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

• been reviewed elsewhere [3][10][11][12][13][14][15][16][17]. The first crystal structure of a monoterpene cyclase [18] was reported in 2002. Subsequently, the first crystal structures of a sesquiterpene [19][20] and a triterpene [21] cyclase were published in 1997. Less than a decade ago, the first

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

• major product, while few of them are known to produce multiple products [1][50][76][114][115][116][117]. Among them, 10-epi-cubebol synthase from Sorangium cellulosum Soce56 is the most prolific bacterial TC known. It produces at least 25 different sesquiterpene skeletons in addition to 10-epi-cubebol

• -isozizaene (33) synthase mutants that produce different sesquiterpene skeletons. Substrate promiscuity and engineering of CYPs. a) Selected examples from using a CYP library to oxidize various monoterpenes. b) Rational engineering of P450BM3 for epoxidation of amorphadiene (21). F87A/A328L and R47L/Y51F

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

• 28–73% of sequence identities. Full-length cDNAs for the four TPS genes were cloned and expressed in Escherichia coli to produce recombinant proteins, which were tested for sesquiterpene synthase and monoterpene synthase activities. While neither PpolyTPS2 nor PpolyTPS3 was active, PpolyTPS1 and

• ]. The number of TPS genes ranges from 1 to 21 in these species. Some of the TPS genes among these species have conserved catalytic functions. For example, TPSs of one orthologous group that include DdTPS6, DpTPS1, AsTPS1, DiTPS1, DfTPS1, and PpTPS18 all catalyze the formation of the sesquiterpene

•  1B). The two unidentified are putative sesquiterpenoids. Compound 3 is a putative hydrocarbon sesquiterpene with a molecular mass of 204 (Figure 1C). In contrast, compound 4 has a molecular formula of C15H22O and a molecular mass of 218 (Figure 1C). It was predicated to be a sesquiterpene aldehyde

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

• [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

Synthetic terpenoids in the world of fragrances: Iso E Super^® is the showcase

• Alexey Stepanyuk and
• Andreas Kirschning

Beilstein J. Org. Chem. 2019, 15, 2590–2602, doi:10.3762/bjoc.15.252

• ) and from fennel oil in fenchone (18). Farnesol (23) is present in many essential oils such as citronella, neroli, cyclamen and lemon grass. Nerolidol (24) is present in neroli, ginger, jasmine, lavender, tea tree and other essential oils. Finally, vetiver oil contains the sesquiterpene khusimol (25

• process is commonly associated with oxidation reactions, while the latter process is often based on the action of lipases. Very recently, a new concept was disclosed that probed sesquiterpene cyclases to accept unnatural farnesyl pyrophosphates and generate unnatural cyclisation products with unusual

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

• synthase [47] and the sesquiterpene trichodiene synthase [48], but is in contrast to the parallel dimer as described for farnesyl diphosphate synthase [49]. Structurally, CotB2 is most closely related to the fungal monoterpene synthase aristolochene (PDB-ID 2OA6; [50]), and epi-isozizaene synthase (PDB-ID

• sesquiterpene synthase pentalenene synthase leads to a product mixture [64], whereas mutation of W273 in the plant-derived epi-aristolochene synthase resulted in total loss of enzymatic function [65]. Consequently, the aromatic character of the side chain in the WXXXXXRY motif is important for the propagation

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

• 58.6) and C-8 (δC 38.2) confirmed the presence of a verbenone moiety and connected the methylpentenoic acid moiety to the quaternary carbon C-7, completing the planar structure of 1. Compound 1 is thus a bergamotene type sesquiterpene, containing a bicyclo[3.1.1] ring system as well as a 2-methylpent-2

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

• synthesised in amorphadiene synthase-catalysed reactions from 8- and 12-methoxyfarnesyl diphosphates due to the highly plastic yet tightly controlled carbocationic chemistry of this sesquiterpene cyclase. Keywords: artemisinin; amorphadiene synthase; oxygenated terpenoids; sesquiterpenoids; substrate

• 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

• closure to form the bisabolyl cation (6). A [1,3]-hydride shift to form carbocation 7 and 1,10-ring closure yield the amorphyl cation (8). Finally, deprotonation generates amorpha-4,11-diene (3) [8][9]. Several sesquiterpene synthases including ADS accept FDP analogues containing a variety of heteroatoms

