Synthesis of legonmycins A and B, C(7a)-hydroxylated bacterial pyrrolizidines

• Wilfred J. M. Lewis,
• David M. Shaw and
• Jeremy Robertson

Beilstein J. Org. Chem. 2021, 17, 334–342, doi:10.3762/bjoc.17.31

• papers addressed their biosynthesis. Thus, the investigation of the metabolites of Streptomyces sp. MA37 (from a soil sample obtained in Legon, Ghana) revealed the production of legonmycins A (3) and B (4) (Figure 2) and found that just four genes (lgnA–D) were necessary for their biosynthesis [22

• . These species include both Gram-positive and Gram-negative bacteria, indicating that pyrrolizidines are potential secondary metabolites of a variety of bacterial genera. The most recent addition to the bacterial pyrrolizidine literature also concerns their biosynthesis and addresses the origin of the

• . The clazamycins, and selected bacterial pyrrolizidines of the vinylogous urea type. For consistency, the standard numbering convention used for the plant pyrrolizidines, as depicted for the clazamycins, is used throughout. Key species in the biosynthesis of legonmycins A (3) and B (4), and the

¹⁹F NMR as a tool in chemical biology

• Diana Gimenez,
• Aoife Phelan,
• Cormac D. Murphy and
• Steven L. Cobb

Beilstein J. Org. Chem. 2021, 17, 293–318, doi:10.3762/bjoc.17.28

• biosynthesis and biodegradation of fluorinated organic compounds is also described. Keywords: biotransformation; chemical biology; fluorine; 19F NMR; probes; protein structure; Introduction Although fluorine is abundant in the environment, it is not a nutrient nor is it a feature of biochemistry for most

• biosynthesis through hBBOX-catalysed GBBNF hydroxylation, both in vitro and in cell lysates [43]. Moreover, by using a competitive substrate for the enzyme, inhibition experiments could be directly employed to determine the IC50 values in the basis of fluoride release, and the extent of GBBNF turnover

• , but only one could be detected (SF5-catechol) despite the 19F NMR analysis showing the presence of multiple fluorometabolites. Detection and biosynthesis of natural organofluorine compounds As naturally-occurring organofluorine compounds are so rare, it is possible to easily detect them in a crude

Progress in the total synthesis of inthomycins

• Bidyut Kumar Senapati

Beilstein J. Org. Chem. 2021, 17, 58–82, doi:10.3762/bjoc.17.7

• biosynthesis [1][4], in vitro antimicrobial activity [4][5], and anticancer activity against human prostate cancer cell lines [6][7]. A recent study suggested that the close analogue (+)-11 of inthomycin C was found to exhibit proteasome inhibition activity [8]. The skeletal structures of inthomycins A–C (1–3

Secondary metabolites of Bacillus subtilis impact the assembly of soil-derived semisynthetic bacterial communities

• Heiko T. Kiesewalter,
• Carlos N. Lozano-Andrade,
• Mikael L. Strube and
• Ákos T. Kovács

Beilstein J. Org. Chem. 2020, 16, 2983–2998, doi:10.3762/bjoc.16.248

• ). For the biosynthesis of B. subtilis NRPs, the phosphopantetheinyl transferase Sfp is needed since it has been shown to activate the peptidyl carrier protein domains, converting it from the inactive apo-form to the active holo-form [37]. B. subtilis has four sfp-dependent SMs, of which three are

On the mass spectrometric fragmentations of the bacterial sesterterpenes sestermobaraenes A–C

• Anwei Hou and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2020, 16, 2807–2819, doi:10.3762/bjoc.16.231

• rearrangement to a2•+ and a hydride shift to b2•+ (Scheme 3A). This hydride migration is in reverse order compared to a similar step along the cationic cyclisation cascade during the biosynthesis of 2 (Scheme S1 in Supporting Information File 1). The subsequent inductive ring opening to c2•+ and α-cleavage of

• sesterterpenes have a common intrinsic reactivity that is in the first instance reflected by their joint biosynthesis, but also by their similar behaviour in the comparably high-energy chemistry of mass spectrometric fragmentation reactions. Further support for the similar reactivity of the investigated

