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

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

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

• at the nerolidyl cation (Figure 5b) [28][29][30][31]. The biosynthesis of 1–8 and 10–11 are likely to be derived from sativene with a key oxidation at C-15 followed by a Baeyer–Villiger oxidation to break the C-14–C-15 bond (Figure 5c). Based on an isotope labelling study, the γ-butyrolactone moiety

• Cochliobolus sp.) [1][26], were reported in B. sorokiniana for the first time, while, known metabolites 6 and 7 [20], 9 [34], 11 [2], and 12 [16] were previously reported from B. sorokiniana (syn. C. sativus and H. sativum). The terpene synthase responsible for the biosynthesis of the sativene/longifolene

• 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

Isolation and characterisation of irinans, androstane-type withanolides from Physalis peruviana L.

• Annika Stein,
• Dave Compera,
• Bianka Karge,
• Mark Brönstrup and
• Jakob Franke

Beilstein J. Org. Chem. 2019, 15, 2003–2012, doi:10.3762/bjoc.15.196

• irinans, from Physalis peruviana with highly unusual truncated backbones that resemble mammalian androstane sex hormones. Based on biomimetic chemical reactions, we propose a model that links these compounds to withanolide biosynthesis. Irinans have potent antiproliferative activities, that are however

• characteristic of Physalis species. The biosynthesis of androstanes in mammals requires three enzymatic steps starting from cholesterol (9, Figure 3B) [27]. Cholesterol (9) is converted to pregnenolone (10) by the cytochrome P450 cholesterol side-chain cleavage enzyme (P450scc), which cleaves the C20–C22 bond

• involved. While the order of oxidative steps in withanolide biosynthesis is still completely elusive [29], we propose that this fragmentation occurs at a late stage, when most typical withanolide functionalisations have already been introduced. Indeed, irinan A (2), irinan B (3) and cinedione (8) can be

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

• -copaene, β-copaene, α-cubebene, β-cubebene and the bicyclic δ-cadinene were biosynthesized via (S)-(−)-germacrene D rather than via (R)-(+)-germacrene D as intermediate. Keywords: biosynthesis; deuterium labeling; germacrene; HS-SPME; terpenes; TOF–MS; Introduction The aroma profile of grape berries at

• mevalonate-dependent biosynthesis pathway (MVA) localized in the cytoplasm as well as via the mevalonate-independent 1-deoxy-ᴅ-xylulose 5-phosphate/2-C-methyl-ᴅ-erythritol 4-phosphate metabolic pathway (DOXP/MEP) localized in plastids [5]. In the MVA pathway, which was first described in yeast and animals

• leads to the formation of DMAPP and IPP, was discovered in a study focused on hopanoids [7]. Today it is known that the sesquiterpenes in Vitis vinifera are formed from FPP whose biosynthesis relies on both, the DOXP/MEP and the MVA pathway, and that they specifically accumulate in the wax layer of the

Inherent atomic mobility changes in carbocation intermediates during the sesterterpene cyclization cascade

• Hajime Sato,
• Takaaki Mitsuhashi,
• Mami Yamazaki,
• Ikuro Abe and
• Masanobu Uchiyama

Beilstein J. Org. Chem. 2019, 15, 1890–1897, doi:10.3762/bjoc.15.184

• the first detailed analysis of the inherent atomic mobility in carbocation intermediates during sesterterpene biosynthesis. We identified two methyl groups as the least mobile of all the carbons of the carbocation intermediates in the first half of the cyclization cascade. Our analysis suggests that

• these two methyl groups are critical for the preorganization of GFPP in the biosynthetic pathways leading to sesterfisherol and quiannulatene. Keywords: biosynthesis; carbocation; DFT; substrate recognition; terpene cyclase; Introduction Terpene synthases are thought to have four main roles: (i

• 5/6/8/5 tetracyclic intermediate. This, in turn, is transformed to a 4/6-membered ring in quiannulatene biosynthesis, whereas 5/5 ring formation proceeds in sesterfisherol biosynthesis (Scheme 1, Scheme 2, and Scheme 3). Based on our DFT calculations, this regioselectivity is determined by the