Genome mining in Trichoderma viride J1-030: discovery and identification of novel sesquiterpene synthase and its products

• Xiang Sun,
• You-Sheng Cai,
• Yujie Yuan,
• Guangkai Bian,
• Ziling Ye,
• Zixin Deng and
• Tiangang Liu

Beilstein J. Org. Chem. 2019, 15, 2052–2058, doi:10.3762/bjoc.15.202

• Xiang Sun You-Sheng Cai Yujie Yuan Guangkai Bian Ziling Ye Zixin Deng Tiangang Liu Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education and School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, P. R. China 10.3762/bjoc.15.202 Abstract Sesquiterpene

• synthases in Trichoderma viride have been seldom studied, despite the efficiency of filamentous fungi for terpenoid production. Using the farnesyl diphosphate-overexpressing Saccharomyces cerevisiae platform to produce diverse terpenoids, we herein identified an unknown sesquiterpene synthase from T. viride

• by genome mining and determined the structure of its corresponding products. One new 5/6 bicyclic sesquiterpene and its esterified derivative were characterised by GC–MS and 1D and 2D NMR spectroscopy. To the best of our knowledge, this is the first well-identified sesquiterpene synthase from T

Bipolenins K–N: New sesquiterpenoids from the fungal plant pathogen Bipolaris sorokiniana

• Chin-Soon Phan,
• Hang Li,
• Simon Kessler,
• Peter S. Solomon,
• Andrew M. Piggott and
• Yit-Heng Chooi

Beilstein J. Org. Chem. 2019, 15, 2020–2028, doi:10.3762/bjoc.15.198

• array of secondary metabolites, including sesquiterpenes [1][2][3][4][5][6][7], sesquiterpene-xanthones [8], diterpenes [9], sesterterpenes [10], cochlioquinones and peptides [11]. Moreover, several of these secondary metabolites are known to play important roles in mediating the virulence of these

• backbone of 1–11 remains unknown. Given that the genome of B. sorokiniana BRIP10943 has been sequenced [14], we surveyed the genome for potential terpene synthases that may be responsible for the biosynthesis of these compounds. Four putative sesquiterpene synthases were found, corresponding to the genes

• COCSADRAFT_31812, COCSADRAFT_346586, COCSADRAFT_83129 and COCSADRAFT_26102 annotated in the published genome B. sorokiniana ND90Pr in GenBank. However, it is difficult to determine which sesquiterpene synthase is responsible for biosynthesis of the sativene-type sesquiterpene backbone at this stage. The

Analysis of sesquiterpene hydrocarbons in grape berry exocarp (Vitis vinifera L.) using in vivo-labeling and comprehensive two-dimensional gas chromatography–mass spectrometry (GC×GC–MS)

• Philipp P. Könen and
• Matthias Wüst

Beilstein J. Org. Chem. 2019, 15, 1945–1961, doi:10.3762/bjoc.15.190

• the unlabeled and deuterated compounds, mechanisms for sesquiterpene formation in V. vinifera could be proposed and already known pathways could be confirmed or disproved. For example, the HS-SPME–GC×GC–TOF–MS measurements of fed sample material showed that the tricyclic sesquiterpene hydrocarbons α

• sesquiterpene ketone rotundone was identified for the first time in 2008 as a key aromatic substance for the peppery aroma of the red wine variety Shiraz, sesquiterpenes have increasingly been in the focus of wine research [4]. It is known that these natural products are synthesized in Vitis vinifera L. via the

• berry exocarp [8]. The biosynthesis of the diverse sesquiterpene structures in V. vinifera is, however, still largely unexplored, especially with respect to the cyclization mechanisms. Studies by Steele et al., Bülow et al., Martin et al. and theoretical studies by Tantillo show the complexity of the

Archangelolide: A sesquiterpene lactone with immunobiological potential from Laserpitium archangelica

• Silvie Rimpelová,
• Michal Jurášek,
• Lucie Peterková,
• Jiří Bejček,
• Vojtěch Spiwok,
• Miloš Majdl,
• Michal Jirásko,
• Miloš Buděšínský,
• Juraj Harmatha,
• Eva Kmoníčková,
• Pavel Drašar and
• Tomáš Ruml

