Characterization of non-heme iron aliphatic halogenase WelO5* from Hapalosiphon welwitschii IC-52-3: Identification of a minimal protein sequence motif that confers enzymatic chlorination specificity in the biosynthesis of welwitindolelinones

• Qin Zhu and
• Xinyu Liu

Beilstein J. Org. Chem. 2017, 13, 1168–1173, doi:10.3762/bjoc.13.115

• welwitindolinone pathway in H. welwitschii IC-52-3 contains a unique protein coded by welU3 gene. We have recently characterized WelU3 protein by in vitro reconstitution and demonstrated it is a dedicated enzyme for the biosynthesis of 1 from 3-geranyl 3-(isocyanovinyl)indolenine [16], a common intermediate used

Glycoscience@Synchrotron: Synchrotron radiation applied to structural glycoscience

• Serge Pérez and
• Daniele de Sanctis

Beilstein J. Org. Chem. 2017, 13, 1145–1167, doi:10.3762/bjoc.13.114

• interacting proteins The carbohydrate-mediated recognition events that have a high biological relevance give a pivotal role to the study of protein–carbohydrate interactions. Those interactions drive several distinct biological events, going from the enzymes involved in the biosynthesis, to the hydrolysis and

• have been solved over the last 25 years, with a particular emphasis on the number of structures determined at high resolution. Glycosyl transferases: The biosynthesis of oligosaccharides is performed by a ubiquitous class of enzymes: the glycosyl transferases (GTs). The catalytic mechanism underlying

• the biosynthesis of glycosidic linkage requires the transfer of a sugar residue from a donor to an acceptor [35]. Acceptor substrates are carbohydrates, proteins, lipids, DNA, flavonol, antibiotics and steroids. In contrast, glycosyl donor substrates are mostly sugar nucleotides, such as UDP-GlcNAc

From chemical metabolism to life: the origin of the genetic coding process

• Antoine Danchin

Beilstein J. Org. Chem. 2017, 13, 1119–1135, doi:10.3762/bjoc.13.111

• convincing way [31]. Other coenzymes, possibly generated by such a swinging-arm thioester-dependent catalysis, may have been precursors of nucleotides, the essential building blocks of nucleic acids. As a matter of fact, extant biosynthesis of nucleotides (built on purine and pyrimidine carbon–nitrogen

• aromatic heterocycles) is based on the incorporation of amino acids in the core of nucleotide precursors. Pyrimidine nucleotide biosynthesis uses aspartate and combines together ubiquitous molecules, water, carbon dioxide, ammonium and phosphate (forming carbamoyl phosphate, also a precursor of arginine

• , an amino acid absent from the very first steps of prebiotic metabolism), while purine biosynthesis combines glycine and aspartate, together with phosphorylated derivatives of ribose. These pathways open up a major chemical challenge. Ribose is a very unstable metabolite. Any scenario that advances

Total syntheses of the archazolids: an emerging class of novel anticancer drugs

• Stephan Scheeff and
• Dirk Menche

Beilstein J. Org. Chem. 2017, 13, 1085–1098, doi:10.3762/bjoc.13.108

• of important cellular functions, including pH-control [17][18], membrane trafficking, protein degradation, release of neurotransmitters [18], urinary acidification [19], bone resorption [20], sperm maturation [21], cholesterol biosynthesis [22] and cytokine secretion [23]. In recent years, a key role

Opportunities and challenges for the sustainable production of structurally complex diterpenoids in recombinant microbial systems

• Katarina Kemper,
• Max Hirte,
• Markus Reinbold,
• Monika Fuchs and
• Thomas Brück

Beilstein J. Org. Chem. 2017, 13, 845–854, doi:10.3762/bjoc.13.85

• with recombinant terpene biosynthesis modules, they are very suitable hosts for heterologous production of high value terpenes. Yet, in contrast to the number of extracted and characterized terpenes, little is known about the specific biosynthetic enzymes that are involved especially in the formation

• terpene producing Escherichia coli, this review shall give an insight in recent progresses regarding manipulation of mostly diterpene synthases. Keywords: enzyme engineering; heterologous production in E. coli; metabolic pathway optimization; modular biosynthesis; plant diterpenes; Introduction

