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

• Hui Hong Yuhui Sun Yongjun Zhou Emily Stephens Markiyan Samborskyy Peter F. Leadlay Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge, CB2 1GA, United Kingdom Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Wuhan University, Ministry of Education

• or module of enzymes. Examples of deviation from this paradigm, in which a module catalyses either multiple extensions or none are of interest from both a mechanistic and an evolutionary viewpoint. We present evidence that in the biosynthesis of the 36-membered macrocyclic aminopolyol lactones

• gene cluster for biosynthesis of the polyketide β-lactone ebelactone in Streptomyces aburaviensis has shown that, contrary to a recently-published proposal, the ebelactone polyketide synthase faithfully follows the colinear modular paradigm. Keywords: colinearity; ebelactone; enzyme catalysis

New furoisocoumarins and isocoumarins from the mangrove endophytic fungus Aspergillus sp. 085242

• Ze’en Xiao,
• Senhua Chen,
• Runlin Cai,
• Shao’e Lin,
• Kui Hong and
• Zhigang She

Beilstein J. Org. Chem. 2016, 12, 2077–2085, doi:10.3762/bjoc.12.196

• District, Shenzhen, 518102, China Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education of China, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China 10.3762/bjoc.12.196 Abstract The chemical investigation of the mangrove endophytic fungus Aspergillus

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

• containing water or deuterium oxide allowed for detailed insights into the cyclisation mechanisms of the bacterial terpene cyclases. Keywords: absolute configuration; biosynthesis; enzyme mechanisms; structure elucidation; terpenes; Introduction Terpenes are structurally fascinating natural products with

• isotopic labelling experiments. The proposed biosynthesis of 7-epi-α-eudesmol (4) starts with a 1,10-cyclisation of FPP to the (E,E)-germacradienyl cation (B) which is attacked by water to form hedycaryol (4a). Its reprotonation at C-1 initiates a second cyclisation to cation C that undergoes deprotonation

• experiments give the same results. Additionally we have demonstrated that the 7-epi-α-eudesmol biosynthesis proceeds via reprotonation of the neutral intermediate hedycaryol by usage of (6-13C)FPP as substrate in an incubation experiment with recombinant purified enzyme in deuterium oxide. Finally, incubation

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

• Bayreuth, Germany 10.3762/bjoc.12.148 Abstract This review highlights the biosynthesis of heterocycles in polyketide natural products with a focus on oxygen and nitrogen-containing heterocycles with ring sizes between 3 and 6 atoms. Heterocycles are abundant structural elements of natural products from

• all classes and they often contribute significantly to their biological activity. Progress in recent years has led to a much better understanding of their biosynthesis. In this context, plenty of novel enzymology has been discovered, suggesting that these pathways are an attractive target for future

• studies. Keywords: biosynthesis; chemoenzymatic synthesis; enzymology; heterocycles; polyketides; Introduction Heterocycles Heterocycles are important structural elements, which are present in natural products from all classes and also in many biologically active synthetic compounds. They often

Discovery of an inhibitor of the production of the Pseudomonas aeruginosa virulence factor pyocyanin in wild-type cells

• Bernardas Morkunas,
• Balint Gal,
• Warren R. J. D. Galloway,
• James T. Hodgkinson,
• Brett M. Ibbeson,
• Yaw Sing Tan,
• Martin Welch and
• David R. Spring

Beilstein J. Org. Chem. 2016, 12, 1428–1433, doi:10.3762/bjoc.12.137

• network with the Las system at the top of the network. The regulator of the pyocyanin biosynthesis genes is RhlR and transcription of the rhlR gene is itself regulated by LasR. Hence, it has been hypothesised that LasR inhibition should result in the attenuation of pyocyanin production [8][9][20]. This

• hypothesis has been validated with a number of synthetic small molecules which inhibit LasR and pyocyanin production, respectively [8][9][20][23][24][25][26]. Many such inhibitors of pyocyanin biosynthesis are based on the same general structural framework as OdDHL. For example, we have recently reported the

