Natural resorcylic lactones derived from alternariol

• Joachim Podlech

Beilstein J. Org. Chem. 2024, 20, 2171–2207, doi:10.3762/bjoc.20.187

2-Heteroarylethylamines in medicinal chemistry: a review of 2-phenethylamine satellite chemical space

• Carlos Nieto,
• Alejandro Manchado,
• Ángel García-González,
• David Díez and
• Narciso M. Garrido

Beilstein J. Org. Chem. 2024, 20, 1880–1893, doi:10.3762/bjoc.20.163

• decarboxylase (Scheme 8) [45][46][47]. Histamine is commonly degradated by two enzymes: diamine oxidase (DAO) to produce (imidazol-4-yl)acetic acid (44), or histamine N-methyltransferase (HMT) to N-methylhistamine 45. Monoamine oxidase B (MAO-B) transforms N-methylhistamine into (N-methylimidazol-4-yl)acetic

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

• . There are several options for chemical methylation (see text), but only one example is shown. Enzymatic synthesis is highlighted in red as this is the focus of this highlight. PURE = protein synthesis using recombinant elements, MT = methyltransferase. Biological methylation. A) Methyl donors from

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

• methyltransferase (IPPMT) from Streptomyces monomycini. Notably, polymethylated C41, C42, and C43 carotenoids were produced by combining the endogenous terpene biosynthesis pathway and IPPMT, demonstrating the potential of this approach to expand the terpene structural space [52]. In addition to methylation of the

• introducing a GPP C2-methyltransferase from Pseudanabaena limnetica to yeast together with an engineered C11-specific TS, 40 C11 terpene scaffolds were produced, which significantly increased the chemical space of terpenoids [54]. More recently, the GPP C6-methyltransferase BezA was discovered in Streptomyces

• 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

Substrate specificity of a ketosynthase domain involved in bacillaene biosynthesis

• Zhiyong Yin and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2024, 20, 734–740, doi:10.3762/bjoc.20.67

• -labelled carbons. Biosynthetic model for bacillaene (1). M1–M17 indicate modules 1–17. A = adenylation domain, ACP = acyl carrier protein, AT = acyltransferase, C = condensation domain, DH = dehydratase, KR = ketoreductase, KS = ketosynthase, MT = methyltransferase, PCP = peptidyl carrier protein, TE

Chemoenzymatic synthesis of macrocyclic peptides and polyketides via thioesterase-catalyzed macrocyclization

• Senze Qiao,
• Zhongyu Cheng and
• Fuzhuo Li

Beilstein J. Org. Chem. 2024, 20, 721–733, doi:10.3762/bjoc.20.66

• of monomers in the final product intimately correlates with the order of modules in the assembly line (Scheme 1a). Beyond several additional domains, including ketoreductase (KR), dehydratase (DH), enoyl reductase (ER), and methyltransferase (MT) domains and epimerase (E) domains, which are

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

• cyclases responsible for DMOA-derived compounds. To achieve this goal, we first aimed to establish a production system for the 4-desmethyl analogue of (6R,10′R)-epoxyfarnesyl-DMOA methyl ester by utilizing the polyketide synthase FncE, the prenyltransferase FncB, the O-methyltransferase InsA1, and the FAD

Chemical and biosynthetic potential of Penicillium shentong XL-F41

• Ran Zou,
• Xin Li,
• Xiaochen Chen,
• Yue-Wei Guo and
• Baofu Xu

Beilstein J. Org. Chem. 2024, 20, 597–606, doi:10.3762/bjoc.20.52

• activate the BGCs of this strain, we employed a combination of elicitors in our fermentation media, including histone deacetylase inhibitors and DNA methyltransferase inhibitors. We developed two specialized media, XISR I and XISR III, which outperformed the traditional potato dextrose broth (PDB) in

• cytochrome P450, pyridoxal-dependent decarboxylase, glutamine synthase, and tryptophan dimethyltransferase (Figure 5). These genes are likely crucial for the biosynthesis of the newly isolated alkaloids, 1 and 2. In examining the XL-F41 genome for methyltransferase domain-containing BGCs, we found a

• methyltransferase near BGC 7.3, suggesting its involvement in adding a methoxy group at the C16 position of compound 1. From these key enzyme genes, we propose a hypothetical biosynthetic pathway (Figure 5). Compounds 1 and 2 are hypothesized to be synthesized from a tryptophan precursor via a shared biosynthetic