• plant diterpenes in well-established recombinant hosts, such as Escherichia coli [21][22][23]. Recent developments in this field will be reviewed in this work. Review Biosynthesis of diterpenes and transfer to heterologous production system Integration of biosynthetic gene clusters from plants into a

Lipids: fatty acids and derivatives, polyketides and isoprenoids

• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2017, 13, 793–794, doi:10.3762/bjoc.13.78

• African reed frog that are likely amphibian signaling compounds [1]. Sensu lato, and this is the definition relevant to this Thematic Series: lipids include all kinds of apolar (or less polar) primary and secondary metabolites, including molecules that are formed via fatty acid biosynthesis, the

• biosynthetically related polyketide pathways, and terpenoid biosynthesis. I hope that the present Thematic Series of the Beilstein Journal of Organic Chemistry on the interdisciplinary topic of “Lipids” will cover many topics of high interest to readers from chemistry, biochemistry, biophysics, medicine, pharmacy

N-Propargylamines: versatile building blocks in the construction of thiazole cores

• S. Arshadi,
• E. Vessally,
• L. Edjlali,
• R. Hosseinzadeh-Khanmiri and
• E. Ghorbani-Kalhor

Beilstein J. Org. Chem. 2017, 13, 625–638, doi:10.3762/bjoc.13.61

• prevent gout flare-ups [5][6][7]. Ritonavir (norvir), is an HIV protease inhibitor. It works by blocking the growth of HIV [8][9]. Tiazofurin is a C-nucleoside analogue with antineoplastic activity and acts by inhibition of the guanosine triphosphate (GTP) biosynthesis through a reduction of PI and PIP

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

• valine and its C-methylation with methionine and the polyol carbons are derived from a glycolysis intermediate, possibly hydroxymalonyl-ACP. Keywords: biosynthesis; butyrolactol; contiguous polyol; hydroxymalonyl-ACP; polyketide; Streptomyces; tert-butyl; Introduction Actinomycetes produce structurally

• ] (Figure 2). Although no experimental evidence is available, pivaloyl-CoA (2,2-dimethylpropanoyl-CoA) is supposed to be a starter for its biosynthesis [15]. Additionally, trimethylation of malonyl-CoA is proposed for the synthesis of the tert-butyl starter in the biosynthesis of apratoxin A [16]. Another

• alternative alignment of the methylene and the oxygenated carbons. Meanwhile, a 1,2-diol in polyketides is known to be formed by hydroxylation of methylene carbons as seen in the biosynthesis of erythromycin or amphotericin B [17][18]. The contiguously hydroxylated carbon chain of 1 is quite unusual as a

Solid-phase enrichment and analysis of electrophilic natural products

• Frank Wesche,
• Yue He and
• Helge B. Bode

Beilstein J. Org. Chem. 2017, 13, 405–409, doi:10.3762/bjoc.13.43

• producing microbes. Much more compounds have been identified than originally thought, but often these are produced only at a very low level. This is also reflected by the genome sequences of bacteria and fungi that often encode numerous biosynthesis gene clusters (BGC) with most of the corresponding natural

• ), Scheme 1) is such a resin able to react with a broad range of azides [15]. Thus, the metabolic fate of azide-containing biosynthesis intermediates or building blocks can be studied and natural products containing these azides can be identified. Herein we describe the application of the CARR enrichment

• media mimicking the insect hemolymph [18][19][20]. Clearly the biosynthesis of this compound is strictly regulated and moreover it is a highly labile compound that is probably rapidly degraded [21]. Only a very weak signal of m/z 271.1 [M + H]+ could be detected at 8.5 min, which can be associated with

Polyketide stereocontrol: a study in chemical biology

• Kira J. Weissman

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

• biosynthesis of reduced polyketides in bacteria by modular polyketide synthases (PKSs) proceeds with exquisite stereocontrol. As the stereochemistry is intimately linked to the strong bioactivity of these molecules, the origins of stereochemical control are of significant interest in attempts to create

