Mechanisms of ring formation in inophore polyether tetronates

• Grant number: 17/50140-4
• Support Opportunities: Regular Research Grants
• Start date: September 01, 2017
• End date: August 31, 2019
• Field of knowledge: Biological Sciences - Biochemistry - Chemistry of Macromolecules
• Agreement: University of Warwick
• Mobility Program: SPRINT - Projetos de pesquisa - Mobilidade
• Principal Investigator: Marcio Vinicius Bertacine Dias
• Grantee: Marcio Vinicius Bertacine Dias
• Principal researcher abroad: Manuela Tosin
• Institution abroad: University of Warwick, England
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 15/09188-8 - Biosynthesis of polyether and aminoglycoside antibiotics: structural investigation of unusual enzymes or with synthetic biology applicability, AP.R

Abstract

Nature has the extraordinary capacity of producing structurally exquisite molecules that possess useful bioactivities for human and animal health. A field of high interest and intense active includes the mechanisms of natural products ring formation because the peculiarity of the involved enzymes. Tetronasin and tetronomycin are tetronate containing natural products, which have similar structures, although the configuration of their 10 chiral centers are completely opposite. We have solved the crystal structures of epoxide hydrolases that drive the formation of one of the rings in these natural products and they have very peculiar active sites. In addition, other cyclises from the biosynthesis of these compounds seems to be Diels Alderases, a family of enzymes recently described that has a very exquisite mechanism of catalysis and in these biosynthesis of these tetronates, they are claimed to be involved in [4+2] cycloadditions and have been demonstrate to be essential in the production of tetronomycin and tetronasin. In this project, we aim to jointly with a Research group from the University of Warwick elucidate the mechanism of ring formation for the polyether tetronates tetronasin and tetronomycin. For so, substrate analogues for these enzymes will be synthetised, which will be used in the co-crystallization experiments with these enzymes. The structure of the enzymes in complexes with these ligands will be obtained and we expect to add crucial information about the biosvnthesis of these medicallv relevant molecules. (AU)

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)

LITTLE, RORY; PAIVA, FERNANDA C. R.; JENKINS, ROBERT; HONG, HUI; SUN, YUHUI; DEMYDCHUK, YULIYA; SAMBORSKYY, MARKIYAN; TOSIN, MANUELA; LEEPER, FINIAN J.; DIAS, MARCIO V. B.; et al. Unexpected enzyme-catalysed [4+2] cycloaddition and rearrangement in polyether antibiotic biosynthesis. NATURE CATALYSIS, v. 2, n. 11, p. 1045-1054, NOV 2019. (15/09188-8, 17/50140-4, 18/00351-1)