Chemo-enzymatic total synthesis: current approaches toward the integration of chemical and enzymatic transformations

• Ryo Tanifuji and
• Hiroki Oguri

Beilstein J. Org. Chem. 2024, 20, 1693–1712, doi:10.3762/bjoc.20.151

• . Subsequently, the downstream HR-iPKS module, SorbB, catalyzes both the extension of polyketide chain from 30 using two additional malonyl-CoAs and C-methylations exploiting two units of SAM (S-adenosyl methionine) to generate thioester 31 on the ACP domain. Then, the reduction (Red) domain located at the C

Methyltransferases from RiPP pathways: shaping the landscape of natural product chemistry

• Maria-Paula Schröder,
• Isabel P.-M. Pfeiffer and
• Silja Mordhorst

Beilstein J. Org. Chem. 2024, 20, 1652–1670, doi:10.3762/bjoc.20.147

• -translational modifications; ribosomal peptides; SAM-dependent enzymes; Introduction In the complex landscape of natural product biosynthesis, ribosomally synthesised and post-translationally modified peptides (RiPPs) stand out as a fascinating class of compounds with both structural diversity and unique

• ; this reaction is catalysed by S-adenosylmethionine (SAM or AdoMet)-dependent methyltransferases (MTs). These enzymes are known for their excellent chemo-, regio-, and stereoselectivity [3][4][5][6]. Their ability to introduce methyl groups at specific positions within ribosomal peptides equips the

• environmentally friendly, whereas chemical methylating agents are usually toxic and unselective [3]. Nonetheless, a drawback is that MTs rely on the costly cofactor SAM, which is required in stoichiometric amounts. Furthermore, it is unstable in physiological conditions and produces S-adenosylhomocysteine (SAH

Polymer degrading marine Microbulbifer bacteria: an un(der)utilized source of chemical and biocatalytic novelty

• Weimao Zhong and
• Vinayak Agarwal

Beilstein J. Org. Chem. 2024, 20, 1635–1651, doi:10.3762/bjoc.20.146

• this branching methyl could be derived from via S-adenosylmethionine (SAM). Phytoplankton and bacteria have had a long-term coexistence and complex interactions ranging from mutualism, antagonism, and competition to parasitism in the ocean [133]. Algicidal bacteria often emerge in the late stage of an

Cofactor-independent C–C bond cleavage reactions catalyzed by the AlpJ family of oxygenases in atypical angucycline biosynthesis

• Jinmin Gao,
• Liyuan Li,
• Shijie Shen,
• Guomin Ai,
• Bin Wang,
• Fang Guo,
• Tongjian Yang,
• Hui Han,
• Zhengren Xu,
• Guohui Pan and
• Keqiang Fan

Beilstein J. Org. Chem. 2024, 20, 1198–1206, doi:10.3762/bjoc.20.102

• contraction reactions, yielding a benzofluorene intermediate 4 and the dimer 5, both featuring a kinamycin skeleton (Scheme 1) [11][12]. Recent investigations unveiled the catalytic activity of the O-methyltransferase-like protein AlpH, which catalyzes a unique SAM-independent coupling of ʟ-glutamylhydrazine

Enhancing structural diversity of terpenoids by multisubstrate terpene synthases

• Min Li and
• Hui Tao

Beilstein J. Org. Chem. 2024, 20, 959–972, doi:10.3762/bjoc.20.86

• FPP is catalyzed by the C-methyltransferase SpSodMT. In 2018, the biosynthesis of an unusual homosesquiterpene, sodorifen (102, Figure 1), from Serratia plymuthica 4RX13 was elucidated [57]. The in vitro and in vivo results revealed that a SAM-dependent-C-methyltransferase catalyzed methylation and

Production of non-natural 5-methylorsellinate-derived meroterpenoids in Aspergillus oryzae

• Jia Tang,
• Yixiang Zhang and
• Yudai Matsuda

Beilstein J. Org. Chem. 2024, 20, 638–644, doi:10.3762/bjoc.20.56

• acid (5-MOA)-derived meroterpenoids. (C) Reactions catalyzed by the terpene cyclases involved in DMOA-derived meroterpenoid pathways. Generation of unnatural 5-MOA-derived meroterpenoids. (A) Working concept to synthesize unnatural 5-MOA-derived meroterpenoids. SAM: S-adenosyl-ʟ-methionine; FPP

Functions of enzyme domains in 2-methylisoborneol biosynthesis and enzymatic synthesis of non-natural analogs

• Binbin Gu,
• Lin-Fu Liang and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2023, 19, 1452–1459, doi:10.3762/bjoc.19.104

