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Structure ; 32(7): 941-952.e3, 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38677288

RESUMO

Itaconate is a key anti-inflammatory/antibacterial metabolite in pathogen-macrophage interactions that induces adaptive changes in Pseudomonas aeruginosa-exposed airways. However, the impact and mechanisms underlying itaconate metabolism remain unclear. Our study reveals that itaconate significantly upregulates the expression of pyoverdine in P. aeruginosa and enhances its tolerance to tobramycin. Notably, the enzymes responsible for efficient itaconate metabolism, PaIch and PaCcl, play crucial roles in both utilizing itaconate and clearing its toxic metabolic intermediates. By using protein crystallography and molecular dynamics simulations analyses, we have elucidated the unique catalytic center and substrate-binding pocket of PaIch, which contribute to its highly efficient catalysis. Meanwhile, analysis of PaCcl has revealed how interactions between domains regulate the conformational changes of the active sites and binding pockets, influencing the catalytic process. Overall, our research uncovers the significance and mechanisms of PaIch and PaCcl in the efficient metabolism of itaconate by P. aeruginosa.


Assuntos
Proteínas de Bactérias , Domínio Catalítico , Simulação de Dinâmica Molecular , Pseudomonas aeruginosa , Succinatos , Pseudomonas aeruginosa/metabolismo , Pseudomonas aeruginosa/enzimologia , Succinatos/metabolismo , Succinatos/química , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Cristalografia por Raios X , Hidroliases/metabolismo , Hidroliases/química , Hidroliases/genética , Ligação Proteica , Sítios de Ligação , Especificidade por Substrato
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