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

• insights into the distribution and diversity of the biosynthetic gene clusters of aliphatic azoxy natural products, we searched for a pair of VlmA and VlmH, two key enzymes in the azoxy bond formation, encoded in close genetic loci in the reference genome of 3,146 actinobacteria in the NCBI database. A

• gene clusters from each group indicated that several protein families are frequently observed in the genome neighborhoods of specific “VlmA” groups, such as Ady1-like methyltransferases (PF04072), homologous pairs of VlmJ/VlmK-like exo-olefin-forming enzymes (PF19279/PF03972), seryl-tRNA synthetases

• (PF02403), putative Trp halogenase-like enzymes (PF04820), and putative 3-oxoacyl-[acyl-carrier-protein (ACP)] synthase III-like enzymes (PF08541) (Figures S7 and S8 in Supporting Information File 1). The various protein families encoded in the proximity of the “VlmA'' gene suggest the manifold

Understanding the competing pathways leading to hydropyrene and isoelisabethatriene

• Shani Zev,
• Marion Ringel,
• Ronja Driller,
• Bernhard Loll,
• Thomas Brück and
• Dan T. Major

Beilstein J. Org. Chem. 2022, 18, 972–978, doi:10.3762/bjoc.18.97

• and downstream functionalizing enzymes, like P450s, together produce more than 80,000 known terpenes and terpenoids [1][2][3]. Hydropyrene synthase (HpS) from Streptomyces clavuligerus generates a mixture of diterpenes named hydropyrene (HP) (52%) and diterpenoid named hydropyrenol (HPol) (26%) as its

• ) proceed from the same substrate (GGPP) with an initial C1–C10 cyclization. In other TPS enzymes, the initial fold of GGPP in the active site can result in different initial cyclization, for example C1–C6, C1–C7, C1–C10, C1–C11, C1–C14, and C1–C15. The main difference between the two pathways to HP and IE

• proceed until completion along their respective pathways. Hence, the difference in the product profile in WT and enzyme variants may be largely due to different folding of the initial substrate. Future in-enzyme studies can shed light on the preferred folding of GGDP inside the WT and variant enzymes and

Anti-inflammatory aromadendrane- and cadinane-type sesquiterpenoids from the South China Sea sponge Acanthella cavernosa

• Shou-Mao Shen,
• Qing Yang,
• Yi Zang,
• Jia Li,
• Xueting Liu and
• Yue-Wei Guo

Beilstein J. Org. Chem. 2022, 18, 916–925, doi:10.3762/bjoc.18.91

• ). Different enantiomeric ratios could explain the properties of the active sites in the corresponding terpene synthases, which remain unclear for further investigations [22]. The diversified structures of terpenes were constructed by terpene synthase [26] along with the post-modification enzymes, such as P450

• enzymes and other oxygenases [27]. The plausible biosynthetic pathways of the isolated sesquiterpenoids 1–7 were proposed, as shown in Scheme 1. Aromadendrane- [(+)-1 and 2], aristolane- (3) and candinane-type sesquiterpenes [(+)-4/(−)-4, (+)-5/(−)-5, 6 and 7)] were all originated from E,E-farnesyl

• yet been discovered. Phenolic sesquiterpenoids, for instance, illudacetalic acid and illudinine from Omphalotus olearius, were also discovered. Based on bioinformatics analysis, their aromatic rings were proposed to be constructed by putative P450 enzymes or oxidoreductase [33]. The Huang group

Efficient production of clerodane and ent-kaurane diterpenes through truncated artificial pathways in Escherichia coli

• Fang-Ru Li,
• Xiaoxu Lin,
• Qian Yang,
• Ning-Hua Tan and
• Liao-Bin Dong

Beilstein J. Org. Chem. 2022, 18, 881–888, doi:10.3762/bjoc.18.89

• cyclase) act on geranylgeranyl diphosphate (GGDP) to perform regio- and stereoselective cyclizations or skeleton rearrangement reactions via carbocation chemistry to form diverse and versatile carbon skeletons; and ii) multiple post-modification enzymes, most often cytochrome P450s, decorate the carbon

• mitigate pressures on gatekeeper enzymes [15][16][17][18]. However, these systems are still dependent on the entry points within the MVA or MEP pathways [17][18]. Recently, the Stephanopoulos and Williams groups reported two-step artificial pathways to efficiently produce isoprenoid precursors IPP and