Molecular basis for the plasticity of aromatic prenyltransferases in hapalindole biosynthesis

• Takayoshi Awakawa and
• Ikuro Abe

Beilstein J. Org. Chem. 2019, 15, 1545–1551, doi:10.3762/bjoc.15.157

• Aromatic prenyltransferases (PTases) are enzymes that catalyze Friedel–Crafts reactions between aromatic compounds and isoprenoid diphosphates. In hapalindole biosynthesis, the aromatic PTases AmbP1 and AmbP3 exhibit surprisingly plastic selectivities. AmbP1 not only transfers the geranyl group on the C-3

• (DMATS)-type [6][7], and the membrane-bound type PTases [8][9]. Some of them exhibit broad substrate specificities and accept various aromatic compounds as prenyl acceptors. For example, NphB (also called Orf-2), the first reported ABBA-type PTase in naphtherpin biosynthesis, accepts several aromatic

• -type PTase TleC, which accepts C5 to C20 isoprenoid diphosphates in the biosynthesis of teleocidin B [11]. More interestingly, some PTases change their regiospecificity according to the chain length of the isoprenoid diphosphate, as exemplified by the DMATS-type PTase AtaPT [12]. To get knowledge about

Synthesis and biological evaluation of truncated derivatives of abyssomicin C as antibacterial agents

• Leticia Monjas,
• Peter Fodran,
• Johanna Kollback,
• Carlo Cassani,
• Thomas Olsson,
• Maja Genheden,
• D. G. Joakim Larsson and
• Carl-Johan Wallentin

Beilstein J. Org. Chem. 2019, 15, 1468–1474, doi:10.3762/bjoc.15.147

• covalent inhibitor of 4-amino-4-deoxychorismate (ADC) synthase, which is the enzyme that catalyzes the conversion of chorismate and glutamine into ADC and glutamate, the first step in the biosynthesis of p-aminobenzoic acid (PABA) in bacteria [6]. Specifically, AbC binds via a Michael addition between a

Genomics-inspired discovery of massiliachelin, an agrochelin epimer from Massilia sp. NR 4-1

• Jan Diettrich,
• Hirokazu Kage and
• Markus Nett

Beilstein J. Org. Chem. 2019, 15, 1298–1303, doi:10.3762/bjoc.15.128

• -producing bacterium Massilia sp. NR 4-1 and predicted to direct the biosynthesis of a molecule that is structurally related to the thiazoline-containing siderophore micacocidin. In order to track this compound, we analyzed the metabolic profiles of Massilia cultures grown under different iron concentrations

• the discovery of novel natural products in the genera Janthinobacterium [8] and Collimonas [9][10], which are taxonomically closely related to Massilia. Bioinformatic analysis of the 6.36 Mbp-sized genome of strain NR 4-1 using antiSMASH 4.0 [11][12] revealed a total of 16 biosynthesis gene clusters

• (BGCs), of which one (RS19155-RS19175) could be linked with the production of violacein. Another BGC bears notable similarities to a locus from the plant pathogenic bacterium Ralstonia solanacearum GMI1000, which is involved in the biosynthesis of the siderophore micacocidin [13][14]. Differences in the

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

• analysis of this genus is discussed. Keywords: biosynthesis; evolution; geosmin; Streptomyces; terpenes; Introduction Streptomyces are soil bacteria that belong to the order of actinomycetales and are a rich source of natural products with broad biotechnological interest. Species of this genus have a

• crystal structure was also the first reported for a bacterial terpene synthase [47]. Pentalenene synthase catalyses the cyclisation of FPP into pentalenene, which is the first step in the biosynthesis of the antibiotic pentalenolactone. This mechanism has been extensively studied and involves the initial

• ionisation of the substrate FPP and the formation of a humulyl cation as an intermediate in the biosynthesis of pentalenene [45][46][48][49], while the later steps of the cyclisation cascade were subject to revision based on the findings of quantum chemical calculations [50][51]. The α-amorphene synthase