A myo-inositol dehydrogenase involved in aminocyclitol biosynthesis of hygromycin A

• Michael O. Akintubosun and
• Melanie A. Higgins

Beilstein J. Org. Chem. 2024, 20, 589–596, doi:10.3762/bjoc.20.51

• dehydrogenase Hyg17 to form neo-inosose, followed by a transamination to neo-inosamine-2 by the aminotransferase Hyg8. The methyltransferase Hyg6 would then install a methyl group which would set up cyclization of the methylenedioxy group by Hyg7. This biosynthetic pathway has been proposed based on gene

Recent developments in the engineered biosynthesis of fungal meroterpenoids

• Zhiyang Quan and
• Takayoshi Awakawa

Beilstein J. Org. Chem. 2024, 20, 578–588, doi:10.3762/bjoc.20.50

• metabolic genes for ease of gene transfer and high substance production capabilities [10][11]. The expression of trt4 (polyketide synthase, PKS), trt2 (prenyltransferase, PT), trt5 (methyltransferase, MT), trt8 (flavin-dependent monooxygenase, FMO), and trt1 (meroterpenoid cyclase, CYC) in A. oryzae NSAR1

• ) were expressed in A. oryzae to produce the intermediate 15. Next, genes encoding a short-chain oxidoreductase (SDR), methyltransferase (MT), cytochrome P450 oxygenase (P450), and FMO from various fungi were additionally expressed in A. oryzae expessing subABCDE to produce 22 bioactive meroterpenoids

Discovery of unguisin J, a new cyclic peptide from Aspergillus heteromorphus CBS 117.55, and phylogeny-based bioinformatic analysis of UngA NRPS domains

• Sharmila Neupane,
• Marcelo Rodrigues de Amorim and
• Elizabeth Skellam

Beilstein J. Org. Chem. 2024, 20, 321–330, doi:10.3762/bjoc.20.32

• bond formation. Additional common domains include epimerization (E) domains for converting naturally occurring ʟ-amino acids to ᴅ-amino acids, methyltransferase (MT) domains that typically methylate specific N atoms, and terminal condensation (CT) domains which cyclize the growing peptide chain and

• analyzed by LC–MS for comparison of the retention times. Structures of unguisins. Chemical structures of unguisin J (1) and unguisin B (2). Key gHMBC and gCOSY correlations, and NOESY interactions of 1. Clinker analysis of identified unguisin-encoding BGCs. UngE’ is a methyltransferase that methylates

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

• by two sequential cyclisation reactions to A and B, and terminal quenching with water. This hypothesis was confirmed by the discovery of the biosynthetic genes coding for a GPP methyltransferase (GPPMT) and a type I terpene synthase termed 2-methylisoborneol synthase (2MIBS) [23][24]. Interestingly

• , the pathway to 1 can be reconstituted in vitro using the methyltransferase humMT from Micromonospora humi for the methylation of dimethylallyl diphosphate (DMAPP) to 2-methylisopentenyl diphosphate (2-Me-IPP) [25], followed by coupling with DMAPP to 2-Me-GPP and terpene cyclisation using farnesyl

Intermediates and shunt products of massiliachelin biosynthesis in Massilia sp. NR 4-1

• Till Steinmetz,
• Blaise Kimbadi Lombe and
• Markus Nett

Beilstein J. Org. Chem. 2023, 19, 909–917, doi:10.3762/bjoc.19.69

• protein RS02200: FAAL: fatty acyl-AMP ligase; ACP: acyl carrier protein; KS: β-ketoacyl synthase; AT: acyltransferase; KR: ketoreductase; C: condensation; A: adenylation; MT: methyltransferase; PCP: peptidyl carrier protein. A discrete enzyme, the thiazolinyl imide reductase RS02195 (Red), catalyzes the

A Streptomyces P450 enzyme dimerizes isoflavones from plants

• Run-Zhou Liu,
• Shanchong Chen and
• Lihan Zhang

Beilstein J. Org. Chem. 2022, 18, 1107–1115, doi:10.3762/bjoc.18.113

• coclaurine [28]. The absence of the product 1 in vitro is reasonable because the biosynthesis of 1 requires an additional methyltransferase from S. cattleya for the methoxy group formation. Substrate scope and reaction mechanism After identification of CYP158C1 as the isoflavone dimerization enzyme, we next