Synthesis of odorants in flow and their applications in perfumery

• Merlin Kleoff,
• Paul Kiler and
• Philipp Heretsch

Beilstein J. Org. Chem. 2022, 18, 754–768, doi:10.3762/bjoc.18.76

• min isoamyl acetate (10) is obtained in 59% yield according to GC analysis [26]. Related methods for the enzyme-catalyzed acetylation of isoamyl alcohol (9) have been developed utilizing biphasic systems, supercritical carbon dioxide as a solvent, or packed-bed reactors with immobilized enzymes [27

Identification of the new prenyltransferase Ubi-297 from marine bacteria and elucidation of its substrate specificity

• Jamshid Amiri Moghaddam,
• Huijuan Guo,
• Karsten Willing,
• Thomas Wichard and
• Christine Beemelmanns

Beilstein J. Org. Chem. 2022, 18, 722–731, doi:10.3762/bjoc.18.72

• cyanobacteria (Figure 3) [27]. The gene sequence eboA-E encodes five yet uncharacterized enzymes, including EboA, a putative metallo-dependent hydrolase TatD (EboB), a putative UbiA prenyltransferase (EboC), a putative 3-dehydroquinate synthase (EboD) likely catalyzing the second step in the shikimate pathway

• prenyltransferase enzymes [33]. The Asp-rich motif of G2-Ptases, known to coordinate Mg2+ ions and pyrophosphate, was detectable in all homologous sequences retrieved from marine Flavobacteria and Saccharomonospora genomes and was similar to the DXXDXXXD motif in E. coli UbiA, but distinct from the motif of other

• and amplified sequences were then cloned into an expression pET28 plasmid containing an N-terminal 6-histidine tag sequence. Heterologous production of enzymes was achieved in E. coli BL21 and western blot analysis indicated the accumulation of His-tagged UbiA-297 (35 kD) within concentrated cell

Structural basis for endoperoxide-forming oxygenases

• Takahiro Mori and
• Ikuro Abe

Beilstein J. Org. Chem. 2022, 18, 707–721, doi:10.3762/bjoc.18.71

• photosensitizers or visible light, non-enzymatically reacts with the biosynthetic intermediates to produce endoperoxide structures [16][22][23]. However, over the past three decades, only a few endoperoxide-forming enzymes have been identified, including the cyclooxygenases in the biosynthesis of prostaglandins

• ][16], the details of the complex biosynthetic enzymes producing these compounds have remained enigmatic. Therefore, this review will focus on the enzymatic synthesis of endoperoxide natural products, by summarizing the recent structural and mechanistic analyses of endoperoxide formation reactions by

• reduced to produce PGH2. PGH2 is metabolized by downstream enzymes to yield a series of prostaglandins, which play important roles in inflammatory responses [35][36][37]. Although the active site architectures of COX-1 and COX-2 are not completely identical, the reaction mechanisms and catalytic residues

Heteroleptic metallosupramolecular aggregates/complexation for supramolecular catalysis

• Prodip Howlader and
• Michael Schmittel

Beilstein J. Org. Chem. 2022, 18, 597–630, doi:10.3762/bjoc.18.62

• ], Fujita [56], and others [57] have reported several template-free assemblies giving access to novel structures. The primary objective of these nanovessels as supramolecular catalysts is to encapsulate organic reactant/s to lower the activation barrier, thereby mimicking the functions of enzymes (without

• the years [15][16][17][18][19][20][21][22] a more accurate understanding of the self-assembly of diverse components and the development of functionally integrated smart architectures for catalysis as “artificial enzymes” certainly demands further attention. Enticed by this idea, Mukherjee and co

Shift of the reaction equilibrium at high pressure in the continuous synthesis of neuraminic acid

• Jannis A. Reich,
• Miriam Aßmann,
• Kristin Hölting,
• Paul Bubenheim,
• Jürgen Kuballa and
• Andreas Liese

Beilstein J. Org. Chem. 2022, 18, 567–579, doi:10.3762/bjoc.18.59

• reasons, the synthesis of N-acetylneuraminic acid (Neu5Ac) in a continuous fixed-bed reactor by an immobilized epimerase and aldolase was investigated in detail. The immobilized enzymes showed high stability, with half-life times > 173 days under storage conditions (6 °C in buffer) and reusability over 50

