Discovery and biosynthesis of bacterial drimane-type sesquiterpenoids from Streptomyces clavuligerus

• Dongxu Zhang,
• Wenyu Du,
• Xingming Pan,
• Xiaoxu Lin,
• Fang-Ru Li,
• Qingling Wang,
• Qian Yang,
• Hui-Min Xu and
• Liao-Bin Dong

Beilstein J. Org. Chem. 2024, 20, 815–822, doi:10.3762/bjoc.20.73

• positions of the A ring of drimenol by heterologous expression and gene knockout. Furthermore, we tested the substrate promiscuity of CavA with drimenol analogs. CavA exhibited the ability to accept albicanol (5) and drim-8-ene-11-ol (6) as substrates, leading to the formation of the hydroxylated

• to note that CavA exhibits limited substrate promiscuity, predominantly targeting the drimenol skeleton with minor variations. This selectivity may be attributed to the structural configuration of the enzyme, which appears to be finely tuned to recognize and interact with specific features of the

Research progress on the pharmacological activity, biosynthetic pathways, and biosynthesis of crocins

• Zhongwei Hua,
• Nan Liu and
• Xiaohui Yan

Beilstein J. Org. Chem. 2024, 20, 741–752, doi:10.3762/bjoc.20.68

• , and UGTs are the key players in crocin biosynthesis. Empowered by the genomic, transcriptomic, and metabolomic analysis and biochemical characterization, many such enzymes have been identified. Some proteins, exemplified by GjCCD4a and GjUGT94E13, exhibit broad substrate promiscuity and high catalytic

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

• macrocyclizations (Scheme 1c). NAC thioester and other related mimics (such as coenzyme A (CoA), phosphopantetheine, and thiophenol) span the gap between the chemical synthesis and biosynthesis languages and expand the substrate promiscuity of TE domains. This bridge makes the in vitro TE-catalyzed macrocyclization

Synthesis of C6-modified mannose 1-phosphates and evaluation of derived sugar nucleotides against GDP-mannose dehydrogenase

• Sanaz Ahmadipour,
• Alice J. C. Wahart,
• Jonathan P. Dolan,
• Laura Beswick,
• Chris S. Hawes,
• Robert A. Field and
• Gavin J. Miller

Beilstein J. Org. Chem. 2022, 18, 1379–1384, doi:10.3762/bjoc.18.142

• sugar nucleotides To evaluate pyrophosphorylative coupling using the C6-modified mannose 1-phosphates we selected the recombinant GDP-mannose pyrophosphorylase (GDP-Man PP) from Salmonella enterica, previously established to have a broad promiscuity for GDP-Man synthesis [4][6][15]. Glycosyl 1

• ). Conclusion We have developed a synthetic approach to a small series of C6-modified mannose 1-phosphates (6-amino, 6-chloro and 6-thio) and with these tools further explored the substrate promiscuity of the mannose pyrophosphorylase from S. enterica, observing that larger (than canonical OH) chlorine is

Cytochrome P450 monooxygenase-mediated tailoring of triterpenoids and steroids in plants

• Karan Malhotra and
• Jakob Franke

Beilstein J. Org. Chem. 2022, 18, 1289–1310, doi:10.3762/bjoc.18.135

• promiscuity which facilitates duplication events resulting in neofunctionalisation [15]. Ellarinacin (15) is a defence-related arborinane-type triterpenoid that was recently discovered in bread wheat (Triticum aestivum) by genome mining (Figure 6B) [26]. The ellarinacin gene cluster encodes the three CYP

• classes in plants, we expect that this number will rise quickly in years to come. Several of our examples highlight the substrate promiscuity embedded within ancient CYP families, which enables rapid functional extension to acquire unique catalytic functions during duplication events [15][26][79]. The

Me₃Al-mediated domino nucleophilic addition/intramolecular cyclisation of 2-(2-oxo-2-phenylethyl)benzonitriles with amines; a convenient approach for the synthesis of substituted 1-aminoisoquinolines