• compounds during biosynthesis and mass spectrometric fragmentations is given by the notable observation of hydride shifts that occur in both of these processes. However, the three compounds show also some differences in their mass spectrometric fragmentation, e.g., for compound 2 a strong fragment ion is

3-Acetoxy-fatty acid isoprenyl esters from androconia of the ithomiine butterfly Ithomia salapia

• Florian Mann,
• Daiane Szczerbowski,
• Lisa de Silva,
• Melanie McClure,
• Marianne Elias and
• Stefan Schulz

Beilstein J. Org. Chem. 2020, 16, 2776–2787, doi:10.3762/bjoc.16.228

• , acylated isoprenyl esters of fatty acids, is described, representing a combination of fatty acid and terpene biosynthesis. We also reveal small but reproducible differences between the two subspecies that could potentially be involved in species recognition and reproductive isolation. Results Extracts from

• formed from hedycaryol (7) during GC/MS analysis by a Cope-rearrangement [20][21], indicating that 7 might be originally present in the hairpencils. That said, we cannot disprove that this rearrangement could also occur in the androconia. Hedycaryol is an early product of sesquiterpene biosynthesis

• originate from the terpene building block 3-methyl-3-butenyl (isoprenyl) pyrophosphate. Because isoprenyl pyrophosphate is partly converted to 3-methyl-2-butenyl (prenyl) pyrophosphate during terpene biosynthesis, the presence of prenyl esters could not be excluded. Nevertheless, the two ester types can be

A consensus-based and readable extension of Linear Code for Reaction Rules (LiCoRR)

• Benjamin P. Kellman,
• Yujie Zhang,
• Emma Logomasini,
• Eric Meinhardt,
• Karla P. Godinez-Macias,
• Austin W. T. Chiang,
• James T. Sorrentino,
• Chenguang Liang,
• Bokan Bao,
• Yusen Zhou,
• Sachiko Akase,
• Isami Sogabe,
• Thukaa Kouka,
• Elizabeth A. Winzeler,
• Iain B. H. Wilson,
• Matthew P. Campbell,
• Sriram Neelamegham,
• Frederick J. Krambeck,
• Kiyoko F. Aoki-Kinoshita and
• Nathan E. Lewis

Beilstein J. Org. Chem. 2020, 16, 2645–2662, doi:10.3762/bjoc.16.215

• . Krambeck Kiyoko F. Aoki-Kinoshita Nathan E. Lewis See end of main text. 10.3762/bjoc.16.215 Abstract Systems glycobiology aims to provide models and analysis tools that account for the biosynthesis, regulation, and interactions with glycoconjugates. To facilitate these methods, there is a need for a

• , cytoplasm (bacteria and archaea), or lysosome (degradation, Man-6-P dephosphorylation and lysosomal glycoprotein biosynthesis [33][34] or paucimannose recycling [35]), are important constraints on glycosylation [36], therefore, the addition of this information to the Linear Code reaction rules provides

• earliest Krambeck et al. adaptation. Some symbols are only seen in the Krambeck et al. adaptation. Besides the “ # ” as the number symbol, Krambeck et al. also uses “Gnbis” to refer to the specific structure of bisecting GN, which is “Ma3(GNb4)(...Ma6)Mb4.” Several reaction rules for N-glycan biosynthesis

Leveraging glycomics data in glycoprotein 3D structure validation with Privateer

• Haroldas Bagdonas,
• Daniel Ungar and
• Jon Agirre

Beilstein J. Org. Chem. 2020, 16, 2523–2533, doi:10.3762/bjoc.16.204

• the lack of carbohydrate-specific modelling tools have often been named as the principal causes for these issues [18]. Heterogeneity of glycoproteins Unlike protein synthesis, which is encoded in the genome and follows a clear template, glycan biosynthesis is not template-directed. A single

• glycoprotein will exist in multiple possibilities of products that can emerge from the glycan biosynthesis pathways, and these are known as glycoforms [22]. More specifically, the variation can appear in terms of which potential glycosylation sites are occupied at any time – macroheterogeneity – or variations

• in the compositions of the glycans added to specific glycosylation sites – microheterogeneity. This variation in the microheterogeneous composition patterns arises due to the competition of glycan-processing enzymes in biosynthesis pathways [23]. Implications for the structure determination of