• particular, the circular reactor showed great potential to study reactions at high pressure while allowing for easy sampling. Additionally, an increase in affinity of pyruvate towards both tested enzymes was observed when high pressure was applied, as evidenced by a decrease of KI for the epimerase and KM

• derivatives from Neu5Ac can inhibit viral enzymes [3]. Neu5Ac and its production have been described over the past three decades [4], however, no major breakthrough in its synthesis has been achieved so far [5]. Additionally, some reports underline the importance of sialic acids (rather than Neu5Ac in

Menadione: a platform and a target to valuable compounds synthesis

• Acácio S. de Souza,
• Ruan Carlos B. Ribeiro,
• Dora C. S. Costa,
• Fernanda P. Pauli,
• David R. Pinho,
• Matheus G. de Moraes,
• Fernando de C. da Silva,
• Luana da S. M. Forezi and
• Vitor F. Ferreira

Beilstein J. Org. Chem. 2022, 18, 381–419, doi:10.3762/bjoc.18.43

• (DNA and RNA), enzymes, structural proteins, and cell membrane lipids. These effects can lead to dysfunctions that activate the apoptosis process resulting in cell death [42][43][44][45][46]. In addition to participating in redox cycles as biomolecules in various biochemical processes, the 1,4

A resorcin[4]arene hexameric capsule as a supramolecular catalyst in elimination and isomerization reactions

• Tommaso Lorenzetto,
• Fabrizio Fabris and
• Alessandro Scarso

Beilstein J. Org. Chem. 2022, 18, 337–349, doi:10.3762/bjoc.18.38

• hexameric capsule 16 acts mimicking enzymes by combination of the activation of substrates by protonation, stabilization of cationic intermediate species with consequent acceleration of its conversion and selective product formation thanks to weak intermolecular interactions between the cationic

Site-selective reactions mediated by molecular containers

• Rui Wang and
• Yang Yu

Beilstein J. Org. Chem. 2022, 18, 309–324, doi:10.3762/bjoc.18.35

• mimicking the recognition and catalysis behavior of enzymes with designed and synthesized molecular containers such as cyclodextrins, cucurbiturils, calixarenes, and resorcinarenes, chemists try to tackle problems of traditional synthetic chemistry, including increase in reactivity, induction of selectivity

• mixture was formed without the O-coupled 1,4-adduct 15. This indicated that the molecular container A favored the O-coupling pathway while suppressed others. This work showed the powerful site-selective control ability of molecular containers, which was normally only observed in natural enzymes. Reduction

• functionalization of C–H bonds brings reaction economy and effectiveness. However, owing to the rifeness of the reactivity-similar C–H bonds, it is hard to achieve discriminate control over the product site-selectivity. In nature, the site-selective oxidation of C–H bonds is facilitated by enzymes with the donor

New advances in asymmetric organocatalysis

• Radovan Šebesta

Beilstein J. Org. Chem. 2022, 18, 240–242, doi:10.3762/bjoc.18.28

• undoubtedly the most efficient way to prepare chiral compounds that our society requires as medicines, materials, or crop protecting agents. Traditionally, enzymes and metal complexes with chiral ligands served as the main type of enantioselective catalysts. Even though small chiral organic compounds have

Anomeric 1,2,3-triazole-linked sialic acid derivatives show selective inhibition towards a bacterial neuraminidase over a trypanosome trans-sialidase

• Peterson de Andrade,
• Sanaz Ahmadipour and
• Robert A. Field

Beilstein J. Org. Chem. 2022, 18, 208–216, doi:10.3762/bjoc.18.24

• differentiate both enzymes. Moreover, such selectivity might be reasoned based on a possible steric hindrance caused by a bulky hydrophobic loop that sits over the TcTS active site and may prevent the hydrophobic inhibitors from binding. The present study is a step forward in exploiting subtle structural

• both enzymes (Figure 3A) (and TcTS transferase activity in the presence of an acceptor substrate, such as lactose – Figure 3B) by releasing the fluorophore 4-methylumbelliferone (MU) for detection upon cleavage of the substrate 2'-(4-methylumbelliferyl) α-ᴅ-N-acetylneuraminic acid (MUNANA). Compounds

