Kinetic and equilibrium mechanisms of substrate binding to Mycobacterium tuberculosis enoyl reductase: implications to function-based antitubercular agent design
| Autor: | Igor B. Vasconcelos, Luiz Augusto Basso, Diógenes Santiago Santos |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
pre-steady-state kinetics
chemistry.chemical_classification biology Chemistry Stereochemistry INHA Isoniazid Rational design Cooperativity General Chemistry Reductase enoyl-ACP(CoA) reductase biology.organism_classification Mycolic acid Mycobacterium tuberculosis fluorescence titration tuberculosis Biochemistry mycolic acid medicine Antitubercular Agent medicine.drug |
| Zdroj: | Journal of the Brazilian Chemical Society, Volume: 21, Issue: 8, Pages: 1503-1508, Published: 2010 Journal of the Brazilian Chemical Society v.21 n.8 2010 Journal of the Brazilian Chemical Society Sociedade Brasileira de Química (SBQ) instacron:SBQ |
| ISSN: | 0103-5053 |
| Popis: | Tuberculosis (TB) remains the leading cause of mortality due to a single bacterial pathogen, Mycobacterium tuberculosis. There is a need for the development of new antimycobacterial agents. M. tuberculosis 2-trans-enoyl-ACP(CoA) reductase (InhA) is the main target of isoniazid, the most prescribed anti-TB agent. Here we present pre-steady state kinetics and equilibrium data of 2-trans-dodecenoyl-CoA substrate binding to InhA. These results indicate both positive homotropic cooperativity upon substrate binding to InhA, and a bimolecular association process followed by a slow isomerization of the enzyme-substrate binary complex. The data here described should help the rational design of new agents against a validated and druggable protein target with potential anti-TB activity. A tuberculose (TB) continua sendo a principal causa de mortalidade devido a um único patógeno bacteriano, o Mycobacterium tuberculosis. Há, portanto, a necessidade de desenvolvimento de novos agentes antimicobacterianos. A 2-trans-enoil-ACP(CoA) redutase (InhA) de M. tuberculosis é o principal alvo da isoniazida. Aqui nós apresentamos dados de equilíbrio e cinética em estado pré-estacionário da ligação do substrato 2-trans-dodecenoil-CoA à InhA. Os resultados demonstram cooperatividade homotrópica positiva da ligação deste substrato à InhA e um processo de associação bimolecular seguido por uma lenta isomerização do complexo binário enzima-substrato. Os dados aqui descritos devem auxiliar no desenho racional de novos inibidores de um alvo protéico validado e com potencial utilização no tratamento da TB. |
| Databáze: | OpenAIRE |
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