• pyocyanin biosynthesis in P. aeruginosa may be inhibitors of LasR-based quorum sensing. However, it has previously been reported that P. aeruginosa can exhibit near full virulence, including pyocyanin production, in the absence of LasR utilising solely the rhl, and pqs signalling systems [30]. Additional

Cyclisation mechanisms in the biosynthesis of ribosomally synthesised and post-translationally modified peptides

• Andrew W. Truman

Beilstein J. Org. Chem. 2016, 12, 1250–1268, doi:10.3762/bjoc.12.120

• heterocyclisation to form thiazolines or oxazolines, and radical-mediated reactions between unactivated carbons. Future prospects for RiPP pathway discovery and characterisation will also be highlighted. Keywords: biosynthesis; cyclisation; enzymes; peptides; RiPPs; Introduction Nature employs a number of routes

• RiPP pathways, which are often small and lacking in homology to one another [9]. There has therefore been a massive increase in the study of their biosynthesis in recent years. RiPPs usually originate from a larger precursor peptide that consists of an N-terminal leader sequence and a core peptide that

• highly similar, and is distinct from their generation in non-ribosomal peptides. The first in vitro reconstitution of a TOMM was carried out with microcin B17 [28][32][33], which showed that there are four essential proteins for its biosynthesis: the precursor peptide (the “A” protein McbA) that is post

Towards the total synthesis of keramaphidin B

• Pavol Jakubec,
• Alistair J. M. Farley and
• Darren J. Dixon

Beilstein J. Org. Chem. 2016, 12, 1096–1100, doi:10.3762/bjoc.12.104

• , in their landmark paper entitled ‘On the Biosynthesis of Manzamines’ postulated that keramaphidin B was a common intermediate in the biosynthesis of the manzamine alkaloids [2]. Several years later, Baldwin and co-workers synthesised keramaphidin B following a biomimetic pathway via an intramolecular

• Diels–Alder reaction as the late stage key step. After extensive purification, the authors were able to isolate keramaphidin B in just 0.3% yield, but nevertheless they provided evidence for the biosynthesis [3]. A year later, Baldwin et al. completed an alternative synthesis by performing an

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

• 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

• structural details and biological activity of the metabolites. Additionally, putative gene clusters for secondary metabolite biosynthesis are included in this review. For this reason we were mining the four available genomes from bacteria of the Nannocystineae using the antiSMASH 3 tool [41] (see Table 1

• terpene biosynthesis gene clusters. The genus Haliangium Haliangium ochraceum sp. nov. (initially termed H. luteum, DSM 14365T) and H. tepidum sp. nov. (DSM 14436T) were isolated from seaweed and sea grass, respectively, with both samples being obtained from a sandy beach in Miura, Japan by Fudou et al

A cross-metathesis approach to novel pantothenamide derivatives

• Jinming Guan,
• Matthew Hachey,
• Lekha Puri,
• Vanessa Howieson,
• Kevin J. Saliba and
• Karine Auclair

Beilstein J. Org. Chem. 2016, 12, 963–968, doi:10.3762/bjoc.12.95

• pathways such as the acyl carrier protein activation required for fatty acid biosynthesis [13][14][15][16]. In S. aureus, however, recent studies suggest that the antimicrobial activity correlates better with an inhibition of PanK, the regulatory enzyme in CoA biosynthesis in several organisms [17

• if 16 was targeting CoA biosynthesis as reported for other pantothenamides, the IC50 was also measured in the presence of excess pantothenate (100 µM), in the presence or absence of pantetheinase. The dramatic loss of activity observed confirms that compound 16 acts on the CoA biosynthesis

Indenopyrans – synthesis and photoluminescence properties

• Andreea Petronela Diac,
• Ana-Maria Ţepeş,
• Albert Soran,
• Ion Grosu,
• Anamaria Terec,
• Jean Roncali and
• Elena Bogdan