• model was proposed that proceeds through the S-adenosylmethionine (SAM) dependent methylation of geranyl diphosphate (GPP) to 2-methyl-GPP (2-Me-GPP), followed by a terpene cyclisation to 1 (Scheme 1A) [10]. The cyclisation cascade requires isomerisation to (R)-2-methyllinalyl diphosphate [22], followed

• ) Enzyme precipitation after 12 h in elution buffer at 4 °C. The biosynthesis of 2-methylisoborneol (1). A) SAM-dependent methylation of GPP to 2-Me-GPP by GPPMT and terpene cyclisation to 1 by 2MIBS. B) Non-natural formation using the enzymes humMT for the methylation of DMAPP to 2-Me-IPP, FPPS for the

Make or break: the thermodynamic equilibrium of polyphosphate kinase-catalysed reactions

• Michael Keppler,
• Sandra Moser,
• Henning J. Jessen,
• Christoph Held and
• Jennifer N. Andexer

Beilstein J. Org. Chem. 2022, 18, 1278–1288, doi:10.3762/bjoc.18.134

• can be embedded in complex biosynthetic networks such as in vitro S-adenosylmethionine (SAM)- or carbon dioxide fixation cycles, and de novo nucleobase synthesis [38][39][40][41]. For the biocatalytic synthesis of ATP or derivatives, up to three consecutive phosphorylation reactions are coupled in a

Enzymes in biosynthesis

• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2022, 18, 1131–1132, doi:10.3762/bjoc.18.116

• , requiring a sophisticated enzymology [4]. Recent developments show us that there is still much more to discover, e.g., altemicidin was shown to be enzymatically constructed from NAD+ and SAM that usually serve as enzyme cosubstrates in redox transformations and methylations but are rarely used to construct

New azodyrecins identified by a genome mining-directed reactivity-based screening

• Atina Rizkiya Choirunnisa,
• Kuga Arima,
• Yo Abe,
• Noritaka Kagaya,
• Kei Kudo,
• Hikaru Suenaga,
• Junko Hashimoto,
• Manabu Fujie,
• Noriyuki Satoh,
• Kazuo Shin-ya,
• Kenichi Matsuda and
• Toshiyuki Wakimoto

Beilstein J. Org. Chem. 2022, 18, 1017–1025, doi:10.3762/bjoc.18.102

• vitro assay elucidated the tailoring step of azodyrecin biosynthesis, which is mediated by the S-adenosylmethionine (SAM)-dependent methyltransferase Ady1. This study paves the way for the targeted isolation of aliphatic azoxy natural products through a genome-mining approach and further investigations

• the biosynthesis of the methyl ester, which is unique to azodyrecins. To this end, we characterized the putative SAM-dependent methyltransferase Ady1 in vitro to assess its activity against the carboxylic acid 11, which was prepared by the hydrolysis of compound 8 under basic conditions. When acid 11

• was incubated with recombinant Ady1 in the presence of SAM, it was converted to 8, showing that Ady1 can install the methyl ester of azodyrecins (Figure 4). The in vitro characterization of Ady1 and the functional annotation of ady clusters allowed the prediction of the entire biosynthetic pathway of

Introducing a new 7-ring fused diindenone-dithieno[3,2-b:2',3'-d]thiophene unit as a promising component for organic semiconductor materials

• Valentin H. K. Fell,
• Joseph Cameron,
• Alexander L. Kanibolotsky,
• Eman J. Hussien and
• Peter J. Skabara

Beilstein J. Org. Chem. 2022, 18, 944–955, doi:10.3762/bjoc.18.94

• , solvent choice [81], and application of self-assembled monolayers (SAM). SAMs are coated on the dielectric medium, improving surface roughness [82] and reduce interfacial defects [83]. Details about device fabrication are described in Supporting Information File 1. Device optimisation was necessary since

• device was measured upon annealing for 30 minutes at 150 °C with 1.33 × 10−4 cm2 V−1 s−1, using a solution of 10 mg mL−1 in CHCl3 and octadecyltrichlorosilane (OTS) as the SAM [82]. Averaged over seven devices on that wafer, an average hole mobility of 4.69 × 10−5 cm2 V−1 s−1 was measured. However, two

Synthesis of O⁶-alkylated preQ₁ derivatives

• Laurin Flemmich,
• Sarah Moreno and
• Ronald Micura

Beilstein J. Org. Chem. 2021, 17, 2295–2301, doi:10.3762/bjoc.17.147

• methylation reaction is likely to be catalyzed by the product of the gene huiC, which encodes a SAM-dependent methyltransferase [18]. To the best of our knowledge, in contrast to m6preQ0 [17] the reduced counterpart 7-aminomethyl-O6-methyl-7-deazaguanine m6preQ1 has not yet been reported to be isolated from