Beilstein J. Org. Chem. 2019, 15, 1933–1944, doi:10.3762/bjoc.15.189

• Sciences of the Czech Republic, Flemingovo náměstí 2, 166 10 Prague 6, Czech Republic Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, v.v.i., 14220 Prague 4, Czech Republic 10.3762/bjoc.15.189 Abstract Sesquiterpene lactones are secondary plant metabolites with sundry

• studied by us and others, there are only scarce reports on the biological activity of archangelolide. Here we present the preparation of its fluorescent derivative based on a dansyl moiety using azide–alkyne Huisgen cycloaddition having obtained the two sesquiterpene lactones from the seeds of Laserpitium

• fluorescent conjugate; sarco/endoplasmic reticulum calcium ATPase; sesquiterpene lactone; trilobolide analogue; Introduction Sesquiterpene lactones (SLs) have been attracting interest already for some time due to the plethora of biological effects they elicit. Various SLs show anticancer, antimicrobial

Phylogenomic analyses and distribution of terpene synthases among Streptomyces

• Lara Martín-Sánchez,
• Kumar Saurabh Singh,
• Mariana Avalos,
• Gilles P. van Wezel,
• Jeroen S. Dickschat and
• Paolina Garbeva

Beilstein J. Org. Chem. 2019, 15, 1181–1193, doi:10.3762/bjoc.15.115

• encoding for geosmin synthase. Some species such as Streptomyces sp. SirexAA-E harbour a silent geosmin synthase encoding gene in their genomes and do not produce this degraded sesquiterpene under laboratory culture conditions [9]. It will therefore be interesting to investigate whether the geosmin

• of type I terpene synthases, including the aspartate-rich motif, the NSE triad, the pyrophosphate sensor and the RY pair [19][20][21]. Both domains have a catalytic activity, the N-terminal domain for the conversion of FPP into the intermediate sesquiterpene alcohol (1(10)E,5E)-germacradien-11-ol (12

• crystal structure of 2-MIB synthase. The function of this domain is unknown, but it is conserved in most 2-MIB synthases and not present in any other terpene synthase [20][28]. epi-Isozizaene (3) is a tricyclic sesquiterpene precursor of the antibiotic albaflavenone (17) (Scheme 3) [29]. Furthermore, both

Mechanistic investigations on multiproduct β-himachalene synthase from Cryptosporangium arvum

• Jan Rinkel and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2019, 15, 1008–1019, doi:10.3762/bjoc.15.99

• . In vitro studies showed not only a high promiscuity with respect to its numerous sesquiterpene products, including the structurally demanding terpenes longicyclene, longifolene and α-longipinene, but also to its substrates, as additional activity was observed with geranyl- and geranylgeranyl

• potential was also exploited in the preparation of sesquiterpene isotopomers, which provided insights into their EIMS fragmentation mechanisms. Keywords: enzyme mechanisms; isotopes; mass spectrometry; promiscuity; terpenes; Introduction The organic chemist usually prefers to work with pure compounds

• 17 is a simple 1,14-cyclisation product, and all cyclised monoterpenes are derived from the extensively studied terpinyl cation [35][36], this work focusses on elucidating the more interesting sesquiterpene cyclase mechanism of HcS. Most sesquiterpene products 1–6 of HcS including the main product 1

New terpenoids from the fermentation broth of the edible mushroom Cyclocybe aegerita

• Frank Surup,
• Florian Hennicke,
• Nadine Sella,
• Maria Stroot,
• Steffen Bernecker,
• Sebastian Pfütze,
• Marc Stadler and
• Martin Rühl

Beilstein J. Org. Chem. 2019, 15, 1000–1007, doi:10.3762/bjoc.15.98

• of C. aegerita [16], two putative sesquiterpene synthase gene clusters have been identified on the basis of the published Δ6-protoilludene gene cluster of Omphalotus olearius [17]. The protein sequences of the genes clustering adjacent to the putative sesquiterpene synthase genes going by the gene

• correspondence between both putative sesquiterpene synthases and the analysed secondary metabolites 1–4 C. aegerita AAE-3 was cultivated in a stirred vessel bioreactor. Mycelial samples were analysed for the presence of the gene transcripts and 1 and 3 (Figure 2). At the beginning of the fermentation, the

• putative sesquiterpene synthase gene with the gene ID AAE3_04120 was upregulated with a maximum of transcripts at day 7 of cultivation. The second gene with the gene ID AAE3_10454 showed a more slight increase expression peaking at day 11 and day 14. The peak area of 1 in the supernatant increased until

