RESUMO
BACKGROUND: The pentose phosphate pathway (PPP) has received significant attention because of the role of NADPH and R-5-P in the maintenance of cancer cells, which are necessary for the synthesis of fatty acids and contribute to uncontrollable proliferation. The HsG6PD enzyme is the rate-limiting step in the oxidative branch of the PPP, leading to an increase in the expression levels in tumor cells; therefore, the protein has been proposed as a target for the development of new molecules for use in cancer. METHODS: Through in vitro studies, we assayed the effects of 55 chemical compounds against recombinant HsG6PD. Here, we present the kinetic characterization of four new HsG6PD inhibitors as well as their functional and structural effects on the protein. Furthermore, molecular docking was performed to determine the interaction of the best hits with HsG6PD. RESULTS: Four compounds, JMM-2, CCM-4, CNZ-3, and CNZ-7, were capable of reducing HsG6PD activity and showed noncompetitive and uncompetitive inhibition. Moreover, experiments using circular dichroism and fluorescence spectroscopy showed that the molecules affect the structure (secondary and tertiary) of the protein as well as its thermal stability. Computational docking analysis revealed that the interaction of the compounds with the protein does not occur at the active site. CONCLUSIONS: We identified two new compounds (CNZ-3 and JMM-2) capable of inhibiting HsG6PD that, compared to other previously known HsG6PD inhibitors, showed different mechanisms of inhibition. GENERAL SIGNIFICANCE: Screening of new inhibitors for HsG6PD with a future pharmacological approach for the study and treatment of cancer.
Assuntos
Inibidores Enzimáticos/química , Glucosefosfato Desidrogenase/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/química , Domínio Catalítico , Ensaios Enzimáticos , Expressão Gênica , Glucosefosfato Desidrogenase/química , Glucosefosfato Desidrogenase/genética , Glucosefosfato Desidrogenase/metabolismo , Humanos , Cinética , Simulação de Acoplamento Molecular , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Estabilidade Proteica , Estrutura Terciária de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade , Especificidade por Substrato , TermodinâmicaRESUMO
Technological performance represents an opportunity to add market value to wheat, especially considering international market and industrial sector which seek to achieve distinctive quality of their products. Genetic, metereological, and management factors are crucial to obtain the desired quality. With respect to the selection of an adequate cultivar, knowledge about the climatic limitations of the wheat-growing region and soil fertility, and accomplishing the management practices recommended by research can substantially contribute toward obtaining the physical, chemical, and biological characteristics that lend quality to flour and flour-based products, as discussed in this review.
A aptidão tecnológica representa uma oportunidade de agregar valor de mercado ao trigo, principalmente em face do mercado internacional e do setor industrial, o qual busca diferencial de qualidade aos seus produtos. Os fatores genéticos, meteorológicos e de manejo são determinantes para a obtenção da qualidade desejada. Nesse sentido, a adequada escolha da cultivar, o conhecimento das limitações climáticas da região de cultivo e da fertilidade do solo e a execução dos tratos culturais recomendados pela pesquisa podem contribuir substancialmente para a obtenção das características físicas, químicas e biológicas que conferem qualidade à farinha e aos produtos derivados de farinha, conforme abordado nesta revisão.
RESUMO
Technological performance represents an opportunity to add market value to wheat, especially considering international market and industrial sector which seek to achieve distinctive quality of their products. Genetic, metereological, and management factors are crucial to obtain the desired quality. With respect to the selection of an adequate cultivar, knowledge about the climatic limitations of the wheat-growing region and soil fertility, and accomplishing the management practices recommended by research can substantially contribute toward obtaining the physical, chemical, and biological characteristics that lend quality to flour and flour-based products, as discussed in this review.
A aptidão tecnológica representa uma oportunidade de agregar valor de mercado ao trigo, principalmente em face do mercado internacional e do setor industrial, o qual busca diferencial de qualidade aos seus produtos. Os fatores genéticos, meteorológicos e de manejo são determinantes para a obtenção da qualidade desejada. Nesse sentido, a adequada escolha da cultivar, o conhecimento das limitações climáticas da região de cultivo e da fertilidade do solo e a execução dos tratos culturais recomendados pela pesquisa podem contribuir substancialmente para a obtenção das características físicas, químicas e biológicas que conferem qualidade à farinha e aos produtos derivados de farinha, conforme abordado nesta revisão.
RESUMO
Technological performance represents an opportunity to add market value to wheat, especially considering international market and industrial sector which seek to achieve distinctive quality of their products. Genetic, metereological, and management factors are crucial to obtain the desired quality. With respect to the selection of an adequate cultivar, knowledge about the climatic limitations of the wheat-growing region and soil fertility, and accomplishing the management practices recommended by research can substantially contribute toward obtaining the physical, chemical, and biological characteristics that lend quality to flour and flour-based products, as discussed in this review.
A aptidão tecnológica representa uma oportunidade de agregar valor de mercado ao trigo, principalmente em face do mercado internacional e do setor industrial, o qual busca diferencial de qualidade aos seus produtos. Os fatores genéticos, meteorológicos e de manejo são determinantes para a obtenção da qualidade desejada. Nesse sentido, a adequada escolha da cultivar, o conhecimento das limitações climáticas da região de cultivo e da fertilidade do solo e a execução dos tratos culturais recomendados pela pesquisa podem contribuir substancialmente para a obtenção das características físicas, químicas e biológicas que conferem qualidade à farinha e aos produtos derivados de farinha, conforme abordado nesta revisão.