Mechanistische Charakterisierung und Engineering der Sesterviolen‐Synthase aus <i>Streptomyces violens</i>

Gu, Bin-Bin; Goldfuß, Bernd; Dickschat, Jeroen S.

doi:10.1002/ange.202215688

Angewandte Chemie

2022

DOI: 10.1002/ange.202215688

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Mechanistische Charakterisierung und Engineering der Sesterviolen‐Synthase aus Streptomyces violens

Bin-Bin Gu

Bernd Goldfuß

Jeroen S. Dickschat

Abstract: Die Sesterviolen‐Synthase aus Streptomyces violens wurde identifiziert und repräsentiert die zweite bekannte Sesterterpen‐Synthase aus Bakterien. Es wurden Isotopenmarkierungsexperimente in Verbindung mit DFT‐Rechnungen durchgeführt, die detaillierte Einblicke in ihren komplexen Cyclisierungsmechanismus lieferten. Enzym‐Engineering durch ortsgerichtete Mutagenese ermöglichte den Zugang zu einer hochergiebigen Enzymvariante, die sechs zusätzliche Nebenprodukte und das Hauptprodukt in ausreichenden Mengen liefer… Show more

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2024

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Cited by 5 publications

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Zwei Sesterterpen‐Syntasen aus Lentzea atacamensis demonstrieren die Rolle der Konformationsvariabilität in der Terpenbiosynthese

Gu,

Goldfuss,

Dickschat

2024

Angewandte Chemie

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Mining of two multiproduct sesterterpene synthases from Lentzea atacamensis resulted in the identification of the synthases for lentzeadiene (LaLDS) and atacamatriene (LaATS). The main product of LaLDS (lentzeadiene) is a new compound, while one of the side products (lentzeatetraene) is the enantiomer of brassitetraene B and the other side product (sestermobaraene F) is known from a surprisingly distantly related sesterterpene synthase. LaATS produces six new compounds, one of which is the enantiomer of the known sesterterpene Bm1. Notably, for both enzymes the products cannot all be explained from one and the same starting conformation of geranylfarnesyl diphosphate, demonstrating the requirement of conformational flexibility of the substrate in the enzymes’ active sites. For lentzeadiene an intriguing thermal [1,5]‐sigmatropic rearrangement was discovered, reminiscent of the biosynthesis of vitamin D3. All enzyme reactions and the [1,5]‐sigmatropic rearrangement were investigated through isotopic labeling experiments and DFT calculations. The results also emphasize the importance of conformational changes during terpene cyclizations.

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Zwei Sesterterpen‐Syntasen aus Lentzea atacamensis demonstrieren die Rolle der Konformationsvariabilität in der Terpenbiosynthese

Gu,

Goldfuss,

Dickschat

2024

Angewandte Chemie

Self Cite

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Strukturelle Einblicke in die Terpencyclasedomänen Zweier Pilzlicher Sesterterpensyntasen und Enzymengineering zur Diversifizierung von Sesterterpenen

Xu,

Lei

et al. 2024

Angewandte Chemie

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Little is known about the structures and catalytic mechanisms of sesterterpene synthases (StTSs), which greatly hinders the structure‐based engineering of StTSs for structural diversity expansion of sesterterpenes. We here report on the crystal structures of the terpene cyclization (TC) domains of two fungal StTSs: sesterfisherol synthase (NfSS) and sesterbrasiliatriene synthase (PbSS). Both TC structures contain benzyltriethylammonium chloride (BTAC), pyrophosphate (PPi), and magnesium ions (Mg2+), clearly defining the catalytic active sites. A combination of theory and experiments including carbocationic intermediates modeling, site‐directed mutagenesis, and isotope labeling provided detailed insights into the structural basis for their catalytic mechanisms. Structure‐based engineering of NfSS and PbSS resulted in the formation of 20 sesterterpenes including 13 new compounds and four pairs of epimers with different configurations at C18. These results expand the structural diversity of sesterterpenes and provide important insights for future synthetic biology research.

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Two Sesterterpene Synthases from Lentzea atacamensis Demonstrate the Role of Conformational Variability in Terpene Biosynthesis

Gu,

Goldfuss,

Dickschat

2024

Angew Chem Int Ed

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Mechanistische Charakterisierung und Engineering der Sesterviolen‐Synthase aus Streptomyces violens

Cited by 5 publications

References 40 publications

Zwei Sesterterpen‐Syntasen aus Lentzea atacamensis demonstrieren die Rolle der Konformationsvariabilität in der Terpenbiosynthese

Zwei Sesterterpen‐Syntasen aus Lentzea atacamensis demonstrieren die Rolle der Konformationsvariabilität in der Terpenbiosynthese

Strukturelle Einblicke in die Terpencyclasedomänen Zweier Pilzlicher Sesterterpensyntasen und Enzymengineering zur Diversifizierung von Sesterterpenen

Two Sesterterpene Synthases from Lentzea atacamensis Demonstrate the Role of Conformational Variability in Terpene Biosynthesis

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