How and why plants and human N-glycans are different: Insight from molecular dynamics into the “glycoblocks” architecture of complex carbohydrates

• Carl A. Fogarty,
• Aoife M. Harbison,
• Amy R. Dugdale and
• Elisa Fadda

Beilstein J. Org. Chem. 2020, 16, 2046–2056, doi:10.3762/bjoc.16.171

• important implications in terms of the N-glycans’ biosynthesis and biodegradation [29]. As an additional interesting point, we found that the folding of the (1-6) arm over the chitobiose region is completely independent of core α(1-6) fucosylation [24], with the result that core-fucosylated and non-core

The biomimetic synthesis of balsaminone A and ellagic acid via oxidative dimerization

• Sharna-kay Daley and
• Nadale Downer-Riley

Beilstein J. Org. Chem. 2020, 16, 2026–2031, doi:10.3762/bjoc.16.169

• ) [17] and violet-quinone (3) [18] (Figure 1). Similar to those natural products, the biomimetic synthesis of balsaminone A (4) and ellagic acid (5) can be attained using oxidative dimerization reactions, based on their proposed biosynthesis (Scheme 1 and Scheme 2) [19][20]. These pathways, which start

• represent the most efficient routes to these bioactive natural products to date. Selected natural products synthesized via oxidative dimerization. Proposed biosynthesis of balsaminone A (4) [19]. Proposed biosynthesis of ellagic acid (5) [20]. Previous syntheses of balsaminone A (4) [22] and ellagic acid (5

Synthesis of monophosphorylated lipid A precursors using 2-naphthylmethyl ether as a protecting group

• Jundi Xue,
• Ziyi Han,
• Gen Li,
• Khalisha A. Emmanuel,
• Cynthia L. McManus,
• Qiang Sui,
• Dongmian Ge,
• Qi Gao and
• Li Cai

Beilstein J. Org. Chem. 2020, 16, 1955–1962, doi:10.3762/bjoc.16.162

• ][8][9]. Various lipid A derivatives have since been synthesized to dissociate endotoxic effects from beneficial immunomodulatory activities. Lipid X, 2-N;3-O-di[(R)-3-hydroxytetradecanoyl]-ᴅ-glucosamine-1-phosphate, is the naturally occurring early monosaccharide precursor of lipid A biosynthesis

Synthesis, docking study and biological evaluation of ᴅ-fructofuranosyl and ᴅ-tagatofuranosyl sulfones as potential inhibitors of the mycobacterial galactan synthesis targeting the galactofuranosyltransferase GlfT2

• Marek Baráth,
• Jana Jakubčinová,
• Zuzana Konyariková,
• Stanislav Kozmon,
• Katarína Mikušová and
• Maroš Bella

Beilstein J. Org. Chem. 2020, 16, 1853–1862, doi:10.3762/bjoc.16.152

• substrate of mycobacterial galactofuranosyltransferase GlfT2 in the transition state, we evaluated these compounds by computational methods, as well as in an enzyme assay for the possible inhibition of the mycobacterial galactan biosynthesis. Our data show that despite favorable docking scores to the active

• site of GlfT2, none of these compounds serve as efficient inhibitors of the enzymes involved in the mycobacterial galactan biosynthesis. Keywords: GlfT2; molecular modeling; mycobacterium tuberculosis; synthesis; transition state inhibitors; Introduction Tuberculosis (TB) is one of the most prevalent

• targets for new antitubercular drug developments [6]. Mycobacterial galactan is synthesized by two bifunctional galactofuranosyltransferases, GlfT1 and GlfT2 (Supporting Information File 1, Figure S1). The former one initiates the galactan biosynthesis by addition of the first two Galf residues to

Antibacterial scalarane from Doriprismatica stellata nudibranchs (Gastropoda, Nudibranchia), egg ribbons, and their dietary sponge Spongia cf. agaricina (Demospongiae, Dictyoceratida)

• Cora Hertzer,
• Stefan Kehraus,
• Nils Böhringer,
• Fontje Kaligis,
• Robert Bara,
• Dirk Erpenbeck,
• Gert Wörheide,
• Till F. Schäberle,
• Heike Wägele and
• Gabriele M. König

