Strategies to access the [5-8] bicyclic core encountered in the sesquiterpene, diterpene and sesterterpene series

• Cécile Alleman,
• Charlène Gadais,
• Laurent Legentil and
• François-Hugues Porée

Beilstein J. Org. Chem. 2023, 19, 245–281, doi:10.3762/bjoc.19.23

Navigating and expanding the roadmap of natural product genome mining tools

• Friederike Biermann,
• Sebastian L. Wenski and
• Eric J. N. Helfrich

Beilstein J. Org. Chem. 2022, 18, 1656–1671, doi:10.3762/bjoc.18.178

• ])) [28]. In contrast, discrete multi-enzymatic assemblies utilize distinct, monofunctional enzymes. Examples are terpene (e.g., cyclooctatin (8) [29]), ribosomally synthesized and post-translationally modified peptide (RiPP), or NRPS-independent alkaloid pathways. In the case of terpene biosynthesis

Understanding the role of active site residues in CotB2 catalysis using a cluster model

• Keren Raz,
• Ronja Driller,
• Thomas Brück,
• Bernhard Loll and
• Dan T. Major

Beilstein J. Org. Chem. 2020, 16, 50–59, doi:10.3762/bjoc.16.7

• melanosporofaciens, which catalyzes the formation of cycloocta-9-en-7-ol, a precursor to the next-generation anti-inflammatory drug cyclooctatin. In this work, we present evidence for the significant role of the active site's residues in CotB2 on the reaction energetics using quantum mechanical calculations in an

• cascade can provide important information towards a biosynthetic strategy for cyclooctatin and the biomanufacturing of related terpene structures. Keywords: active site; CotB2 cyclase; diterpene; mechanism; quantum mechanics; Introduction Enzymes catalyze numerous complex biochemical reactions in

• , representing the first committed step in the biosynthesis of the next-generation anti-inflammatory drug cyclooctatin. The intracellular target of cyclooctatin is an as of yet uncharacterized lysophospholipase, which is involved in early steps of the inflammatory signaling cascade [38][39][40]. In the last

Current understanding and biotechnological application of the bacterial diterpene synthase CotB2

• Ronja Driller,
• Daniel Garbe,
• Norbert Mehlmer,
• Monika Fuchs,
• Keren Raz,
• Dan Thomas Major,
• Thomas Brück and
• Bernhard Loll

Beilstein J. Org. Chem. 2019, 15, 2355–2368, doi:10.3762/bjoc.15.228

• , Technical University of Munich (TUM), Lichtenbergstr. 4, 85748 Garching, Germany Department of Chemistry, Bar-Ilan University, Ramat-Gan 52900, Israel 10.3762/bjoc.15.228 Abstract CotB2 catalyzes the first committed step in cyclooctatin biosynthesis of the soil bacterium Streptomyces melanosporofaciens. To

• mutagenesis have exciting applications for the sustainable production of high value bioactive substances. Keywords: biotechnology; CotB2; crystal structure; cyclooctatin; diterpene; reaction mechanism; terpene synthase; Introduction Terpenes represent one of the most diverse groups of natural biomolecules

• inexpensive carbon sources. Prominent examples of optimized terpene production pathways in E. coli are taxadiene, a precursor of the anticancer drug taxol [28], amorpha‐4,11‐diene, an antimalarial drug precursor [29], and cyclooctatin [30]. The scope of this review encompasses a detailed consideration of 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

• the recombinant enzyme from Streptomyces malaysiensis [43]. The diterpene 7 is a precursor to the lysophospholipase inhibitor cyclooctatin (20) formed by the action of two genetically clustered cytochrome P450 monooxygenases CotB3 and CotB4 (Scheme 4) [40][44], while no derivatives from 8 are

• streptomycetes. Biosynthesis of cyclooctatin (20) from 7. Supporting Information Supporting Information File 136: Additional figures and tables. Acknowledgements This work was supported by NWO ALWOP.178 grant. This is publication 6728 of the NIOO-KNAW.

Recent highlights in biosynthesis research using stable isotopes

• Jan Rinkel and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2015, 11, 2493–2508, doi:10.3762/bjoc.11.271

• performed to investigate the mechanisms for intermedeol and neomeranol B biosynthesis [62]. Cyclooctat-9-en-7-ol (52), a member of the fusicoccane family of diterpenoids, is the biosynthetic precursor of cyclooctatin (45) [63], a potent inhibitor of lysophospholipase, which was isolated from Streptomyces

• diterpenoid product cyclooctat-9-en-7-ol (52). Further oxidation by the cytochrome P450-hydroxylases CotB3 and CotB4 yields the biologically active compound cyclooctatin (45) [67]. This outstanding study exemplifies the scope of isotopic labeling experiments in the elucidation of terpene biosynthesis by

• pattern in cyclooctatin (45) after feeding of [U-13C6]glucose to a S. albus transformant. Labeling in the resulting geranylgeranyl diphosphate (GGPP, 44) is added for clarity. Bold bonds show intact C2-fragments and asterisks indicate carbons without direct coupling. The carbon numbers shown for 45 derive