Beilstein J. Org. Chem. 2016, 12, 825–834, doi:10.3762/bjoc.12.81

• context are benzo[b]indeno-[2,1-e]pyran-10,11-diones, which stimulate the biosynthesis of erythropoietin and are used to treat anemia [10]. Another application includes the use of some amino-spiroindenopyran derivatives as selective sensors for thallium(I) ions in human urine [11]. Pyran-containing

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

• natural products. These uridine-derived nucleoside-peptide antibiotics inhibit the bacterial membrane protein translocase I (MraY), a key enzyme in the intracellular part of peptidoglycan biosynthesis. This review describes the structures of naturally occurring muraymycins, their mode of action, synthetic

• access to muraymycins and their analogues, some structure–activity relationship (SAR) studies and first insights into muraymycin biosynthesis. It therefore provides an overview on the current state of research, as well as an outlook on possible future developments in this field. Keywords: antibiotics

• methicillin-resistant Staphylococcus aureus (MRSA) [18][19] and vancomycin-resistant Enterococcus (VRE) [20]. This development raises the demand for antibiotics exploiting yet unused modes of action. Potential targets within bacteria include peptidoglycan biosynthesis, protein biosynthesis, DNA and RNA

Synthesis and in vitro cytotoxicity of acetylated 3-fluoro, 4-fluoro and 3,4-difluoro analogs of D-glucosamine and D-galactosamine

• Štěpán Horník,
• Lucie Červenková Šťastná,
• Petra Cuřínová,
• Jan Sýkora,
• Kateřina Káňová,
• Roman Hrstka,
• Ivana Císařová,
• Martin Dračínský and
• Jindřich Karban

Beilstein J. Org. Chem. 2016, 12, 750–759, doi:10.3762/bjoc.12.75

• Background: Derivatives of D-glucosamine and D-galactosamine represent an important family of the cell surface glycan components and their fluorinated analogs found use as metabolic inhibitors of complex glycan biosynthesis, or as probes for the study of protein–carbohydrate interactions. This work is

• glycan and glycosaminoglycan biosynthesis [2][3], to inhibit amino sugars processing enzymes [4][5], to probe interactions of amino sugars with their target enzymes and lectins [6][7], or to increase the hydrolytic stability of the glycosidic bond in amino sugar glycosides [8][9]. For example, acetylated

• 4-fluoro analogs of D-glucosamines 1–3, D-galactosamine 4, and 6-fluoro-D-galactosamine 9 (Figure 1) acted as metabolic inhibitors of the biosynthesis of cell-surface O- and N-linked glycans (including their lactosamine and sialyl LewisX terminal epitopes) [2][3][10][11], and glycosaminoglycans [3

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

• possess impressive capacities for natural product biosynthesis. Here, we will present the results from recent chemical investigations of this bacterial group, compare the biosynthetic potential with that of non-predatory bacteria and discuss the link between predation and secondary metabolism. Keywords

• further characterized by their large genome sizes and their striking potential for the production of structurally diverse natural products with antimicrobial activities [12][30][31][32][33][34][35]. For many years, it has been speculated whether antibiotic biosynthesis is functionally linked to the

• , it becomes obvious that the Cystobacterineae strains consistently possess more biosynthesis gene clusters per Mbp of DNA than the analyzed Sorangiineae and that they also devote a larger percentage of their total nucleotides to natural product biosynthesis. Noteworthy in this context, the genera

cis–trans-Amide isomerism of the 3,4-dehydroproline residue, the ‘unpuckered’ proline

• Vladimir Kubyshkin and
• Nediljko Budisa

Beilstein J. Org. Chem. 2016, 12, 589–593, doi:10.3762/bjoc.12.57

• [26][27][28] have also been characterized. 3,4-Dehydroproline (Dhp, 2, Figure 1) has been reported to exhibit a rather flat ring structure, as the result of theoretical analysis of Ac-Dhp-NHMe models [29][30]. It has also been demonstrated that Dhp inhibits collagen biosynthesis and suppresses the