An efficient synthesis of the guaiane sesquiterpene (−)-isoguaiene by domino metathesis

• Yuzhou Wang,
• Ahmed F. Darweesh,
• Patrick Zimdars and
• Peter Metz

Beilstein J. Org. Chem. 2019, 15, 858–862, doi:10.3762/bjoc.15.83

• ; metathesis; Michael addition; organocatalysis; terpenes; Introduction The guaiane sesquiterpene (−)-isoguaiene (1) has been isolated from the liverworts Pellia epiphylla [1] and Dumortiera hirsuta [2] as well as from several Pimpinella species [3][4], while the (+)-enantiomer of 1 has been isolated from the

• required to effect the relay metathesis of 3 to (−)-isoguaiene (1) in refluxing benzene in a good yield of 51%. Thus, by application of a domino metathesis strategy featuring trienyne 3, only 9 steps were needed to secure the guaiane sesquiterpene 1 in 19.7% overall yield starting from (S)-citronellal (5

• sesquiterpene (−)-isoguaiene (1) using either a trienyne or a dienediyne metathesis and highly diastereoselective organocatalytic Michael additions of aldehydes derived from 5 as the key steps. Structures of the sesquiterpene (−)-isoguaiene (1) and the trisnorsesquiterpene clavukerin A (2). Retrosynthetic

Stereochemical investigations on the biosynthesis of achiral (Z)-γ-bisabolene in Cryptosporangium arvum

• Jan Rinkel and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2019, 15, 789–794, doi:10.3762/bjoc.15.75

• sesquiterpene. Since the stereoinformation of both chiral putative intermediates, nerolidyl diphosphate (NPP) and the bisabolyl cation, is lost during formation of the achiral product, the intriguing question of their absolute configurations was addressed by incubating both enantiomers of NPP with the

• still present. In this group, there are acyclic compounds like the linear sesquiterpene (E)-β-farnesene (1, Figure 1), which is known as an alarm pheromone in aphids [4][5], but also monocyclic terpenes like α-humulene (2), a widely occurring sesquiterpene in many essential oils [6][7]. Whereas the

• terpinyl cation has been investigated using deuterium labelling, demonstrating different stereochemical courses in the plant Salvia officinalis [8][9] and in the bacterium Streptomyces clavuligerus [10]. Also the highly unusual methylated sesquiterpene sodorifen (4) possesses a mirror plane [11] making any

Synthesis and biological investigation of (+)-3-hydroxymethylartemisinin

• Toni Smeilus,
• Farnoush Mousavizadeh,
• Johannes Krieger,
• Xingzhao Tu,
• Marcel Kaiser and
• Athanassios Giannis

Beilstein J. Org. Chem. 2019, 15, 567–570, doi:10.3762/bjoc.15.51

• sesquiterpene lactone is still unknown [5]. Whereas artemisinins are almost non-toxic to normal cells, several studies have confirmed their potent antitumor activity [6][7]. In addition, they have been reported to possess immunosuppressive, anti-inflammatory, antiviral, antifungal and antiparasitic activities

• [8][9][10]. Recently, it was shown that artemisinin interacts with the mammalian protein gephyrin and by stabilizing it, it enhances GABAA receptor signaling resulting in in vivo conversion of pancreatic α-cells into functional β-like cells [11]. Therefore, this sesquiterpene lactone may also find an

Volatiles from the hypoxylaceous fungi Hypoxylon griseobrunneum and Hypoxylon macrocarpum

• Jan Rinkel,
• Alexander Babczyk,
• Tao Wang,
• Marc Stadler and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2018, 14, 2974–2990, doi:10.3762/bjoc.14.277

• ]. Many of these compounds are of interest, because they are markers for the production of fungal toxins and thus can help to distinguish between toxigenic and closely related non-toxigenic species. For example, the sesquiterpene trichodiene (1, Figure 1) is the precursor of the trichothecene family of

• mycotoxins [2], a class of highly bioactive secondary metabolites that belong to the strongest known inhibitors of protein biosynthesis in eukaryotes [3]. Similarly, the sesquiterpene aristolochene (2) is the parent hydrocarbon of PR toxin [4][5] and has been used as a marker to differentiate between toxin