• Krishna M. S. Adusumalli,
• Lakshmi N. S. Konidena,
• Hima B. Gandham,
• Krishnaiah Kumari,
• Krishna R. Valluru,
• Satya K. R. Nidasanametla,
• Venkateswara R. Battula and
• Hari K. Namballa

Beilstein J. Org. Chem. 2021, 17, 2765–2772, doi:10.3762/bjoc.17.186

• ] receptors. They are useful in the synthesis of phosphorescent materials [22][23][24], fluorosensors [25]. and also found as chiral ligands in a variety of transition metal catalysts [26][27][28][29][30]. Given the pharmacological promiscuity of this scaffold, extensive efforts from different groups led to

Fabclavine diversity in Xenorhabdus bacteria

• Sebastian L. Wenski,
• Harun Cimen,
• Natalie Berghaus,
• Sebastian W. Fuchs,
• Selcuk Hazir and
• Helge B. Bode

Beilstein J. Org. Chem. 2020, 16, 956–965, doi:10.3762/bjoc.16.84

• further structural elements, such as C-domains for the amino acid specificity [29][30]. However, an A-domain promiscuity is common in NRPS, exemplified by the biosynthesis of microcystins from cyanobacteria, RXPs or xenematide from Xenorhabdus and Photorhabdus [31][32][33]. The second strategy includes

• the anterior midgut of larvae [43]. Consequently, this mode of action could also be possible for fabclavines. Conclusion This study revealed a large chemical diversity for fabclavine derivatives among different Xenorhabdus strains, which is achieved by the promiscuity of single enzymes or domains

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

• functional promiscuity of terpene biosynthetic pathways renders terpene biosynthesis susceptible to rational pathway engineering using the latest developments in the field of synthetic biology. These engineered pathways will not only facilitate the rational creation of both known and novel terpenoids, their

• along with a large suite of related molecules, the taxanes [17]. This pathway promiscuity can be illustrated with another popular example of a terpene family: the cannabinoids, with more than 100 members used for both medical and recreational purposes. While its most prominent member (−)-trans-Δ

• bioactivities [24][25]. Modifying the cannabinoid profile through engineering would therefore be of significant interest. The biosynthetic promiscuity, the hallmark of terpene biosynthesis, sets terpenes apart from other natural product classes and is a product of their distinctive biosynthetic logic

Facile regiodivergent synthesis of spiro pyrrole-substituted pseudothiohydantoins and thiohydantoins via reaction of [e]-fused 1H-pyrrole-2,3-diones with thiourea

• Aleksandr I. Kobelev,
• Nikita A. Tretyakov,
• Ekaterina E. Stepanova,
• Maksim V. Dmitriev,
• Michael Rubin and
• Andrey N. Maslivets

Beilstein J. Org. Chem. 2019, 15, 2864–2871, doi:10.3762/bjoc.15.280

• heterocycles are relatively new and insufficiently investigated structures in medicinal chemistry [17][18]. The introduction of spiro-fused cyclic moieties in small molecules increases the degree of their structural (shape) complexity, which may lead to the reduced binding promiscuity and improved clinical

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

• shape of the substrate binding site. Conclusion The multiple structures of AmbP1 and AmbP3 with different substrate sets provide useful knowledge to understand the molecular basis of the promiscuous PTases. Their promiscuity is mainly caused by the hydrophobic binding pocket for the prenyl acceptor and

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

Back to the future: Why we need enzymology to build a synthetic metabolism of the future

• Tobias J. Erb

Beilstein J. Org. Chem. 2019, 15, 551–557, doi:10.3762/bjoc.15.49

• methylsuccinyl-CoA oxidase in the CETCH cycles that were engineered from a promiscuous short chain acyl-CoA oxidase and a FAD-dependent methylsuccinyl-CoA dehydrogenase, respectively [13][40][41]. These efforts in exploiting the promiscuity of enzymes to create novel catalysts might profit from new computational

