The molecular structure of an epoxide hydrolase from Trichoderma reesei in complex with urea or amide-based inhibitors

Author(s)

de Oliveira, Gabriel S. ^[1] ; Adriani, Patricia P. ^[1] ; Ribeiro, Joao Augusto ^[2] ; Morisseau, Christophe ^[3] ; Hammock, Bruce D. ^[3] ; Dias, Marcio Vinicius B. ^[2] ; Chambergo, Felipe S. ^[1]

Affiliation

^[1] Univ Sao Paulo, Escola Artes Ciencias & Humanidades, 1000 Arlindo Bettio Ave, BR-03828000 Sao Paulo - Brazil

^[2] Univ Sao Paulo, Inst Ciencias Biomed, Dept Microbiol, 1374 Ave Prof Lineu Prestes, BR-05508900 Sao Paulo - Brazil

^[3] Univ Calif Davis, Ctr Comprehens Canc, Dept Entomol & Nematol, One Shields Ave, Davis, CA 95616 - USA

• Document type: Journal article
• Source: International Journal of Biological Macromolecules; v. 129, p. 653-658, MAY 15 2019.
• Web of Science Citations: 0

Abstract

Epoxide hydrolases (EHs) are enzymes involved in the metabolism of endogenous and exogenous epoxides, and the development of EH inhibitors has important applications in the medicine. In humans, EH inhibitors are being tested in the treatment of cardiovascular diseases and show potent anti-inflammatory effects. EH inhibitors are also considerate promising molecules against infectious diseases. EHs are functionally very well studied, but only a few members have its three-dimensional structures characterized. Recently, a new EH from the filamentous fungi Trichoderma reseei (TrEH) was reported, and a series of urea or amide-based inhibitors were identified. In this study, we describe the crystallographic structures of TrEH in complex with five different urea or amide based inhibitors with resolutions ranging from 2.6 to 1.7 angstrom. The analysis of these structures reveals the molecular basis of the inhibition of these compounds. We could also observe that these inhibitors occupy the whole extension of the active site groove and only a few conformational changes are involved. Understanding the structural basis EH interactions with different inhibitors might substantially contribute for the study of fungal metabolism and in the development of novel and more efficient antifungal drugs against pathogenic Trichoderma species. (C) 2019 Elsevier B.V. All rights reserved. (AU)

• FAPESP's process: 13/15906-5 - Fragment based drug discovery (FBDD) applied to two enzymes of folate biosynthetic pathway from Mycobacterium tuberculosis
• Grantee: João Augusto Ribeiro
• Support type: Scholarships in Brazil - Doctorate
• FAPESP's process: 16/12859-4 - Screening of Substrates and Inhibitors for epoxide hydrolase from Trichoderma reesei
• Grantee: Gabriel Stephani de Oliveira
• Support type: Scholarships abroad - Research Internship - Doctorate (Direct)
• FAPESP's process: 15/03329-9 - Cloning and characterization of the enzymes epoxide hydrolases from Trichoderma reesei
• Grantee: Gabriel Stephani de Oliveira
• Support type: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 15/09188-8 - Biosynthesis of polyether and aminoglycoside antibiotics: structural investigation of unusual enzymes or with synthetic biology applicability
• Grantee: Marcio Vinicius Bertacine Dias
• Support type: Regular Research Grants
• FAPESP's process: 18/00351-1 - Applied structural biology involved in the biosynthesis of natural products: biotechnolgical aplications and study of unusual molecular reactions
• Grantee: Marcio Vinicius Bertacine Dias
• Support type: Regular Research Grants
• FAPESP's process: 14/24107-1 - Characterization and study of oxidases enzymes from filamentous fungi
• Grantee: Felipe Santiago Chambergo Alcalde
• Support type: Program for Research on Bioenergy (BIOEN) - Regular Program Grants
• FAPESP's process: 17/25705-8 - Characterization and study of Enzymes to biomass degradation.
• Grantee: Felipe Santiago Chambergo Alcalde
• Support type: Regular Research Grants