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Metabolic engineering applied to the elucidation of the biosynthetic pathway and sustainable production of quinonemethide triterpenes via heterologous expression in Saccharomyces cerevisiae

Grant number: 21/05646-2
Support Opportunities:Scholarships in Brazil - Doctorate
Effective date (Start): April 01, 2022
Field of knowledge:Physical Sciences and Mathematics - Chemistry - Organic Chemistry
Principal Investigator:Maysa Furlan
Grantee:Otávio Aguiar de Souza
Host Institution: Instituto de Química (IQ). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
Associated research grant:13/07600-3 - CIBFar - Center for Innovation in Biodiversity and Drug Discovery, AP.CEPID
Associated scholarship(s):23/04093-5 - Heterologous large-scale production of populninic acid in Nicotiana benthamiana system via combinatorial biosynthesis using P450 enzymes and the substrate maytenoic acid, BE.EP.DR


Among the classes of secondary metabolites produced by plants, triterpenes have attracted special attention due to their great biological potential. The Quinonemethide Triterpenes (QMTs), chemical markers of the Celastraceae family, are potent antitumoral and antioxidant compounds. Biosynthetic studies of QMTs in young plants of Maytenus ilicifolia have shown that, in this species, their production occurs in small quantities in the root barks. The main bioactive QMTs present in this species are pristimerin and maytenin, substances with several biological activities, such as antifungal and antitumoral. Previous studies carried out by our group indicated that, in the first stage of the QMTs metabolic pathway, the cyclization of 2,3-epoxidosqualene occurs, catalyzed by an oxidosqualene cyclase (OSC - friedelin synthase) leading to the first precursor, friedelin, a pentacyclic triterpene found in the leaves of M. ilicifolia, and which has been the target of studies on cloning, site-directed mutations and heterologous expression in Saccharomyces cerevisiae to increase its production. Continuing this proposal, our group identified the cytochrome P450 oxidoreductase enzyme genes (CYPs) involved in the oxidation of friedelin to maytenoic acid, second intermediate in the biosynthesis of QMTs. However, the subsequent oxidation steps and the respective CYPs that lead to the formation of QMTs remain as a biogenetic proposal. Thus, this project aims to continue this proposal and elucidate the biosynthetic pathway of QMTs, enabling their sustainable production. Therefore, the coding sequences (cds) of cloned CYPs from M. ilicifolia will be expressed individually and in different combinations in metabolically modified S. cerevisiae. From metabolomic fingerprints, the substances produced from the different strains will be analyzed and their identity will be confirmed by spectrometric and spectroscopic techniques, and computational and multivariate statistical tools. (AU)

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