• of both enzymes in complex with DANA reveals a bulky hydrophobic loop that sits over the active site of TcTS (PDB code 1MS1 – coloured red) (Figure 5A) but is absent for neuraminidase (PDB code 2VK6 – coloured green) (Figure 5B). In this case, induced structural rearrangements caused DANA to be

Synthesis and late stage modifications of Cyl derivatives

• Phil Servatius and
• Uli Kazmaier

Beilstein J. Org. Chem. 2022, 18, 174–181, doi:10.3762/bjoc.18.19

• histones [6][7][8][9][10]. Blockade of the deacylating process causes hyperacetylation of histones and unregulated gene activity, that results in untimely cell death. Eighteen different HDAC enzymes are known so far and they are divided into four classes based on structural homology with yeast proteins [11

• ]. Three of these enzyme classes (I, II, and IV) contain Zn2+ within the active site, and therefore these enzymes can be affected by typical Zn2+-binding HDAC inhibitors. In cellular systems, an acetylated lysine of a histone is entering the cavity of the active site and gets coordinated to Zn2

Ready access to 7,8-dihydroindolo[2,3-d][1]benzazepine-6(5H)-one scaffold and analogues via early-stage Fischer ring-closure reaction

• Irina Kuznetcova,
• Felix Bacher,
• Daniel Vegh,
• Hsiang-Yu Chuang and
• Vladimir B. Arion

Beilstein J. Org. Chem. 2022, 18, 143–151, doi:10.3762/bjoc.18.15

• particular enzymes. Preliminary results indicate that scaffold C shows good affinity to proto-oncogene tyrosine-protein kinase Src, a well-known anticancer target [47], with IC50 = 0.26 µM and is a suitable candidate for further structural optimization. Paullone related indolobenzazepinone isomers. 7,12

1,2-Naphthoquinone-4-sulfonic acid salts in organic synthesis

• Ruan Carlos B. Ribeiro,
• Patricia G. Ferreira,
• Amanda de A. Borges,
• Luana da S. M. Forezi,
• Fernando de Carvalho da Silva and
• Vitor F. Ferreira

Beilstein J. Org. Chem. 2022, 18, 53–69, doi:10.3762/bjoc.18.5

• cause several damages to its components, such as carbohydrates, lipids, membrane components, and enzymes that are critical for DNA replication [9][10][11][12]. Most synthetic strategies toward naphthoquinones with potential biological activity start from natural and synthetic naphthoquinones, inserting

Synthetic strategies toward 1,3-oxathiolane nucleoside analogues

• Umesh P. Aher,
• Dhananjai Srivastava,
• Girij P. Singh and
• Jayashree B. S

Beilstein J. Org. Chem. 2021, 17, 2680–2715, doi:10.3762/bjoc.17.182

• -oxathiolane nucleosides via resolution methods. The chemical as well as enzymatic procedures are reviewed and segregated in this review for effective synthesis of 1,3-oxathiolane nucleoside analogues. Keywords: chiral auxiliaries; enzymes; Lewis acids; N-glycosylation; 1,3-oxathiolane sugar and nucleosides

• natural nucleosides with β-ᴅ-configuration in the carbohydrate part. These molecules are known to have a common HIV transcriptase inhibition mechanism, in which cytoplasmic enzymes progressively phosphorylate the analogues to 5'-triphosphates. This then competes with the naturally occurring nucleoside

• triphosphate substrate to bind to cellular DNA polymerase and viral reverse transcriptase [9]. The effectiveness of nucleoside analogues depends on the ability to replicate naturally occurring nucleosides, interfering with viral as well as cellular enzymes and hampering essential metabolism processes of

α-Ketol and α-iminol rearrangements in synthetic organic and biosynthetic reactions

• Scott Benz and
• Andrew S. Murkin

Beilstein J. Org. Chem. 2021, 17, 2570–2584, doi:10.3762/bjoc.17.172

• reactions nevertheless accomplishes the same goal of connecting two carbon-skeleton alterations conveniently in one pot with a combined yield of 45%. α-Ketol rearrangements in biosynthetic reactions At the time of this review, only two enzymes have been identified that catalyze an α-ketol rearrangement as

• the only identified enzymes that catalyze α-ketol rearrangements so far, there is little doubt additional examples are to be discovered. The remainder of this section provides cases of biological pathways and reactions that have been hypothesized to involve α-ketol rearrangements. In a study proposing