Biosynthesis of α-pyrones

• Till F. Schäberle

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

• chemists [15]. Hence, the phenomenal abundance of natural products and of chemically synthesized derivatives therefrom justifies several reviews, and comprehensive articles exist [1][16]. However, in the present review the diverse biosynthesis of α-pyrones will be the focus. Different mechanisms for the

• 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

• biosynthesis was investigated using various 13C-labeled precursors [55]. Hence, it was concluded that beside four acetate units also two propionate units and one butyrate unit form the backbone, while the O-methylation is S-adenosyl-methionine dependent. Also cyclooxygenase-2 (COX-2) inhibitors are an

Natural products in synthesis and biosynthesis II

• Jeroen S. Dickschat

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

• Jeroen S. Dickschat Kekulé-Institut für Organische Chemie und Biochemie, Rheinische Friedrich-Wilhelms-Universität Bonn, Gerhard-Domagk-Straße 1, D-53121 Bonn, Germany 10.3762/bjoc.12.44 Keywords: biosynthesis; natural products; synthesis; As a continuation of the first two Thematic Series in

Dynamic behavior of rearranging carbocations – implications for terpene biosynthesis

• Stephanie R. Hare and
• Dean J. Tantillo

Beilstein J. Org. Chem. 2016, 12, 377–390, doi:10.3762/bjoc.12.41

• theoretical tools. Then we describe studies dealing with carbocations that are not involved in terpene formation, but which reveal reactivity principles that may have implications for terpene biosynthesis. This is followed by descriptions of the relatively few studies published so far that are concerned with

• commonly used [35][36][37][38][39][40]. In particular, the B3LYP and mPW1PW91 functionals, along with small to medium sized basis sets have seen the most use in studying carbocation rearrangements of relevance to biosynthesis [6]. Using molecular dynamics trajectories to rationalize experimental results is

• about lifetimes of particular structures and product distributions – not merely for reactions of academic interest, but for reactions that occur in Nature during the biosynthesis of complex natural products. While characterizing the dynamical behavior of reactive species is challenging, it can be

Mycothiol synthesis by an anomerization reaction through endocyclic cleavage

• Shino Manabe and
• Yukishige Ito

Beilstein J. Org. Chem. 2016, 12, 328–333, doi:10.3762/bjoc.12.35

• cell from toxic chemicals. The inhibition of the mycothiol biosynthesis is considered as a treatment for tuberculosis. Mycothiol contains an α-aminoglycoside, which is difficult to prepare stereoselectively by a conventional glycosylation reaction. In this study, mycothiol was synthesized by an

• enzymes involved may be considered as novel antimicrobacterial targets, especially for tuberculosis, and several compounds with inhibitory activity have been synthesized [17][18]. In addition, another function of MSH was recently reported; it is involved in the biosynthesis of lincomycin A, a sulfur

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

• light on the ecology and evolution of defensive associations. Keywords: biosynthesis; chemical ecology; natural products; secondary metabolism; structure elucidation; symbiosis; Introduction Although natural products represent the most consistently successful drug leads [1][2], many pharmaceutical

• citrus psyllid and the β-proteobacterium ”Candidatus Profftella armatura” [54][55]. A genome analysis of Profftella, which resides in a symbiotic organ called the bacteriome, revealed that 15% of the drastically reduced genome encoded horizontally acquired genes for the biosynthesis of the polyketide

• aridifolia [118][119]. Additional insights into the dalesconol biosynthesis was gained from a characterization of minor dalesconols and biosynthetic intermediates only present in chemical extracts prepared from a large-scale fermentation. The ascomycete fungus Pseudallescheria boydii, isolated from the gut

A journey in bioinspired supramolecular chemistry: from molecular tweezers to small molecules that target myotonic dystrophy