Beilstein J. Org. Chem. 2020, 16, 1596–1605, doi:10.3762/bjoc.16.132

• study. Sesterterpenes are a rare terpene class, accounting for less than 2% of all known terpenoids, with only a few reports on their biosynthesis [72][73][74][75][76]. However, their frequent occurrence in marine organisms is striking and sponges are considered as the prime source of these terpenoids

• tempting to argue that the sesterterpene biosynthesis could be performed or mediated by their microbial symbionts. This further indicates a close association, interconnectedness, and probable co-evolution between microorganisms, sponges and nudibranchs [9]. D. stellata was not only found to sequester and

Fabclavine diversity in Xenorhabdus bacteria

• Sebastian L. Wenski,
• Harun Cimen,
• Natalie Berghaus,
• Sebastian W. Fuchs,
• Selcuk Hazir and
• Helge B. Bode

Beilstein J. Org. Chem. 2020, 16, 956–965, doi:10.3762/bjoc.16.84

• ), and polyketide synthases (PKS). Selected Xenorhabdus and Photorhabdus mutant strains were generated applying a chemically inducible promoter in front of the suggested fabclavine (fcl) biosynthesis gene cluster (BGC), followed by the analysis of the occurring fabclavines. Subsequently, known and

• actinomycetes and myxobacteria, the genera Photorhabdus and Xenorhabdus are promising sources to discover new SMs since up to 6.5% of their overall genome sequence are associated with SM biosynthesis [5][6]. This includes antimicrobials like isopropylstilbene, xenocoumacins, amicoumacin, and several other SMs

• . budapestensis and X. szentirmaii, and a 50 kb biosynthesis gene cluster (BGC) was identified to be responsible for their formation (Figure 1) [20]. These compounds were of special interest because of their broad-spectrum bioactivity against Gram-positive and -negative bacteria, fungi, and protozoa [20][21

Understanding the role of active site residues in CotB2 catalysis using a cluster model

• Keren Raz,
• Ronja Driller,
• Thomas Brück,
• Bernhard Loll and
• Dan T. Major

Beilstein J. Org. Chem. 2020, 16, 50–59, doi:10.3762/bjoc.16.7

• , representing the first committed step in the biosynthesis of the next-generation anti-inflammatory drug cyclooctatin. The intracellular target of cyclooctatin is an as of yet uncharacterized lysophospholipase, which is involved in early steps of the inflammatory signaling cascade [38][39][40]. In the last

• rational biosynthesis of novel terpenes might be possible by careful design of CotB2 mutants. Future studies using multiscale techniques to model the enzyme reaction in a complete enzyme environment will allow careful evaluation of the usefulness of such active site theozyme models. Conclusion In this work

Synthesis of C-glycosyl phosphonate derivatives of 4-amino-4-deoxy-α-ʟ-arabinose

• Lukáš Kerner and
• Paul Kosma

Beilstein J. Org. Chem. 2020, 16, 9–14, doi:10.3762/bjoc.16.2

• the looming antibiotic crisis [5]. 4-Amino-4-deoxy-ʟ-arabinose units are activated as the phosphodiester-linked undecaprenyl derivative [6], which is then transferred by the action of several Ara4N transferases (ArnT, Figure 1) [7]. The synthesis of potential inhibitors of the biosynthesis of Ara4N

Chemical synthesis of tripeptide thioesters for the biotechnological incorporation into the myxobacterial secondary metabolite argyrin via mutasynthesis

• David C. B. Siebert,
• Roman Sommer,
• Domen Pogorevc,
• Michael Hoffmann,
• Silke C. Wenzel,
• Rolf Müller and
• Alexander Titz

Beilstein J. Org. Chem. 2019, 15, 2922–2929, doi:10.3762/bjoc.15.286

• approach where simpler and fully synthetic intermediates of the natural product’s biosynthesis can be biotechnologically incorporated. Here, we report the synthesis of a series of tripeptide thioesters as mutasynthons containing the native sequence with a dehydroalanine (Dha) Michael acceptor attached to a

• has been observed in many cases that exogenous substrates can be incorporated by bacteria into biosynthesis cascades of natural products. The use of substrates which lead to nonnatural derivatives of the natural product coined the field of mutasynthesis, e.g., siderophore analogue biosynthesis by P

