Building <i>Streptomyces albus</i> as a chassis for synthesis of bacterial terpenoids

Hu, Yi Ling; Zhang, Qi; Liu, Shuang He; Sun, Jia; Yin, Fang Zhou; Wang, Zi Ru; Shi, Jing; Jiao, Rui Hua; Ge, Hui

doi:10.1039/d2sc06033g

Cited by 12 publications

(11 citation statements)

References 48 publications

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“…In a recent study, Hu et al demonstrated heterologous expression of ariD-G genes in S. albus J1074 M, leading to the production of a 6/10-fused eunicellane diterpenoid (9, Figure 3A), albeit without the detection of aridacins (1-3). [42] To elucidate the biosynthetic control of 6/7/5-tricyclic versus 6/10-bicyclic diterpenoids by the ari BGC, we reanalyzed the metabolites from our engineered strains. Based on HPLC-MS analysis, besides the aridacins, which were major products, S. lividans DL10011 also produced trace amounts of 8-11 (Figures 3D, S66 S13).…”

Section: Resultsmentioning

confidence: 99%

Cytochrome P450 Mediated Cyclization in Eunicellane Derived Diterpenoid Biosynthesis**

Wang,

Yang,

et al. 2023

Angew Chem Int Ed

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Terpene cyclization, one of the most complex chemical reactions in nature, is generally catalyzed by two classes of terpene cyclases (TCs). Cytochrome P450s that act as unexpected TC‐like enzymes are known but are very rare. Here, we genome‐mined a cryptic bacterial terpenoid gene cluster, named ari, from the thermophilic actinomycete strain Amycolatopsis arida. By employing a heterologous production system, we isolated and characterized three highly oxidized eunicellane derived diterpenoids, aridacins A–C (1–3), that possess a 6/7/5‐fused tricyclic scaffold. In vivo and in vitro experiments systematically established a non‐canonical two‐step biosynthetic pathway for diterpene skeleton formation. First, a class I TC (AriE) cyclizes geranylgeranyl diphosphate (GGPP) into a 6/10‐fused bicyclic cis‐eunicellane skeleton. Next, a cytochrome P450 (AriF) catalyzes cyclization of the eunicellane skeleton into the 6/7/5‐fused tricyclic scaffold via C2‐C6 bond formation. Based on the results of quantum chemical computations, hydrogen abstraction followed by electron transfer coupled to barrierless carbocation ring‐closure is shown to be a viable mechanism for AriF‐mediated cyclization. The biosynthetic logic of skeleton construction in the aridacins is unprecedented, expanding the catalytic capacity and diversity of P450s and setting the stage to investigate the inherent principles of carbocation generation by P450s in the biosynthesis of terpenoids.

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Section: Resultsmentioning

confidence: 99%

Cytochrome P450 Mediated Cyclization in Eunicellane Derived Diterpenoid Biosynthesis**

Wang,

Yang,

et al. 2023

Angew Chem Int Ed

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“…(Table S16), [29] a single cyclic shunt product, resulting from the only formation of the first CÀ C bond between C1 and C14 (Figure 2C). Inspection of the crystal structure of PhmA revealed the presence of the L229 residue within the nonclassical NSE/DTE motif, which imposes steric effects on the substrate, causing it to adopt a bent conformation (Figure S14A).…”

Section: Forschungsartikelmentioning

confidence: 99%

Biosynthesis of Phomactin Platelet Activating Factor Antagonist Requires a Two‐Enzyme Cascade

Zhang,

Zhu

et al. 2023

Angewandte Chemie

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Phomactin diterpenoids possess a unique bicyclo[9.3.1]‐pentadecane skeleton with multiple oxidative modifications, and are good platelet‐activating factor (PAF) antagonists that can inhibit PAF‐induced platelet aggregation. In this study, we identified the gene cluster (phm) responsible for the biosynthesis of phomactins from a marine fungus, Phoma sp. ATCC 74077. Despite the complexity of their structures, phomactin biosynthesis only requires two enzymes: a type I diterpene cyclase PhmA and a P450 monooxygenase PhmC. PhmA was found to catalyze the formation of the phomactatriene, while PhmC sequentially catalyzes the oxidation of multiple sites, leading to the generation of structurally diverse phomactins. The rearrangement mechanism of the diterpene scaffold was investigated through isotope labeling experiments. Additionally, we obtained the crystal complex of PhmA with its substrate‐analogue FGGPP and elucidated the novel metal ion binding mode and enzymatic mechanism of PhmA through site‐directed mutagenesis. This work provides the first insights into the biosynthesis of phomactins, laying the foundation for the efficient production of phomactin natural products using synthetic biology approaches.

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“…Terpenoids are the largest class of natural products that have multiple biological activities and widespread applications in pharmaceuticals, agriculture, and fragrances. 13,14 Hemiand monoterpenoids, two major types of terpenoids, which include some of the pharmaceutically important natural products, are produced from animals, plants, and microorganisms. 15 Prenylation and geranylation are two important metabolic processes that proceed under enzyme catalysis among many approaches for producing terpenoids.…”

Section: Introductionmentioning

confidence: 99%

Insights into the mechanism and origin of multifunctional ligand effects on chemoselectivity in Pd-catalyzed unnatural prenylation and geranylation of oxindoles with isoprene

Zhao,

Yuan,

Zhang

2024

Org. Chem. Front.

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Building Streptomyces albus as a chassis for synthesis of bacterial terpenoids

Abstract: Terpenoids comprise the most chemically and structurally diverse family of natural products. In contrast to the huge numbers of terpenoids discovered from plants and fungi, only a relatively small number...

Cited by 12 publications

References 48 publications

Cytochrome P450 Mediated Cyclization in Eunicellane Derived Diterpenoid Biosynthesis**

Cytochrome P450 Mediated Cyclization in Eunicellane Derived Diterpenoid Biosynthesis**

Biosynthesis of Phomactin Platelet Activating Factor Antagonist Requires a Two‐Enzyme Cascade

Insights into the mechanism and origin of multifunctional ligand effects on chemoselectivity in Pd-catalyzed unnatural prenylation and geranylation of oxindoles with isoprene

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