• functionality in a defined way in three dimensions, allowing them to bind their biological targets with useful affinity (10−7 to 10−9 M [4]). Erythromycin A (1, Figure 1) is the prototypical polyketide, as its biosynthesis has been studied most heavily to date. The structure incorporates 10 stereocenters, and

• structures by synthetic biology [6]. The aim of this review is to trace how our understanding of these feature of the biosynthesis has developed, and more specifically, the critical role that an array of chemical biology approaches [7] has played in furnishing the underlying data. These include, but are not

Posttranslational isoprenylation of tryptophan in bacteria

• Masahiro Okada,
• Tomotoshi Sugita and
• Ikuro Abe

Beilstein J. Org. Chem. 2017, 13, 338–346, doi:10.3762/bjoc.13.37

• " refers to an appropriate amino acid, depending on the types of modifying enzymes (Figure 1C) [4][5][6][7]. Therefore, in the process of isoprenylated peptide and protein biosynthesis, the cysteine residue of the CaaX motif is isoprenylated by isoprenyltransferase, and then the last three amino acids are

• . natto is obviously distinct from the other laboratory strains with respect to the biofilm formation. The biofilm mainly consists of the highly sticky poly-γ-glutamic acid (γ-PGA) polymer (Figure 2B), and the ComXnatto pheromone activates γ-PGA biosynthesis in B. subtilis subsp. natto at nanomolar levels

• with other biosynthetic studies on prenylated cyanobactins, KgpF functions at the end of the biosynthesis, and recognizes two tryptophan residues in the precursor cyclic peptide to form kawaguchipeptin A. In contrast to typical post-translational modifications, a specific amino acid motif adjacent to

Versatile synthesis of the signaling peptide glorin

• Robert Barnett,
• Daniel Raszkowski,
• Thomas Winckler and
• Pierre Stallforth

Beilstein J. Org. Chem. 2017, 13, 247–250, doi:10.3762/bjoc.13.27

• is known about glorin’s biosynthesis, signaling pathways, or degradation. To facilitate further studies, our chemical route allows for a facile synthesis of glorin derivatives and glorin-based chemical probes. Here, we report the synthesis of glorin (1), as well as the novel synthetic analog

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

• great importance in understanding the biosynthesis of these important antibiotics. Here, we report the cyclisation activity and crystal structure of StaF, the D-O-E ring forming Oxy enzyme from A47934 biosynthesis. Our results show that the specificity of StaF is reduced when compared to Oxy enzymes

• 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

• confirmed that the cytochrome P450s, known as the Oxy enzymes, are each responsible for the installation of a single ring in the GPA aglycones and that there is a conserved order of activity in both type-I and type-IV GPAs. In type-I GPA biosynthesis OxyB acts first to install the C-O-D ring (between

Chemical probes for competitive profiling of the quorum sensing signal synthase PqsD of Pseudomonas aeruginosa

• Michaela Prothiwa,
• Dávid Szamosvári,
• Sandra Glasmacher and
• Thomas Böttcher

Beilstein J. Org. Chem. 2016, 12, 2784–2792, doi:10.3762/bjoc.12.277

• coordinate the production of its broad spectrum of virulence factors to facilitate colonization and infection of its host. Hereby, the enzyme PqsD is a virulence related quorum sensing signal synthase that catalyzes the central step in the biosynthesis of the Pseudomonas quinolone signals HHQ and PQS. We

• roles of the different AQs are still not completely understood [6][8]. Besides HHQ and PQS, in total more than 50 structurally related AQs have been detected in P. aeruginosa [9]. Key to this large diversity of natural AQs are their common biosynthesis steps by enzymes encoded in the pqsABCDE operon [10

• ]. The biosynthesis of AQs has been matter of a long-standing debate that could only recently be resolved. Although HHQ could be produced in vitro by a PqsD catalyzed “head-to-head” decarboxylative Claisen condensation of activated anthranilic acid with β-keto fatty acid derivatives [10][11], isotope

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

• Herpetosiphon aurantiacus. It is composed of three unusual building blocks, including the non-proteinogenic amino acid 3-chloro-L-tyrosine, the α-hydroxy acid L-isoleucic acid, and a methylmalonyl-CoA-derived ethane unit. A candidate genetic locus for auriculamide biosynthesis was identified and encodes four

