2. Academic Validation
  3. Tropinone synthesis via an atypical polyketide synthase and P450-mediated cyclization

Tropinone synthesis via an atypical polyketide synthase and P450-mediated cyclization

  • Nat Commun. 2018 Dec 11;9(1):5281. doi: 10.1038/s41467-018-07671-3.
Matthew A Bedewitz 1,  A Daniel Jones 2 3,  John C D'Auria 4,  Cornelius S Barry 5
Affiliations

Affiliations

  • 1 Department of Horticulture, Michigan State University, East Lansing, MI, 48824, USA.
  • 2 Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, 48824, USA.
  • 3 Department of Chemistry, Michigan State University, East Lansing, MI, 48824, USA.
  • 4 Department of Chemistry & Biochemistry, Texas Tech University, Lubbock, TX, 79409, USA.
  • 5 Department of Horticulture, Michigan State University, East Lansing, MI, 48824, USA. [email protected].
PMID: 30538251 DOI: 10.1038/s41467-018-07671-3
Abstract

Tropinone is the first intermediate in the biosynthesis of the pharmacologically important tropane Alkaloids that possesses the 8-azabicyclo[3.2.1]octane core bicyclic structure that defines this alkaloid class. Chemical synthesis of tropinone was achieved in 1901 but the mechanism of tropinone biosynthesis has remained elusive. In this study, we identify a root-expressed type III polyketide synthase from Atropa belladonna (AbPYKS) that catalyzes the formation of 4-(1-methyl-2-pyrrolidinyl)-3-oxobutanoic acid. This catalysis proceeds through a non-canonical mechanism that directly utilizes an unconjugated N-methyl-Δ1-pyrrolinium cation as the starter substrate for two rounds of malonyl-Coenzyme A mediated decarboxylative condensation. Subsequent formation of tropinone from 4-(1-methyl-2-pyrrolidinyl)-3-oxobutanoic acid is achieved through cytochrome P450-mediated catalysis by AbCYP82M3. Silencing of AbPYKS and AbCYP82M3 reduces tropane levels in A. belladonna. This study reveals the mechanism of tropinone biosynthesis, explains the in planta co-occurrence of pyrrolidines and tropanes, and demonstrates the feasibility of tropane engineering in a non-tropane producing plant.

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