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Determination of the structural bases of Biosynthetic formation of heterocyclic rings in ionophores polyethers

Grant number: 17/23627-0
Support Opportunities:Scholarships in Brazil - Post-Doctorate
Effective date (Start): February 01, 2022
Effective date (End): January 31, 2024
Field of knowledge:Physical Sciences and Mathematics - Chemistry - Organic Chemistry
Principal Investigator:Marcio Vinicius Bertacine Dias
Grantee:Gabriel Stephani de Oliveira
Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil


Natural products represent an important source of bioactive products that human uses for the treatment of various diseases. Although the field of biological chemistry has had considerable advances in the knowledge of how nature produces many of these compounds, there is still a lack of understanding of these events. However, this field of research is becoming extremely competitive, due to the growing interest in the enzymes involved in the biosynthesis of natural products because of its applicability in programs of synthetic biology for the production of new derivatives. The formation of heterocyclic rings in natural products is an event in which their molecular mechanisms are not clearly known. In this project, we propose to study the structural mechanism of the formation of heterocyclic rings in polycyclic polyether ionophores antibiotics: tetronomycin and tetronasin. The analysis of gene clusters, which are responsible for the formation of these antibiotic molecules, show the presence of enzymes that perform opening for cyclization in cyclic ethers, which are epoxidases and epoxide hydrolases, and also there are the intramolecular [4 + 2] cycloaddition reactions catalyzed by diels-alderases. Thus, in this project, we intend to determine the structures of epoxidases, epoxide hydrolases enzymes in complex with substrate analogs, and the diels-alderases involved in the biosynthesis of the compounds tetronomycin and tetronasin. For this, we expect to obtain the involved proteins in its pure and homogeneous form, crystallize them in the apo form and/or in the presence of ligands and determine their structures through protein crystallography. With the determination of these structures, we expect to obtain structural insights into the way in which nature uses to produce these molecules and elucidate their possible catalytic mechanisms. (AU)

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