The dihydroorotate dehydrogenases: Past and present

Author(s)

Reis, Renata A. G. ; Calil, Felipe Antunes ; Feliciano, Patricia Rosa ; Pinheiro, Matheus Pinto ; Nonato, M. Cristina

• Document type: Journal article
• Source: Archives of Biochemistry and Biophysics; v. 632, p. 17-pg., 2017-10-15.

Abstract

The flavoenzyme dihydroorotate dehydrogenase catalyzes the stereoselective oxidation of (S)-dihydroorotate to orotate in the fourth of the six conserved enzymatic reactions involved in the de novo pyrimidine biosynthetic pathway. Inhibition of pyrimidine metabolism by selectively targeting DHODHs has been exploited in the development of new therapies against cancer, immunological disorders, bacterial and viral infections, and parasitic diseases. Through a chronological narrative, this review summarizes the efforts of the scientific community to achieve our current understanding of structural and biochemical properties of DHODHs. It also attempts to describe the latest advances in medicinal chemistry for therapeutic development based on the selective inhibition of DHODH, including an overview of the experimental techniques used for ligand screening during the process of drug discovery. (C) 2017 Elsevier Inc. All rights reserved. (AU)

• FAPESP's process: 12/25075-0 - Development of leishmanicidal drugs based on the selective inhibition of the enzyme dihydroorotate dehydrogenase
• Grantee: Maria Cristina Nonato
• Support Opportunities: Regular Research Grants
• FAPESP's process: 11/23504-9 - Exploring structure-function relationship of DHODH enzyme in the development of new molecules with trypanocidal and leishmanicidal activities
• Grantee: Renata Almeida Garcia Reis
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 07/08703-0 - Design of inhibitors for dihydroorotate dehydrogenase from Trypanosoma cruzi and Leishmania major
• Grantee: Matheus Pinto Pinheiro
• Support Opportunities: Scholarships in Brazil - Doctorate