• Steven C. Zimmerman

Beilstein J. Org. Chem. 2016, 12, 125–138, doi:10.3762/bjoc.12.14

• postdoctoral fellowship, I spent just under two years with Sir Alan Battersby at the University of Cambridge where we completed the total synthesis of sirohydrochlorin, an intermediate in the biosynthesis of vitamin B12. Then in July 1985, it was off to the University of Illinois at Urbana-Champaign. Molecular

Smart molecules for imaging, sensing and health (SMITH)

• Bradley D. Smith

Beilstein J. Org. Chem. 2015, 11, 2540–2548, doi:10.3762/bjoc.11.274

• University in the UK for postdoc studies in the group of legendary Professor Jack Baldwin, at the height of his work on penicillin biosynthesis. The lab was full of very talented people, but the enormous size of the group made it unwieldy. After 15 months and a few quick papers I moved back to the US for a

Synthesis of Xenia diterpenoids and related metabolites isolated from marine organisms

• Tatjana Huber,
• Lara Weisheit and
• Thomas Magauer

Beilstein J. Org. Chem. 2015, 11, 2521–2539, doi:10.3762/bjoc.11.273

• section, we present a biosynthetic proposal, discuss various synthetic approaches towards xenicane diterpenoids and highlight successful total syntheses. Review Biosynthetic hypothesis The proposed biogenesis of xenicanes (Scheme 1) is suggested to be similar to the reported biosynthesis of the

• . Representative members of the caryophyllenes, azamilides and Dictyota diterpenes. Proposed biosynthesis of Xenia diterpenoids (OPP = pyrophosphate, GGPP = geranylgeranyl pyrophosphate, IPP = isoprenyl pyrophosphate, DMAPP = dimethylallyl pyrophosphate). Direct synthesis of the nine-membered carbocycle as

• Danishefsky. Proposed biosynthesis of plumisclerin A (118). Synthesis of the tricyclic core structure of plumisclerin A by Yao. Total synthesis of 4-hydroxydictyolactone (137) by Williams. Photoisomerization of 4-hydroxydictyolactone (137) to 4-hydroxycrenulide (138). The total synthesis of

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

• understanding of biosynthesis. As demonstrated in this article, the usage of isotopes is not at all old-fashioned, but continues to give important insights into biosynthetic pathways of secondary metabolites. This review with 85 cited references is structured by separate discussions of compounds from different

• a special emphasis on mechanistic surprises. Keywords: biosynthesis; enzyme mechanisms; isotopes; labeling experiments; natural products; Introduction This year may be seen as the 80th anniversary of using isotopes in biosynthetical and biochemical research. Since the first experiments performed

• by Schoenheimer and Rittenberg in 1935 using deuterated fatty acids and sterols to follow their fate in a living organism [1], a lot of new synthetic and analytical methods for the detection of isotopes have been developed that today allow for nearly unlimited applications in biosynthesis research

Biocatalysis for the application of CO₂ as a chemical feedstock

• Apostolos Alissandratos and
• Christopher J. Easton

Beilstein J. Org. Chem. 2015, 11, 2370–2387, doi:10.3762/bjoc.11.259

• (RuBisCO). The glycerate 2 is subsequently phosphorylated with ATP for the production of 1,3-bisphosphoglycerate (3), which is in turn reduced with NADPH to 3-phosphoglyceraldehyde (4). For every six equivalents of the aldehyde 4, one is diverted to carbohydrate biosynthesis, while the other five are used

Total synthesis of panicein A₂

• Lili Yeung,
• Lisa I. Pilkington,
• Melissa M. Cadelis,
• Brent R. Copp and
• David Barker

Beilstein J. Org. Chem. 2015, 11, 1991–1996, doi:10.3762/bjoc.11.215

• isolated from Reniera fulva and R. mucosa [2][3]. It has been postulated that the biosynthesis of paniceins centres around the cyclisation of a farnesyl precursor 6 [4] to an abscisane derivative 7 followed by a 1,2-methyl migration and subsequent oxidation to give panicein A (1) [1][3]. Subsequent