their enzyme-catalyzed transfer onto the polyketide synthase. Control over the selection of malonic acid building blocks promises great potential for the experimental alteration of polyketide structure and bioactivity. One requirement for this endeavor is the supplementation of

• the bacterial polyketide fermentation system with tailored synthetic thioester-activated malonates. The membrane permeable N-acetylcysteamine has been proposed as a coenzyme A-mimic for this purpose. Here, the incorporation efficiency into different polyketides of N-acetylcysteamine activated

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

Identification and isolation of insecticidal oxazoles from Pseudomonas spp.

• Florian Grundmann,
• Veronika Dill,
• Andrea Dowling,
• Aunchalee Thanwisai,
• Edna Bode,
• Narisara Chantratita,
• Richard ffrench-Constant and
• Helge B. Bode

Beilstein J. Org. Chem. 2012, 8, 749–752, doi:10.3762/bjoc.8.85

• protein or polyketide synthase or nonribosomal peptide synthetase) bound. Supporting Information Supporting Information File 114: General experimental procedures, isolation of the strain and taxonomic identification, cultivation and extraction, isolation, labeling experiments, synthesis, bioactivity

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

• pathways. Elicitor-treated cell cultures of Sorbus aucuparia served as a model system for studying phytoalexin metabolism. The key enzyme that forms the carbon skeleton is biphenyl synthase. The starter substrate for this type-III polyketide synthase is benzoyl-CoA. In apples, biphenyl synthase is encoded

• ]. 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

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

• similar N-acetylcysteine adduct has been described for a polyketide antibiotic, also leading to a loss of biological activity; therefore, the conjugation has been suggested as representing a detoxification mechanism [18]. The extent of the conversion of endophenazine A to endophenazine E in cultures of S

• napyradiomycin biosynthesis gene cluster from S. aculeolatus [30], and fur18 in the biosynthetic gene cluster of furaquinocin A from Streptomyces sp. KO-3988 [31]. A similar gene, aur1O, is found in the biosynthetic gene cluster of the polyketide antibiotic auricin from S. aureofaciens [32]. The function of

Aldol elaboration of 4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridin-4-ones, masked precursors to acylpyridones

• Raymond C. F. Jones,
• Abdul K. Choudhury,
• James N. Iley,
• Mark E. Light,
• Georgia Loizou and
• Terence A. Pillainayagam

Beilstein J. Org. Chem. 2012, 8, 308–312, doi:10.3762/bjoc.8.33

• product ilicicolin H (9) (Figure 3) [20][21] along with fischerin, apiosporamide and YM-215343, displays a 3-decalinoyl-4-hydroxypyridin-2-one skeleton wherein the decalin unit may arise biosynthetically from a Diels–Alder reaction within the polyketide-derived side chain [1][22]. As a further

Novel fatty acid methyl esters from the actinomycete Micromonospora aurantiaca

• Jeroen S. Dickschat,
• Hilke Bruns and
• Ramona Riclea

Beilstein J. Org. Chem. 2011, 7, 1697–1712, doi:10.3762/bjoc.7.200

• elongation units, and occur due to the logic of FA biosynthesis in even-numbered positions of the FA carbon chain. An alternative mechanism leading to the same methyl branching pattern is well-known from polyketide biosynthesis and involves the incorporation of a malonyl-CoA unit followed by SAM-dependent

• methylation of the new α-carbon. Further alternative starters are known [2][3][4], but these cases are rare. In contrast, the usage of alternative elongation units such as ethylmalonyl-CoA [5], propylmalonyl-CoA [6], isobutylmalonyl-CoA [7], or methoxymalonyl-ACP [8] remains almost limited to polyketide

Marilones A–C, phthalides from the sponge-derived fungus Stachylidium sp.

• Celso Almeida,
• Stefan Kehraus,
• Miguel Prudêncio and
• Gabriele M. König

Beilstein J. Org. Chem. 2011, 7, 1636–1642, doi:10.3762/bjoc.7.192

• the polyketide metabolism, which are common in nature [1]. Secondary metabolites 1 and 2 discovered in the marine-derived Stachylidium sp. were found to be derivatives of the natural product nidulol, whilst compound 3 was a derivative of silvaticol (4) (see Supporting Information File 1), formerly

• derivatives 1 and 2 are distinguished by an additional methyl substituent (11-CH3) at C-8. In terms of biosynthesis, i.e., polyketide metabolism, this substitution is most unusual for phthalides and, to the best of our knowledge, it was only found once in dimethoxydimethylphthalide (DDP) [12]. Biosynthetic

• D in Figure S15; Supporting Information File 1). A third possibility would be the loss of a carbon atom from a pentaketide intermediate. To our knowledge, to date propionate as a starter unit was only described for pseurotin A and austrocorticinic acid in fungal polyketide metabolism [15][16

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

• 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

• iteratively [16]. Nonribosomal peptide, polyketide and hybrid biosyntheses in cyanobacteria Research on NRPS and PKS gene clusters started almost in parallel in freshwater, marine and terrestrial cyanobacteria. A major trait of cyanobacterial pathways is their hybrid character, i.e., the frequent mixture of

Biosynthesis and function of secondary metabolites

• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2011, 7, 1620–1621, doi:10.3762/bjoc.7.190

• polyketide and nonribosomal peptide biosynthetic machineries, which is strongly correlated with the logic of fatty acid biosynthesis as part of the primary metabolism. Insights into the mechanisms of modular polyketide and nonribosomal peptide assembly lines open up the possibility for direct modifications

Phaeochromycins F–H, three new polyketide metabolites from Streptomyces sp. DSS-18

• Jian Li,
• Chun-Hua Lu,
• Bao-Bing Zhao,
• Zhong-Hui Zheng and
• Yue-Mao Shen

Beilstein J. Org. Chem. 2008, 4, No. 46, doi:10.3762/bjoc.4.46