• the future. Enzyme promiscuity: Key and challenge for synthetic metabolism Another problem is that even in databases that list the experimentally confirmed activity of enzymes, an important aspect is very often not well documented: substrate (and reaction) promiscuity. Yet, this information is

• detailed information on the activity of a given enzyme with different substrate analogs. Besides providing the necessary information to identify interesting enzyme candidates for level 4 and level 5 pathway construction, more systematic data on enzyme promiscuity would also allow a more holistic view onto

Non-native autoinducer analogs capable of modulating the SdiA quorum sensing receptor in Salmonella enterica serovar Typhimurium

• Matthew J. Styles and
• Helen E. Blackwell

Beilstein J. Org. Chem. 2018, 14, 2651–2664, doi:10.3762/bjoc.14.243

• Figure 2. For agonism at 100 μM, 119 compounds (79% of the library), and at 1 μM, 71 compounds (47% of the library), activated SdiA by at least 50% (above the negative control). This level of promiscuity in terms of agonist ligands is high for a LuxR-type receptor. For comparison, RhlR and QscR were

• were able to activate SdiA by more than 50% at 100 μM. This level of promiscuity in terms of agonist ligand is extreme in comparison to other well-studied receptors, such as LasR. The most potent agonists of SdiA were found to be AHLs with medium length acyl tails (7–8 carbons), PHLs with meta

Synthetic mRNA capping

• Fabian Muttach,
• Nils Muthmann and
• Andrea Rentmeister

Beilstein J. Org. Chem. 2017, 13, 2819–2832, doi:10.3762/bjoc.13.274

• ]. Recently, we revealed that the N7-cap methyltransferase Ecm1 from Encephalitozoon cuniculi is highly promiscuous. Sterically very demanding AdoMet analogues bearing for example a norbornene or 4-vinylbenzyl moiety were efficiently converted [92][93]. The pronounced promiscuity can be attributed to the

What contributes to an effective mannose recognition domain?

• Christoph P. Sager,
• Deniz Eriş,
• Martin Smieško,
• Rachel Hevey and
• Beat Ernst

Beilstein J. Org. Chem. 2017, 13, 2584–2595, doi:10.3762/bjoc.13.255

• high desolvation penalties and constrainment of flexible loop motifs which together contribute to a significant energy penalty upon binding. Nonetheless, these qualities enable ligand promiscuity and can facilitate other features such as the inactivation via homodimerization as exemplified in BDCA-2

Enzymatic synthesis of glycosides: from natural O- and N-glycosides to rare C- and S-glycosides

• Jihen Ati,
• Pierre Lafite and
• Richard Daniellou

Beilstein J. Org. Chem. 2017, 13, 1857–1865, doi:10.3762/bjoc.13.180

• acceptor. UGT74B1, involved in glucosinolate biosynthesis (see supra), was one of these 17 enzymes. Other studies have identified S-GT activities when assaying the catalytic promiscuity of O-GT with a wide range of aglycone acceptors (Figure 3). OleD from Streptomyces antibioticus has been the first

Characterization of non-heme iron aliphatic halogenase WelO5* from Hapalosiphon welwitschii IC-52-3: Identification of a minimal protein sequence motif that confers enzymatic chlorination specificity in the biosynthesis of welwitindolelinones

• Qin Zhu and
• Xinyu Liu

Beilstein J. Org. Chem. 2017, 13, 1168–1173, doi:10.3762/bjoc.13.115

• , this study, along with the recent characterization of the AmbO5 protein, collectively confirmed the presence of a signature sequence motif in the C-terminus of this newly discovered halogenase enzyme family that confers substrate promiscuity and specificity. These observations may guide the rational