• synthetase (NRPS), mutasynthons often carry thioesters to mimic the natural phosphopantetheinyl conjugate [20]. For the argyrins, the Müller group identified the corresponding biosynthetic gene cluster from Cystobacter sp. SBCb004 [21], studied the biosynthesis (Figure 2) and established a heterologous

Bacterial terpene biosynthesis: challenges and opportunities for pathway engineering

• Eric J. N. Helfrich,
• Geng-Min Lin,
• Christopher A. Voigt and
• Jon Clardy

Beilstein J. Org. Chem. 2019, 15, 2889–2906, doi:10.3762/bjoc.15.283

• functional promiscuity of terpene biosynthetic pathways renders terpene biosynthesis susceptible to rational pathway engineering using the latest developments in the field of synthetic biology. These engineered pathways will not only facilitate the rational creation of both known and novel terpenoids, their

• development will deepen our understanding of a significant branch of biosynthesis. The biosynthetic insights gained will likely empower a greater degree of engineering proficiency for non-natural terpene biosynthetic pathways and pave the way towards the biotechnological production of high value terpenoids

• . Keywords: bacterial sesquiterpenes and diterpenes; cytochrome P450; pathway engineering; synthetic biology; terpene biosynthesis; terpene cyclase; Introduction Evolutionary diversification of terpene biosynthetic pathways has resulted in the largest and most structurally diverse class of specialized

Emission and biosynthesis of volatile terpenoids from the plasmodial slime mold Physarum polycephalum

• Xinlu Chen,
• Tobias G. Köllner,
• Wangdan Xiong,
• Guo Wei and
• Feng Chen

Beilstein J. Org. Chem. 2019, 15, 2872–2880, doi:10.3762/bjoc.15.281

• the monoterpene linalool. There were no qualitative differences in terpenoid composition at two stages of young plasmodia. To understand terpene biosynthesis, we analyzed the transcriptome and genome sequences of P. polycephalum and identified four TPS genes designated PpolyTPS1–PpolyTPS4. They share

• communication [1][2]. Rapid progress has been made in our understanding of the VOC world of microbes, especially bacteria [3][4] and fungi [5][6]. Not only the chemical diversity of microbial VOCs is continuingly to be discovered, our understanding of their biosynthesis is also growing rapidly [7][8]. Among the

• extraction temperatures. In our study, we aimed I) to determine whether P. polycephalum releases volatile terpenoids under normal growing conditions and II) to identify and characterize the genes for terpene biosynthesis in P. polycephalum. Our results will enable us to compare terpene chemistry and their

Nanangenines: drimane sesquiterpenoids as the dominant metabolite cohort of a novel Australian fungus, Aspergillus nanangensis

• Heather J. Lacey,
• Cameron L. M. Gilchrist,
• Andrew Crombie,
• John A. Kalaitzis,
• Daniel Vuong,
• Peter J. Rutledge,
• Peter Turner,
• John I. Pitt,
• Ernest Lacey,
• Yit-Heng Chooi and
• Andrew M. Piggott

Beilstein J. Org. Chem. 2019, 15, 2631–2643, doi:10.3762/bjoc.15.256

• : Aspergillus; biosynthesis; drimane; secondary metabolites; sesquiterpenoid; terpenes; Introduction The fungal genus Aspergillus is well recognised as a source of structurally diverse terpenoids comprising monoterpenoids [1], sesquiterpenoids [2][3][4][5], diterpenoids [6], sesterterpenoids [7][8][9

• three human cell lines. None of the compounds tested showed any activity up to 100 μg mL−1 against the Gram-negative bacterium Escherichia coli (ATCC 25922), the fungus Candida albicans (ATCC 10231) or the plant Eragrostis tef (teff). Proposed biosynthesis and gene cluster The biosynthesis of drimane

• [30]. Therefore, the drimane synthase is likely to be different from the commonly observed sesquiterpene synthase, which belongs to the class I terpene synthases. Recently, the drimane synthase AstC involved in biosynthesis of the astellolides was identified and shown to be a novel member of the

Current understanding and biotechnological application of the bacterial diterpene synthase CotB2

• Ronja Driller,
• Daniel Garbe,
• Norbert Mehlmer,
• Monika Fuchs,
• Keren Raz,
• Dan Thomas Major,
• Thomas Brück and
• Bernhard Loll