Natural products in the predatory defence of the filamentous fungal pathogen Aspergillus fumigatus

• Jana M. Boysen,
• Nauman Saeed and
• Falk Hillmann

Beilstein J. Org. Chem. 2021, 17, 1814–1827, doi:10.3762/bjoc.17.124

• -adenosyl-methionine (SAM) dependent bisthiomethyltransferase GtmA which is not part of the gli-cluster. Amoebicidal secondary metabolites trypacidin and fumagillin of Aspergillus fumigatus. Intermediates of the DHN-melanin biosynthesis in Aspergillus fumigatus. Intermediates and products of the

Breakdown of 3-(allylsulfonio)propanoates in bacteria from the Roseobacter group yields garlic oil constituents

• Anuj Kumar Chhalodia and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2021, 17, 569–580, doi:10.3762/bjoc.17.51

• -(allyldisulfanyl)propanoate (26) were observed. While the presence of 24 can be explained by the O-methylation of the DmdA product 37 with S-adenosylmethionine (SAM, Scheme 4E), compounds 25 and 26 require a second deallylation of 37 to 3-mercaptopropanoic acid (38) possibly by DmdA, the reaction with a

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

• these fluorometabolites, and was instrumental in the discovery of the very first fluorinase, which catalyses the production of 5’-fluoro-5’-deoxyadenosine (5-FDA) from fluoride ion and S-adenosylmethionine (SAM) [1]. While cumbersome as a tool for screening for new fluorometabolites in multiple strains

• an engineered E. coli, which, in addition to expressing the fluorinase, had its fluoride efflux protein, CrcB, deleted and a gene coding for a SAM transport protein heterologously expressed, to ensure an adequate supply of substrates [115]. Nucleocidin was famously isolated from S. calvus in the

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

• -University, Heinrich-Buff-Ring 26–32, 35392 Gießen, Germany Department for Bioresources of the Fraunhofer Institute for Molecular Biology and Applied Ecology, Ohlebergsweg 12, 35392 Gießen, Germany Faculty of Fisheries and Marine Science, Sam Ratulangi University, Jl. Kampus UNSRAT Bahu, 95115 Manado

• finally stored at the Sam Ratulangi University, Manado, Indonesia, in the Reference Collection under the numbers SRU2015/01 and SRU2016/02. A fraction of the sponge material is stored in the Bavarian State Collection for Paleontology and Geology under collection number SNSB-BSPG.GW41291. Extraction and

• Voogd, Steve C. de Cook, and Muhammad Abdul Wahab for discussions regarding the sponge identification. The organisms are listed in the collection event list of the Reference Collection of Sam Ratulangi University, Manado, Indonesia (SRU2015/01 SRU2016/02). Collection permits for all collected samples

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

• antipseudomonal activity. The biosynthetic pathway for argyrin production in Cystobacter sp. SBCb004 (Arg1, radical SAM-dependent methyltransferase; Arg2/Arg3, nonribosomal peptide synthetases; Arg4, O‑methyltransferase; Arg5, tryptophan 2,3-dioxygenase). The initial tripeptide of the biosynthesis of the argyrins

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

• corroborated by 3JHH vicinal coupling constant (JH4,H5 = 15.8 Hz). In fungi and certain kinds of bacteria, methyl substituents in the fatty acid carbon chain or the polyketide chain are derived from the methyl group of S-adenosylmethionine (SAM) (Figure 3A) [13][14]. This methylation reaction usually occurs at

• the nucleophilic carbons originated from the methyl carbon of acetate (C2) since SAM acts as an electrophilic methyl donor. In most of the bacteria including actinomycetes, methyl branching in polyketide chain is derived from methylmalonyl CoA, thereby the methylation position must be also the α

• methyl groups in dinoflagellate compounds are positioned at the carbons derived from the carbonyl carbon of acetate (C1). Precursor labeling studies indicated that the origin of the methyl carbon is not SAM but one carbon fragment derived from the cleavage of another acetate unit (Figure 3C) [15]. The

Norbornadiene-functionalized triazatriangulenium and trioxatriangulenium platforms

• Roland Löw,
• Talina Rusch,
• Tobias Moje,
• Fynn Röhricht,
• Olaf M. Magnussen and
• Rainer Herges

Beilstein J. Org. Chem. 2019, 15, 1815–1821, doi:10.3762/bjoc.15.175

• temperature (Figure 5a). The molecules form a hexagonally ordered self-assembled monolayer (SAM) with an intermolecular distance of (1.23 ± 0.07) nm. This is in agreement with a (√19 × √19) R23.4° superstructure, which was observed in our previous investigations of adlayers of octyl-TATA derivatives [1][6][19