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

• spectrometry and NMR spectroscopy. The relative configurations of 2–4 were assigned by ROESY correlations, and 3JH,H coupling constants in the case of 4. Applying quantitative PCR for gene expression validation, we linked the production of bovistol and its derivatives to the respective biosynthesis gene

• production of bovistol to the putative Δ6-protoilludene synthase AAE3_04120 whose gene is located adjacent to a Diels-Alderase needed for cycloaddition of two illudine monomers. With this information, we made a biosynthesis proposal for these metabolites. Further studies will address this assumption to prove

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

• recombinant enzyme, which resolved in an exclusive cyclisation of (R)-NPP, while (S)-NPP that is non-natural to the (Z)-γ-bisabolene synthase was specifically converted into (E)-β-farnesene. A hypothetical enzyme mechanistic model that explains these observations is presented. Keywords: biosynthesis

• in the biosynthesis of the achiral sesquiterpene (Z)-γ-bisabolene (5) by a TS from a soil bacterium. Results and Discussion Functional characterisation of a bacterial (Z)-γ-bisabolene synthase Within our efforts to characterise bacterial TSs with new functions and mechanisms, a TS (WP_035857999) from

• biosynthesis from FPP featuring the common bisabolyl cation (A) as an intermediate after 1,6-cyclisation (Scheme 1). For this cyclisation, a formal isomerisation of the (E)-configured double bond in FPP to the (Z)-configured double bond in A is needed. To address this problem, a 1,3-suprafacial transposition

Synthesis of the aglycon of scorzodihydrostilbenes B and D

• Katja Weimann and
• Manfred Braun

Beilstein J. Org. Chem. 2019, 15, 610–616, doi:10.3762/bjoc.15.56

• multiple phenolic functionality. These natural products that form as secondary metabolites on a branch of flavonoid biosynthesis found wide interest for their various biological effects like anti-oxidative and biofouling-preventing activity [1]. From crude extracts of the Mongolian medicinal plant

Cyclopropene derivatives of aminosugars for metabolic glycoengineering

• Jessica Hassenrück and
• Valentin Wittmann

Beilstein J. Org. Chem. 2019, 15, 584–601, doi:10.3762/bjoc.15.54

• amide [18], carbamate [19], or most recently a urea linkage [20] have been reported. Terminal alkenes are small which is beneficial for being accepted by the enzymes involved in glycan biosynthesis. However, they react only slowly in the DAinv reaction [20]. In contrast, ring-strained alkenes, such as

• results in stronger staining of soluble proteins than Ac4GlcNCp whereas Ac4GlcNCp gives a stronger cell surface staining suggests that Ac4GlcNCyoc is better accepted by the enzymes producing intracellular glycoproteins while Ac4GlcNCp is better accepted by the enzymes involved in the biosynthesis of

• ] thereby joining the sialic acid biosynthesis pathway. Thus, a possible explanation of the staining of cell surfaces after MGE with glucosamine derivatives is their conversion into sialic acid derivatives and further into sialo glycoconjugates. To investigate this possibility, we carried out MGE

Synthesis and SAR of the antistaphylococcal natural product nematophin from Xenorhabdus nematophila

• Frank Wesche,
• Hélène Adihou,
• Thomas A. Wichelhaus and
• Helge B. Bode

Beilstein J. Org. Chem. 2019, 15, 535–541, doi:10.3762/bjoc.15.47

• -oxopentanoic acid and tryptamine and showed good activities against different Gram-positive pathogens like Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA) comparable with activities of vancomycin. Recently, the biosynthesis of 1 was elucidated by our group as well as the 2

A chemoenzymatic synthesis of ceramide trafficking inhibitor HPA-12

• Seema V. Kanojia,
• Sucheta Chatterjee,
• Subrata Chattopadhyay and
• Dibakar Goswami

Beilstein J. Org. Chem. 2019, 15, 490–496, doi:10.3762/bjoc.15.42

• , suggesting the possibility of its use as an anticancer compound. Besides, inhibition of sphingolipid biosynthesis using HPA-12 has also been reported to inhibit hepatitis C virus replication substantially [4]. In another study, the CERT knockdown disrupted the normal oxidative stress response in Drosophila