• chimera revealed that a C-terminal sequence motif plays a role in the substrate tolerance and provided insights into the origin of substrate promiscuity in this family of proteins [18]. In this work, we report the characterization of the third WelO5-type protein, WelO5*, for the biogenesis of

Opportunities and challenges for the sustainable production of structurally complex diterpenoids in recombinant microbial systems

• Katarina Kemper,
• Max Hirte,
• Markus Reinbold,
• Monika Fuchs and
• Thomas Brück

Beilstein J. Org. Chem. 2017, 13, 845–854, doi:10.3762/bjoc.13.85

• unamenable diterpenes with labdane- and clerodane-type structures [66]. Additional findings were provided by Jia and co-workers [67], who demonstrated high substrate promiscuity of a plant and a fungal Class I diterpene synthase. This study involved general substrates of diterpene cyclases like GGPP and its

• performed in vivo substrate promiscuity tests following a combinatorial approach [41][66]. The resulting products entailed pimarane- and abietane-type diterpenes as well as the trans-clerodane type diterpene kolavenol, a putative intermediate in the salvinorin A biosynthesis. Other bifunctional diterpene

Biocatalysis for the application of CO₂ as a chemical feedstock

• Apostolos Alissandratos and
• Christopher J. Easton

Beilstein J. Org. Chem. 2015, 11, 2370–2387, doi:10.3762/bjoc.11.259

• received much attention for application in biotechnology for CO2-fixation, particularly using engineered photosynthetic hosts, such as plants and algae. The inefficiency of RuBisCO and promiscuity towards oxygen have directed efforts in protein engineering towards the generation of optimised mutants that

A novel and widespread class of ketosynthase is responsible for the head-to-head condensation of two acyl moieties in bacterial pyrone biosynthesis

• Darko Kresovic,
• Florence Schempp,
• Zakaria Cheikh-Ali and
• Helge B. Bode

Beilstein J. Org. Chem. 2015, 11, 1412–1417, doi:10.3762/bjoc.11.152

• products have been shown to be potent antibiotics targeting the newly identified switch region of the bacterial RNA polymerase [24]. Furthermore the promiscuity of MxnB regarding its substrate specificity has been used in mutasynthesis experiments to produce novel myxopyronin derivatives [25]. Recently the

Carbohydrate PEGylation, an approach to improve pharmacological potency

• M. Eugenia Giorgi,
• Rosalía Agusti and
• Rosa M. de Lederkremer

Beilstein J. Org. Chem. 2014, 10, 1433–1444, doi:10.3762/bjoc.10.147

• PEGylation of a glycoprotein can be performed in three steps. First, the sialic acid is removed from the native protein with a sialidase and subsequently Sia-PEG is transfered to the uncovered terminal Gal units of the linked glycan taking advantage of the substrate promiscuity of the sialyltransferase

Quantification of N-acetylcysteamine activated methylmalonate incorporation into polyketide biosynthesis

• Stephan Klopries,
• Uschi Sundermann and
• Frank Schulz

Beilstein J. Org. Chem. 2013, 9, 664–674, doi:10.3762/bjoc.9.75

• promiscuity of wild type MatB malonyl-CoA synthetases was recently described [40], pointing out the need for an artificial and versatile activation mechanism as described here, to enable what we have termed enzyme-directed mutasynthesis. Conclusion Based on the single incorporation of 4 a relative

Natural product biosyntheses in cyanobacteria: A treasure trove of unique enzymes

• Jan-Christoph Kehr,
• Douglas Gatte Picchi and
• Elke Dittmann

Beilstein J. Org. Chem. 2011, 7, 1622–1635, doi:10.3762/bjoc.7.191

• marine cyanobacterium [69]. A single LanM-type enzyme, ProcM, was found to cooperate with 29 different precursor peptides in vitro and in vivo. The enzyme thus showed a remarkable catalytic promiscuity. The precursor peptides were encoded either cis or trans to the ProcM enzyme, and the resulting family