• acid by the enzyme supports the hypothesis that it participates in the biosynthesis of auriculamide. An artificially truncated version of AulA that lacks the first adenylation domain activated this substrate like the full-length enzyme which shows that the first adenylation domain is dispensable

• enzymatic activity, molecules with methylene α-carbons led to low turnover. Such enzymatic plasticity is an important attribute to help in the perpetual search for novel molecules and to access a greater structural diversity by mutasynthesis. Keywords: adenylation; auriculamide; biosynthesis; Herpetosiphon

Identification, synthesis and mass spectrometry of a macrolide from the African reed frog Hyperolius cinnamomeoventris

• Markus Menke,
• Pardha Saradhi Peram,
• Iris Starnberger,
• Walter Hödl,
• Gregory F.M. Jongsma,
• David C. Blackburn,
• Mark-Oliver Rödel,
• Miguel Vences and
• Stefan Schulz

Beilstein J. Org. Chem. 2016, 12, 2731–2738, doi:10.3762/bjoc.12.269

• ; pheromones; Introduction The lactone motif is found in many compounds that are used in chemical communication. Among them, macrocyclic lactones are an important class because of their biosynthetic availability and their inherent compound properties. During the biosynthesis of macrocyclic lactones, a fatty

Biomimetic synthesis and HPLC–ECD analysis of the isomers of dracocephins A and B

• Viktor Ilkei,
• András Spaits,
• Anita Prechl,
• Áron Szigetvári,
• Zoltán Béni,
• Miklós Dékány,
• Csaba Szántay Jr,
• Judit Müller,
• Árpád Könczöl,
• Ádám Szappanos,
• Attila Mándi,
• Sándor Antus,
• Ana Martins,
• Attila Hunyadi,
• György Tibor Balogh,
• György Kalaus (†),
• Hedvig Bölcskei,
• László Hazai and
• Tibor Kurtán

Beilstein J. Org. Chem. 2016, 12, 2523–2534, doi:10.3762/bjoc.12.247

• racemates (2a, 2c/2b, 2d; 3a, 3c/3b, 3d) by HPLC–ECD analysis (Figure 1). The planar structure and absolute configuration of the first-eluted stereoisomer of dracocephins A (±)-2a–d was determined by single-crystal X-ray diffraction analysis as (2R,5”S)-2a [2]. The biosynthesis of these flavonoid

Enduracididine, a rare amino acid component of peptide antibiotics: Natural products and synthesis

• Darcy J. Atkinson,
• Briar J. Naysmith,
• Daniel P. Furkert and
• Margaret A. Brimble

Beilstein J. Org. Chem. 2016, 12, 2325–2342, doi:10.3762/bjoc.12.226

• promising antibiotic activity. This review highlights the presence of enduracididine in natural products, its biosynthesis together with a review of analogues of enduracididine. Reported synthetic approaches to the cyclic guanidine structure of enduracididine are discussed, illustrating the challenges

• which involves binding to Lipid II, inhibiting one of the membrane-associated steps of peptidoglycan biosynthesis [43][44]. Analogues of teixobactin (17) have undergone biological testing and results show that the L-allo-enduracididine (3, blue, Figure 7) residue is important for potent antibacterial

• activity [45]. An approximately 10-fold reduction in activity was observed when the enduracididine residue is substituted for L-arginine [46] and almost complete loss of activity was observed when three of the four D-amino acids of this analogue are substituted for their L-counterparts [47]. Biosynthesis

A detailed view on 1,8-cineol biosynthesis by Streptomyces clavuligerus

• Jan Rinkel,
• Patrick Rabe,
• Laura zur Horst and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2016, 12, 2317–2324, doi:10.3762/bjoc.12.225

• in both cases a syn addition, as could be shown by incubation of (2-13C)geranyl diphosphate in deuterium oxide. Keywords: biosynthesis; enzyme mechanisms; isotopic labelling; stereochemistry; terpenes; Introduction Among all classes of natural products the climax of structural diversity and

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