Natural products of pentacyclic triterpenoids: from discovery to heterologous biosynthesis

Liu, Yanlin; Wang, Jing; Li, Linyong; Song, Wei; Li, Min; Hua, Xin; Wang, Yu

doi:10.1039/d2np00063f

“…the key enzymes for ginsenoside biosynthesis from Pg , including CYP450s, UGTs, and oxidosqualene cyclases (OSCs), were introduced to achieve ginsenosides in yeasts. Three genes have been found from multiple sources, such as higher plants Arabidopsis thaliana , Sorghum bicolor , Solanum lycopersicum , Glycine max , and Oryza sativa [ 67 , 68 ]. However, Pg has been demonstrated as the most important source for producing ginsenosides with high efficiency.…”

Section: Ginsenoside Biosynthesis In Engineered Microorganismsmentioning

confidence: 99%

Microorganisms for Ginsenosides Biosynthesis: Recent Progress, Challenges, and Perspectives

Chu

¹

,

Nguyen

²

,

Tung

³

2023

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Ginsenosides are major bioactive compounds present in the Panax species. Ginsenosides exhibit various pharmaceutical properties, including anticancer, anti-inflammatory, antimetastatic, hypertension, and neurodegenerative disorder activities. Although several commercial products have been presented on the market, most of the current chemical processes have an unfriendly environment and a high cost of downstream processing. Compared to plant extraction, microbial production exhibits high efficiency, high selectivity, and saves time for the manufacturing of industrial products. To reach the full potential of the pharmaceutical resource of ginsenoside, a suitable microorganism has been developed as a novel approach. In this review, cell biological mechanisms in anticancer activities and the present state of research on the production of ginsenosides are summarized. Microbial hosts, including native endophytes and engineered microbes, have been used as novel and promising approaches. Furthermore, the present challenges and perspectives of using microbial hosts to produce ginsenosides have been discussed.

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“…The carbocation‐go stage has been well described, [7,14] and the carbocation‐return stage is closely associated with PT formation, which requires further study. A high number of β ‐amyrin synthases found in nature seems to favor the formation of β ‐amyrin [1] . Among the putative intermediates in Figure 1e (state E–J), more rearrangement mechanisms are involved in the formation of friedelin, which we referred to as the “CSR mechanism,” involving intermediates and catalytic mechanisms that remain elusive.…”

Section: Introductionmentioning

confidence: 99%

Structural and Catalytic Insight into the Unique Pentacyclic Triterpene Synthase TwOSC

Luo,

Ma,

Qiu

et al. 2023

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The oxidosqualene cyclase (OSC) catalyzed cyclization of the linear substrate (3S)‐2,3‐oxidosqualene to diverse pentacyclic triterpenoid (PT) skeletons is one of the most complex reactions in nature. Friedelin has a unique PT skeleton involving a fascinating nine‐step Cation Shuttle‐Run (CSR) cascade arrangement reaction, in which the carbocation formed from C‐2 moves to the other side of the skeleton, runs back to C‐3 to yield a friedelin cation, and finally deprotonated. However, as the data on the crystal structure of plant OSCs are lacking, it remains unknown why the CSR cascade reactions for friedelin biosynthesis and the exact catalytic mechanism of the CSR. In this study, we determined the first cryogenic electron microscopy structure of a plant OSC, friedelin synthase, from Tripterygium wilfordii Hook. f (TwOSC). We also performed quantum mechanics/molecular mechanics simulations to reveal the energy profile for the CSR cascade reaction and identify key residues crucial for PT skeleton yield. Furthermore, we semi‐rationally designed two TwOSC mutants, which significantly improved the yields of friedelin and β‐amyrin, respectively. Our findings provide novel insights into the CSR mechanism under TwOSC enzyme catalysis and propose a new strategy for the semi‐rational design of other OSCs to promote PT biosynthesis.

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“…Pentacyclic triterpenoids (PTs) are widely distributed in higher plants and exhibit a wide range of bioactivities, such as antitumor, [1] anti-inflammatory, [2] and antiviral activity. [3] Recent studies have identified PTs as vaccine adjuvants to boost the immune response.…”

Section: Introductionmentioning

confidence: 99%

Structural and Catalytic Insight into the Unique Pentacyclic Triterpene Synthase TwOSC

Luo,

Ma,

Qiu

et al. 2023

Angewandte Chemie

2

0

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The oxidosqualene cyclase (OSC) catalyzed cyclization of the linear substrate (3S)‐2,3‐oxidosqualene to diverse pentacyclic triterpenoid (PT) skeletons is one of the most complex reactions in nature. Friedelin has a unique PT skeleton involving a fascinating nine‐step Cation Shuttle‐Run (CSR) cascade arrangement reaction, in which the carbocation formed from C‐2 moves to the other side of the skeleton, runs back to C‐3 to yield a friedelin cation, and finally deprotonated. However, as the data on the crystal structure of plant OSCs are lacking, it remains unknown why the CSR cascade reactions for friedelin biosynthesis and the exact catalytic mechanism of the CSR. In this study, we determined the first cryogenic electron microscopy structure of a plant OSC, friedelin synthase, from Tripterygium wilfordii Hook. f (TwOSC). We also performed quantum mechanics/molecular mechanics simulations to reveal the energy profile for the CSR cascade reaction and identify key residues crucial for PT skeleton yield. Furthermore, we semi‐rationally designed two TwOSC mutants, which significantly improved the yields of friedelin and β‐amyrin, respectively. Our findings provide novel insights into the CSR mechanism under TwOSC enzyme catalysis and propose a new strategy for the semi‐rational design of other OSCs to promote PT biosynthesis.

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Natural products of pentacyclic triterpenoids: from discovery to heterologous biosynthesis

Abstract: Natural products of pentacyclic triterpenoids: from their discovery and biosynthetic pathways to their heterologous biosynthesis in plant chassis and microbial cell factories.

Cited by 62 publications

References 342 publications

Microorganisms for Ginsenosides Biosynthesis: Recent Progress, Challenges, and Perspectives

Microorganisms for Ginsenosides Biosynthesis: Recent Progress, Challenges, and Perspectives

Structural and Catalytic Insight into the Unique Pentacyclic Triterpene Synthase TwOSC

Structural and Catalytic Insight into the Unique Pentacyclic Triterpene Synthase TwOSC

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