Beilstein J. Org. Chem. 2019, 15, 2355–2368, doi:10.3762/bjoc.15.228

• , Technical University of Munich (TUM), Lichtenbergstr. 4, 85748 Garching, Germany Department of Chemistry, Bar-Ilan University, Ramat-Gan 52900, Israel 10.3762/bjoc.15.228 Abstract CotB2 catalyzes the first committed step in cyclooctatin biosynthesis of the soil bacterium Streptomyces melanosporofaciens. To

• will focus particularly on bacterial diterpene synthases, in context with other sesqui- and ditperpene synthases of bacterial, fungal and plant origin. The initial step in diterpene biosynthesis (Figure 1) is the incremental condensation of dimethylallyl diphosphate (1) and isopentylen diphosphate (2

• , fungicidal and tumorstatic effects [32]. A key player in the biosynthesis of cyclooctatin 5 is the bacterial diterpene synthase CotB2. Different research teams have investigated CotB2 by means of biochemical [30][31][38], biophysical [33][34][35], structural biology [36][37][38][39] and computational

Isolation and biosynthesis of an unsaturated fatty acid with unusual methylation pattern from a coral-associated bacterium Microbulbifer sp.

• Amit Raj Sharma,
• Enjuro Harunari,
• Tao Zhou,
• Agus Trianto and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2019, 15, 2327–2332, doi:10.3762/bjoc.15.225

• . Compound 1 showed weak growth inhibition against Saccharomyces cerevisiae. Keywords: biosynthesis; fatty acid; marine bacteria; methylation; Microbulbifer; Introduction Marine microbial symbionts are currently recognized as a reservoir of new bioactive compounds [1]. The most well-studied host animal is

• the sponge from which a vast array of natural products has been isolated and symbiotic bacteria are suggested to be responsible for the biosynthesis of such natural products [2]. Although it is well established that corals are associated with diverse microbes, coral-associated bacteria and their

• only single example of C-methylation with SAM at a carbon derived from the carbonyl carbon of acetate (C1; Figure 3D) is reported for sphingolipid biosynthesis in the yeast, Pichia pastoris [16]. SAM-dependent C-methylation takes place at the alkenyl carbon C9 of glucosylceramide, yielding a cationic

Functionalization of 4-bromobenzo[c][2,7]naphthyridine via regioselective direct ring metalation. A novel approach to analogues of pyridoacridine alkaloids

• Benedikt C. Melzer,
• Alois Plodek and
• Franz Bracher

Beilstein J. Org. Chem. 2019, 15, 2304–2310, doi:10.3762/bjoc.15.222

• pyridoacridine alkaloids to be found in diverse marine sources (tunicates, sponges). Their chemistry, pharmacology and biosynthesis have been the subject of a couple of review articles [1][2][3][4]. Another source of polycyclic aromatic alkaloids are tropical plants, e.g., the Annonaceae family [5]. A very

Isolation of fungi using the diffusion chamber device FIND technology

• Benjamin Libor,
• Henrik Harms,
• Stefan Kehraus,
• Ekaterina Egereva,
• Max Crüsemann and
• Gabriele M. König

Beilstein J. Org. Chem. 2019, 15, 2191–2203, doi:10.3762/bjoc.15.216

• adaption of the respective strains to marine conditions (see Supporting Information File 1, Tables S1 and S2 for full experimental data). With the FIND technology we managed to isolate rare fungi. To evaluate the potential for the biosynthesis of bioactive secondary metabolites we performed screenings on

Harnessing enzyme plasticity for the synthesis of oxygenated sesquiterpenoids

• Melodi Demiray,
• David J. Miller and
• Rudolf K. Allemann

Beilstein J. Org. Chem. 2019, 15, 2184–2190, doi:10.3762/bjoc.15.215

• engineering; terpenes; Introduction Amorphadiene synthase (ADS) from Artemisia annua is a key enzyme involved in the biosynthesis of the antimalarial sesquiterpene drug artemisinin (1) [1][2][3][4]. ADS catalyses the Mg2+-dependent conversion of farnesyl diphosphate (FDP, 2) to amorpha-4,11-diene (3) with