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

• substrate 2-methyl-GPP to form 2-MIB (2) [25][26]. An S-adenosylmethionine (SAM) dependent methyl transferase is responsible for the methylation of GPP into 2-methyl-GPP (14, Scheme 2). Its isomerisation to 15 allows for a cyclisation via the cationic intermediates B and C to 2. Genes encoding for SAM

• -MIB (2). First, GPP is methylated to 14 by a SAM-dependent methyltransferase, followed by a terpene synthase catalysed cyclisation through a cationic cascade to 2. Oxidation products derived from 3 by the cytochrome P450 monooxygenase that is genetically clustered with the epi-isozizaene synthase in

Diaminoterephthalate–α-lipoic acid conjugates with fluorinated residues

• Leon Buschbeck,
• Aleksandra Markovic,
• Gunther Wittstock and
• Jens Christoffers

Beilstein J. Org. Chem. 2019, 15, 981–991, doi:10.3762/bjoc.15.96

• , target compound 3 has the highest (0.57), target compound 7 the lowest (0.04) quantum yield. XPS characterization of SAMs. SAMs were prepared from compounds 3 and 7 exploiting the strong binding affinity of the ALA residue to gold surfaces [52]. The resulting layers of compound 3 (SAM 3) and 7 (SAM 7

• ) were characterized by XPS of the C 1s, O 1s, S 2p, N 1s and F 1s emissions (Figure 2 for SAM 3, Figure 3 for SAM 7). The largest contributions of the C 1s spectra at 284.4 eV (SAM 3) and 284.7 eV (SAM 7) correspond to the carbon atoms of the alkyl chains, the aromatic ring and the carbon bound to

• sulfur atoms (Table 2). The peak at 285.5 eV (SAM 3 and SAM 7) corresponds to the carbon atoms with a higher binding energy due to the bond to one more electronegative atom (C−O and C−N) [53]. Figure 2 and Figure 3 show further C 1s peaks lying at binding energies of 288.5 eV, 290.6 eV, and 292.6 eV (SAM

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

• the acyl carrier protein (ACP) of an iterative fungal PKS, can be elongated with malonyl-SCoA (mal-SCoA) followed by C-methylation with S-adenosyl-L-methionine (SAM). Two more rounds of elongation with mal-SCoA, the first extension with C-methylation and action of a ketoreductase (KR), result in a

• tetraketide intermediate that can be cyclised by aldol condensation, followed by elimination of water to result in the aromatic ring system. Thioester hydrolysis and decarboxylation produce 29a that can be converted by SAM-dependent O-methylation into 24. In summary, this hypothetical biosynthetic mechanism

• includes three SAM-dependent methylation steps. A feeding experiment with (methyl-2H3)methionine, the biosynthetic precursor of SAM, resulted in the incorporation of labelling into up to three methyl groups of 24, but not into the fourth methyl group (Figure 5), which is in line with the biosynthetic model

Acyl-group specificity of AHL synthases involved in quorum-sensing in Roseobacter group bacteria

• Lisa Ziesche,
• Jan Rinkel,
• Jeroen S. Dickschat and
• Stefan Schulz

Beilstein J. Org. Chem. 2018, 14, 1309–1316, doi:10.3762/bjoc.14.112

• . gallaeciensis BS107 produced eight different AHLs [8]. The biosynthesis of AHLs is mediated by the enzyme LuxI or its homologs, and often accompanied by a regulator protein, LuxR [18][19]. An ACP-bound fatty acid acyl group 1 is transferred onto the amino group of S-adenosylmethionine (SAM, 2) that is followed

• expressed in E. coli to allow in vitro experiments with suitable acyl precursors to probe AHL formation. After protein purification of the AHL synthases and incubation with the precursors S-adenosyl methionine (SAM) and different acyl derivatives (free fatty acids, SNAC esters, PCEs) the AHL production was

• further purified by HPLC, the crude products proved to be pure enough for the next experiments. The incubation experiments were performed with the three recombinant AHL synthases, SAM, and the different precursors 10–13. The AHL-synthase PgaI2 of P. inhibens showed a higher activity compared to the two D

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

• an even number of carbons are much more widespread. Furthermore, esterification with S-adenosyl-l-methionine (SAM) by a methyltransferase is a very common process in nature, while ethyl esters are rarer and likely require a two-step pathway through reduction of acetyl-CoA to ethanol and its

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

• -SACP. This may be followed by SAM-dependent C-methylation by a methyl transferase domain (MT). The stereochemical course for this reaction can be inferred from the 4R-configuration of the final product 11a, if indeed an iterative PKS is involved that should have the same stereochemical course for the