Synthesis of nonracemic hydroxyglutamic acids

• Dorota G. Piotrowska,
• Iwona E. Głowacka,
• Andrzej E. Wróblewski and
• Liwia Lubowiecka

Beilstein J. Org. Chem. 2019, 15, 236–255, doi:10.3762/bjoc.15.22

• pool; glutamate analogues; Introduction L-Glutamic acid (1, Figure 1) plays an important role in the biosynthesis of purine and pyrimidine nucleobases [1]. It also takes part in metabolic transformation to L-glutamine by L-glutamate synthetase (GS) which is crucial for cell maintenance. In neoplastic

Synthesis and biological activity of methylated derivatives of the Pseudomonas metabolites HHQ, HQNO and PQS

• Sven Thierbach,
• Max Wienhold,
• Susanne Fetzner and
• Ulrich Hennecke

Beilstein J. Org. Chem. 2019, 15, 187–193, doi:10.3762/bjoc.15.18

• (HHQ, 1) are important signaling molecules involved in quorum sensing and as such play an important role in virulence regulation [3][10][11][12]. Another metabolite from the AQ biosynthesis pathway of P. aeruginosa is 2-heptyl-1-hydroxy-4(1H)-quinolone (generally referred to as 2-heptyl-4

• -hydroxyquinoline N-oxide, HQNO), which is not active in quorum sensing, but interferes with the respiratory electron transport via inhibition of the cytochrome bc1 complex and moreover inhibits pyrimidine biosynthesis [9][12][13][14]. Therefore, HQNO is toxic to many organisms. In dual-species co-cultures of P

• suspension was transferred to the chamber of a Clark-type oxygen electrode and the O2 consumption was measured for 2–3 min. Experiments were done in biological triplicates (n = 3). The effect of AQs on the quorum sensing activity in P. aeruginosa was studied by using AQ biosynthesis as measurable output. The

Unexpected loss of stereoselectivity in glycosylation reactions during the synthesis of chondroitin sulfate oligosaccharides

• Teresa Mena-Barragán,
• José L. de Paz and
• Pedro M. Nieto

Beilstein J. Org. Chem. 2019, 15, 137–144, doi:10.3762/bjoc.15.14

• biosynthesis of this polymer. The presence of aromatic rings, such as the 4-methoxyphenyl group at the anomeric position, should be avoided because these groups can significantly modify the binding mode between the CS and the enzymes. For this reason, we introduced an isopropyl group in β-position of the

Lectins of Mycobacterium tuberculosis – rarely studied proteins

• Katharina Kolbe,
• Sri Kumar Veleti,
• Norbert Reiling and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2019, 15, 1–15, doi:10.3762/bjoc.15.1

• ], protozoa [57], and fungi [58], and totally absent in mammals. D-Arabinofuranose can only be found in prokaryotes, for example in Gram-negative bacteria where it is a cytoplasmic intermediate in the biosynthesis of 3-deoxy-D-manno-octulosonic acid (KDO), an essential carbohydrate of the cell wall

• binding domain was recently identified to be present in the arabinofuranosyltransferase EmbC (Rv3793), which is involved in the LAM biosynthesis of the Mtb cell wall [106]. However, the known function of this protein in arabinogalactan biosynthesis suggests the lectin-like domain to be more associated

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

• derivatives. Their structures could only be unambiguously determined by comparison to all isomers with different substitution patterns. The substitution pattern of the main compound from H. griseobrunneum, the new natural product 2,4,5-trimethylanisole, was explainable by a polyketide biosynthesis mechanism

• 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

• (methyl-2H3)methionine. While the methylation pattern of the alternative structure 24c is difficult to understand via a polyketide biosynthesis mechanism, the formation of the assigned structure of 24 by a polyketide synthase (PKS) can be easily rationalised (Scheme 2). The acetate starter unit, bound to

