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Studies concerning the biosynthesis of quinonemethides triterpenes by metabolic engineering: evaluation of the micro- and macromolecular metabolic flow of heterologous system by proteomics and metabolomics techniques.

Grant number: 13/15306-8
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): March 01, 2014
Effective date (End): February 29, 2016
Field of knowledge:Physical Sciences and Mathematics - Chemistry - Organic Chemistry
Principal Investigator:Maysa Furlan
Grantee:Lidiane Gaspareto Felippe
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


The preliminary phytochemical studies of young plants of Maytenus ilicifolia (Celastraceae) allowed the isolation of quinonemethide triterpenes which have showed potent antioxidant and antitumoral activities. However, these metabolites showed low accumulation in the root barks of such species. The biosynthetic studies of triterpenes quinonamethides were developed by the research group of Professor. Dr. Maysa Furlan, using as substrate the 2,3-epoxysqualene in enzymatic extracts of seedlings of M. ilicifolia and the results proved that friedelin is the key intermediate in their biosynthetic pathway. In order to improve the amount of friedelin, a project dealing on metabolic engineering using as a host Saccharomyces cerevisiae has been developed by the group. The main aim of the project is to express the gene of friedelin synthase, from leaves of M. ilicifolia, in such heterologous system. Based on the importance of quinonamethide triterpenes and its precursor, friedelin, as well as the intention to produce these compounds in appreciable amount using controlled and sustainable mechanisms as genetic engineering, it is critical to understand the changes in the biological processes that affect the metabolism of the modified heterologous organism. Based on it, the possibility to understand the cellular response against the metabolite produced provides the opportunity to discover the mechanisms involved in such biosynthesis, the improvement of genetic engineering, as well as increase the production of target metabolite and decrease the bottleneck biosynthetic steps of these pathways. Therefore, the objectives of this project aim to monitor and compare the range in the metabolomic and proteomic profile of the Saccharomyces cerevisiae after transfer of the gene encoding the enzyme friedelin synthase to production of friedelin, and evaluate the resulting metabolic disorder in relation to yeast unmanipulated . These studies will be conducted using proteomic and metabolomic techniques, including mass and nuclear magnetic resonance spectrometric techniques. This orthogonal approach shows the potential of genetically modified to designing a paragraph evolution of a biosynthetic pathway and/or paragraphs discover new chemical entities.

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
SOUZA-MOREIRA, TATIANA M.; ALVES, THAS B.; PINHEIRO, KARINA A.; FELIPPE, LIDIANE G.; DE LIMA, GUSTAVO M. A.; WATANABE, TATIANA F.; BARBOSA, CRISTINA C.; SANTOS, VANIA A. F. F. M.; LOPES, NORBERTO P.; VALENTINI, SANDRO R.; et al. Friedelin Synthase from Maytenus ilicifolia: Leucine 482 Plays an Essential Role in the Production of the Most Rearranged Pentacyclic Triterpene. SCIENTIFIC REPORTS, v. 6, . (12/21005-8, 13/07600-3, 13/15306-8, 14/03819-3, 11/10379-1, 12/09584-2)
BRUNA F. MAZZEU; LIDIANE G. FELIPPE; FERNANDO COTINGUIBA; MASSUO J. KATO; MAYSA FURLAN. Kavalactones and Benzoic Acid Derivatives from Leaves of Piper fuligineum Kunth (Piperaceae). Journal of the Brazilian Chemical Society, v. 29, n. 6, p. 1286-1290, . (13/15306-8, 14/50316-7, 11/16752-6)
MAZZEU, BRUNA F.; FELIPPE, LIDIANE G.; COTINGUIBA, FERNANDO; KATO, MASSUO J.; FURLAN, MAYSA. Kavalactones and Benzoic Acid Derivatives from Leaves of & IT;Piper & IT; & IT;fuligineum & IT; Kunth (Piperaceae). Journal of the Brazilian Chemical Society, v. 29, n. 6, p. 1286-1290, . (13/07600-3, 14/50316-7, 11/16752-6, 13/15306-8)

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