Elucidation of steps of the biosynthetic pathway of quinone-methide triterpenes regulated by CYP450 oxidoreductases

• Grant number: 17/00468-3
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: June 01, 2017
• End date: May 31, 2019
• Field of knowledge: Biological Sciences - Biochemistry
• Principal Investigator: Suzelei de Castro França
• Grantee: Edieidia Souza Pina
• Host Institution: Universidade de Ribeirão Preto (UNAERP). Campus Ribeirão Preto. Ribeirão Preto , SP, Brazil

Abstract

Celastraceae species known to accumulate validated bioactive compounds, used in the production of phytopharmaceuticals, have been the focus of numerous In vitro studies. More recently, pharmacological studie conducted in vitro and in vivo showed that the quinonamethide triterpenoids (QTS) celastrol, maitenin, 22²-hydroxymaytenin and pristimerin are promising substances for use in anticancer therapy for their effectiveness against cancers resistant to chemotherapy drugs in use nowadays. Those metabolites are accumulated in the roots but their low concentration in plants in situ is a limitation for the continuous and large scale production. Studies on the precursor-directed biosynthesis allow the manipulation of production levels and led to metabolic intermediates of interest. In this project we are proposing to elucidate final steps of the QTs biosynthesis carrying out precursor-directed biosynthesis studies using 13C-friedelin for identification of 13C intermediates in root cultures of Cheiloclinium cognatum and additionally the disclosure of the enzymatic regulation by oxidoreductases CYP450, key enzymes that catalyze oxidative reactions responsible for the diversity of TQs biosynthesized in C. cognatum roots. Overall results will lead to the elucidation of the oxidative steps of the biosynthetic pathway of TQs and also to the selection of genes for the construction of a vector to be inserted into Agrobacterium rhizogenes strains for the re-design of metabolic pathways in C. cognatum rootsfor the biosynthesis of chemopreventive and anti-tumorogenesis-TQs, potentially useful in the development of innovative medicines.