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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Recombinant production, crystallization and crystal structure determination of dihydroorotate dehydrogenase from Leishmania (Viannia) braziliensis

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Author(s):
Garcia Reis, Renata Almeida [1] ; Lorenzato, Jr., Eder [1] ; Silva, Valeria Cristina [1] ; Nonato, Maria Cristina [1]
Total Authors: 4
Affiliation:
[1] Fac Ciencias Farmaceut Ribeirao Preto, Dept Quim & Fis, BR-14040903 Ribeirao Preto, SP - Brazil
Total Affiliations: 1
Document type: Journal article
Source: ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY COMMUNICATIONS; v. 71, n. 5, SI, p. 547-552, MAY 2015.
Web of Science Citations: 2
Abstract

The enzyme dihydroorotate dehydrogenase (DHODH) is a flavoenzyme that catalyses the oxidation of dihydroorotate to orotate in the de novo pyrimidine-biosynthesis pathway. In this study, a reproducible protocol for the heterologous expression of active dihydroorotate dehydrogenase from Leishmania (Viannia) braziliensis (LbDHODH) was developed and its crystal structure was determined at 2.12 angstrom resolution. L. (V.) braziliensis is the species responsible for the mucosal form of leishmaniasis, a neglected disease for which no cure or effective therapy is available. Analyses of sequence, structural and kinetic features classify LbDHODH as a member of the class 1A DHODHs and reveal a very high degree of structural conservation with the previously reported structures of orthologous trypanosomatid enzymes. The relevance of nucleotide-biosynthetic pathways for cell metabolism together with structural and functional differences from the respective host enzyme suggests that inhibition of LbDHODH could be exploited for antileishmanicidal drug development. The present work provides the framework for further integrated in vitro, in silico and in vivo studies as a new tool to evaluate DHODH as a drug target against trypanosomatid-related diseases. (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: 14/01257-8 - Development of a model plataform for the search of leishmanicidal compounds based on the selective inhibition of dihydroorotate dehydrogenase
Grantee:Eder Lorenzato Junior
Support Opportunities: Scholarships in Brazil - Master
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