• continued development in these areas can be expected in the coming years. It is becoming apparent that nature also utilizes these rearrangements in natural product biosynthesis, and one might expect to see an increase in the discovery of enzymes governing these reactions. Generalized α-ketol or α-iminol

Cryogels: recent applications in 3D-bioprinting, injectable cryogels, drug delivery, and wound healing

• Luke O. Jones,
• Leah Williams,
• Tasmin Boam,
• Martin Kalmet,
• Chidubem Oguike and
• Fiona L. Hatton

Beilstein J. Org. Chem. 2021, 17, 2553–2569, doi:10.3762/bjoc.17.171

• explored [43], as within the colon are many polysaccharides and a large number of bacteria which secrete enzymes [41]. Within this work, varying the concentration of various pH-sensitive polymers was considered in terms of swelling, and it was shown that abrupt changes in swelling could be obtained at a

Synthesis and investigation on optical and electrochemical properties of 2,4-diaryl-9-chloro-5,6,7,8-tetrahydroacridines

• Najeh Tka,
• Mohamed Adnene Hadj Ayed,
• Mourad Ben Braiek,
• Mahjoub Jabli and
• Peter Langer

Beilstein J. Org. Chem. 2021, 17, 2450–2461, doi:10.3762/bjoc.17.162

• their partially hydrogenated analogues, even though they were used as electron-donor groups for OLED applications [42][43]. On the other hand, tetrahydroacridines have received much attention in medicinal chemistry, due to their ability to inhibit topoisomerase enzymes and block the DNA transcription

Targeting active site residues and structural anchoring positions in terpene synthases

• Anwei Hou and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2021, 17, 2441–2449, doi:10.3762/bjoc.17.161

• motifs (Supporting Information File 1, Figure S1), composed in bacterial and non-plant eukaryotic enzymes of the aspartate-rich motif DDXX(X)D around position 90 and the NSE triad ND(L,I,V)XSXX(K,R)E near position 230 (Figure 1) [9]. While the amino acid sequences of two TPSs can strongly deviate, their

Post-functionalization of drug-loaded nanoparticles prepared by polymerization-induced self-assembly (PISA) with mitochondria targeting ligands

• Janina-Miriam Noy,
• Fan Chen and
• Martina Stenzel

Beilstein J. Org. Chem. 2021, 17, 2302–2314, doi:10.3762/bjoc.17.148

• proteins, enzymes and receptors bind to As(III) molecules [8][9]. It is on the other hand interesting that the zwitterionic micelles represent overall better anticancer efficiency when TPP is attached, while the PEG micelle performance is better without added TPP. The PPM-NP4-TPP micelle represents more

Halides as versatile anions in asymmetric anion-binding organocatalysis

• Lukas Schifferer,
• Martin Stinglhamer,
• Kirandeep Kaur and
• Olga García Macheño

Beilstein J. Org. Chem. 2021, 17, 2270–2286, doi:10.3762/bjoc.17.145

• halogens are often regarded as surrogates for further functionalization, their role in natural and physiological processes is much more diverse. One of these processes is the ability of large complex molecules and enzymes to recognize halide anions via hydrogen bonds in aqueous media [5]. Amongst others

• challenging to design small molecule catalysts that resemble anion-binding properties of enzymes. Hence, a major challenge of small organic receptors to mimic nature’s capability of binding to the targeted anions resides in the supramolecular properties of enzymes and co-factors to form exact matching binding

• targeting of the small receptor molecule and, thus, reducing the need for complexity compared to enzymes or co-factors. Conversely, a multitude of geometries may need to be considered for anions with linear, coplanar, trigonal or tetrahedral topologies (Figure 1b) [5][10]. However, following the advances in

Constrained thermoresponsive polymers – new insights into fundamentals and applications

• Patricia Flemming,
• Alexander S. Münch,
• Andreas Fery and
• Petra Uhlmann

Beilstein J. Org. Chem. 2021, 17, 2123–2163, doi:10.3762/bjoc.17.138

• ., bacteria, biomolecules [15], enzymes [16]) or physical stimuli (e.g., light [17][18][19], temperature [12][18], mechanical forces, as well as electric [20][21] and magnetic fields [22][23][24]) [1][25][26]. As a result of these environmental triggers, smart materials exhibit a defined reversible change in