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

• of their biosynthetic mechanisms. Keywords: biosynthesis; methyltransferase; natural azoxides; reactivity-based screening; Streptomyces; Introduction Azoxy natural products are a rare yet intriguing class of natural products with various beneficial biological properties, such as antibacterial

• 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

The stereochemical course of 2-methylisoborneol biosynthesis

• Binbin Gu,
• Anwei Hou and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2022, 18, 818–824, doi:10.3762/bjoc.18.82

• processing through (R)-2-Me-LPP [23]. The GPP methyltransferase (GPPMT) and the 2-methylisoborneol synthase (2MIBS) and their coding genes were discovered and functionally characterized, giving further evidence for the biosynthetic pathway to compound 1 [23][24][25]. As we have recently demonstrated, the

• biosynthesis of 1 can also be reconstituted in vitro through coupling of dimethylallyl diphosphate (DMAPP) with 2-methyl-IPP (2-Me-IPP; IPP = isopentenyl diphosphate) to 2-Me-GPP using farnesyl diphosphate synthase (FPPS), followed by cyclization through 2MIBS to 1 [26]. A recently described methyltransferase

• from Micromonospora humi can convert DMAPP into (R)-2-Me-IPP with a methyltransferase [27], naturally providing the C6 building block for this hypothetical alternative pathway towards 1 (Scheme 1B). Today the genomes of many bacteria from the genus Streptomyces have been made available, showing that

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

Chemical approaches to discover the full potential of peptide nucleic acids in biomedical applications

• Nikita Brodyagin,
• Martins Katkevics,
• Venubabu Kotikam,
• Christopher A. Ryan and
• Eriks Rozners

Beilstein J. Org. Chem. 2021, 17, 1641–1688, doi:10.3762/bjoc.17.116

4-Hydroxy-3-methyl-2(1H)-quinolone, originally discovered from a Brassicaceae plant, produced by a soil bacterium of the genus Burkholderia sp.: determination of a preferred tautomer and antioxidant activity

• Dandan Li,
• Naoya Oku,
• Yukiko Shinozaki,
• Yoichi Kurokawa and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2020, 16, 1489–1494, doi:10.3762/bjoc.16.124

• methyltransferase [27]. Entry of malonate as the acylate precursor into this pathway is proposed to yield 3 (4 in the original literature) [29]. Thus, 1 is very likely to be biosynthesized by the same mechanism followed by additional methylation on C3. Compound 1 is reportedly inhibitory to Mycobacterium

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

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

• sodorifen [58] biosynthesis for example, require the action of a methyltransferase preceding cyclization. Surprisingly, more and more terpene BGCs are characterized that do not harbor classical TCs, but instead use a variety of different enzyme classes for the cyclization reaction. These atypical terpene

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

• methyltransferase, followed by 1,2-hydride shift and deprotonation, and a subsequent reduction of the exo-methylene intermediate gives rise to a methyl group (Scheme 2) [18]. The presence of the exo-methylene intermediate was experimentally proved but the enzyme responsible for the double bond reduction has not

A review of the total syntheses of triptolide

• Xiang Zhang,
• Zaozao Xiao and
• Hongtao Xu

Beilstein J. Org. Chem. 2019, 15, 1984–1995, doi:10.3762/bjoc.15.194

• pathways involved in the regulation of reactive oxygen species (ROS) and/or nitric oxide (NO) [9], histone methyltransferase [10], HSP70 [11], Jak2, Bcl-2/Bax [12], caspase 8 [13], NF-κB [14], X-linked inhibitor of apoptosis protein (XIAP) [15], MAPK, PI3K [16], and MPK1, ERK-1/2, and JNK-1/2 [17]. The

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

• bioinformatics as well as spectroscopy. First, we analyzed whether the isolated natural product possesses a D- or L-configured thiazoline ring. Previous studies had revealed that the D-thiazoline ring in pyochelin is due to an unusual methyltransferase-like epimerization domain in the biosynthesis protein PchE

• , fatty acyl-AMP ligase; ACP, acyl carrier protein; KS, β-ketoacyl synthase; AT, acyltransferase; KR, ketoreductase; C, condensation; A, adenylation; MT, methyltransferase; PCP, peptidyl carrier protein; TE, thioesterase. The asterisk indicates a methyltransferase-like epimerization domain. C) UV