N-Acylated amino acid methyl esters from marine Roseobacter group bacteria

• Hilke Bruns,
• Lisa Ziesche,
• Nargis Khakin Taniwal,
• Laura Wolter,
• Thorsten Brinkhoff,
• Jennifer Herrmann,
• Rolf Müller and
• Stefan Schulz

Beilstein J. Org. Chem. 2018, 14, 2964–2973, doi:10.3762/bjoc.14.276

• knowledge on their biosynthesis, the underlying gene organization, as well as their function in many bacteria [11][12][13]. In the Roseobacter group, AHLs are involved, e.g., in antibiotic production [9] or cell differentiation [10]. Although many other bacterial signalling compounds must exist, only few of

Olefin metathesis catalysts embedded in β-barrel proteins: creating artificial metalloproteins for olefin metathesis

• Daniel F. Sauer,
• Johannes Schiffels,
• Takashi Hayashi,
• Ulrich Schwaneberg and
• Jun Okuda

Beilstein J. Org. Chem. 2018, 14, 2861–2871, doi:10.3762/bjoc.14.265

• ions such as Mg, Ca, Mn, Fe, Ni, Co, Cu, Zn etc. within a protein are abundant in nature [24]. As metalloenzymes, these metalloproteins are capable of catalyzing various important reactions in biosynthesis and key steps in cellular energy metabolism. The embedded metal ion mainly acts as a Lewis acid

Pd-Catalyzed microwave-assisted synthesis of phosphonated 13α-estrones as potential OATP2B1, 17β-HSD1 and/or STS inhibitors

• Rebeka Jójárt,
• Szabolcs Pécsy,
• György Keglevich,
• Mihály Szécsi,
• Réka Rigó,
• Csilla Özvegy-Laczka,
• Gábor Kecskeméti and
• Erzsébet Mernyák

Beilstein J. Org. Chem. 2018, 14, 2838–2845, doi:10.3762/bjoc.14.262

• ; enzyme; 13α-estrone; Hirao reaction; 17β-HSD1 inhibition; OATP2B1; STS; Introduction The biosynthesis of estrogens occurs via various enzymatic routes. Cytochrome P450 aromatase catalyzes the conversion of nonaromatic steroids to estrogens [1]. Moreover, hydrolysis of estrone 3-sulfate, existing as a

• reduction of the 17-oxo function leading to 17β-estradiol. This last step of the estrogen biosynthesis is catalyzed by the 17β-hydroxy steroid dehydrogenase type 1 isoenzyme (17β-HSD1) [13]. Thus STS and 17β-HSD1 became important drug targets in estrogen-dependent diseases [1][14]. Their inhibition could be

• a powerful strategy for the suppression of local estrogen production. Additionally, the entry of estrone-sulfate into the cells by inhibition of OATPs can be a good alternative [15][16]. Prior suppression of cytosolic enzymes involved in the estradiol biosynthesis, the transport of conjugated

Targeting the Pseudomonas quinolone signal quorum sensing system for the discovery of novel anti-infective pathoblockers

• Christian Schütz and
• Martin Empting

Beilstein J. Org. Chem. 2018, 14, 2627–2645, doi:10.3762/bjoc.14.241

• various potential drug targets present within pqs QS. These range from enzymes within the biosynthesis cascade of the signal molecules PqsABCDE to the receptor of these autoinducers PqsR (MvfR). This review shortly introduces P. aeruginosa and its pathogenicity traits regulated by the pqs system and

• ]. Aforementioned enzyme PqsL is needed for the production of HQNO, as it delivers the N-oxidised substrate 2-HABA for PqsBC-mediated condensation with octanoyl-CoA analogous to HHQ biosynthesis [27]. PQS-mediated pathogenicity traits and molecular targets P. aeruginosa makes use of an arsenal of virulence factors

• response. In terms of pathogenicity traits, they are involved in the regulation of genes encoding for enzymes responsible for phenazine biosynthesis (pyocyanin production), hydrogen cyanide synthesis, Lectins LecA and LecB and additional genes involved in biofilm formation, enzymes for rhamnolipid