• elucidation commercially available standards of 9–11 were used, while a synthesis of 12 was performed in our earlier study [24]. Furthermore, a group of monoterpenes and the sesquiterpene alcohol pogostol (19) that was previously reported from other fungi [29][30] were observed. Monoterpenes were comprised of

Investigation of the electrophilic reactivity of the biologically active marine sesquiterpenoid onchidal and model compounds

• Melissa M. Cadelis and
• Brent R. Copp

Beilstein J. Org. Chem. 2018, 14, 2229–2235, doi:10.3762/bjoc.14.197

• Melissa M. Cadelis Brent R. Copp School of Chemical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand 10.3762/bjoc.14.197 Abstract The structure of the sesquiterpene onchidal (6), a component of the defensive secretion of the shell-less mollusc Onchidella binneyi

Volatiles from three genome sequenced fungi from the genus Aspergillus

• Jeroen S. Dickschat,
• Ersin Celik and
• Nelson L. Brock

Beilstein J. Org. Chem. 2018, 14, 900–910, doi:10.3762/bjoc.14.77

• spore distribution [11]. Furthermore, volatiles can be used as taxonomic markers [12] and can serve as indicators for fungal toxin production, e.g., the fungal emission of the sesquiterpene hydrocarbon trichodiene points to the production of trichothecene mycotoxins [13]. Aspergillus is a well-described

• terpenes, including traces of the widespread monoterpenes limonene (3) and linalool (4). The C12 compounds (8S*,9R*,10S*)-8,10-dimethyl-1-octalin (5) and (8S*,10R*)-8,10-dimethyl-1(9)-octalin (6) are intermediates of the biosynthesis of the earthy odorant geosmin that is itself a degraded sesquiterpene [29

• I TSs (349DEFME and 847NDYGSLARD). Furthermore, two groups of structurally and biosynthetically related sesquiterpenes were found that could each arise from one sesquiterpene synthase (STS). The first of these groups comprised the main compound α-acoradiene (15), accompanied by minor amounts of β

Volatiles from the tropical ascomycete Daldinia clavata (Hypoxylaceae, Xylariales)

• Tao Wang,
• Kathrin I. Mohr,
• Marc Stadler and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2018, 14, 135–147, doi:10.3762/bjoc.14.9

• only been tentatively characterised at the genus level [23][24][25][26][27][28]. The compound actually consitutes one of several chemotaxonomic marker metabolites for the clade in the Hypoxylaceae comprising Daldinia and allied genera [29]. The sesquiterpene alcohol 16 was first isolated from the plant

Herpetopanone, a diterpene from Herpetosiphon aurantiacus discovered by isotope labeling

• Xinli Pan,
• Nicole Domin,
• Sebastian Schieferdecker,
• Hirokazu Kage,
• Martin Roth and
• Markus Nett

Beilstein J. Org. Chem. 2017, 13, 2458–2465, doi:10.3762/bjoc.13.242

• , whereas a plant-derived sesquiterpene with this feature was already reported in 1965. Oplopanone (2, Figure 3) was originally isolated from Oplopanax japonicus [18][19], but can also be found in a number of other plants as well as red algae [20][21]. Comparison of the chemical shifts in 1 with published

Are boat transition states likely to occur in Cope rearrangements? A DFT study of the biogenesis of germacranes

• José Enrique Barquera-Lozada and
• Gabriel Cuevas

Beilstein J. Org. Chem. 2017, 13, 1969–1976, doi:10.3762/bjoc.13.192

• rearrange to yield one or potentially two elemanolide configurations. The schkuriolide (1, Scheme 1) is a sesquiterpene lactone, specifically a (Z,E)-germacranolide, named melampolide, that coexists in the same natural source with the elemanschkuhriolide (3), which is an elemanolide with a stereochemistry

18-Hydroxydolabella-3,7-diene synthase – a diterpene synthase from Chitinophaga pinensis

• Jeroen S. Dickschat,
• Jan Rinkel,
• Patrick Rabe,
• Arman Beyraghdar Kashkooli and
• Harro J. Bouwmeester

Beilstein J. Org. Chem. 2017, 13, 1770–1780, doi:10.3762/bjoc.13.171

• production of volatile terpenes by this bacterium that can be detected in headspace extracts [17][18]. In one of these previous reports [17] we have described a terpene synthase from Chitinophaga pinensis DSM 2588 (accession number WP_012789469) as a sesquiterpene synthase for germacrene A (1), which was