The RFK catalytic cycle of the pathogen Streptococcus pneumoniae shows species-specific features in prokaryotic FMN synthesis

Sebastián, M. (Universidad de Zaragoza) ; Velázquez-Campoy, A. (Universidad de Zaragoza) ; Medina, M. (Universidad de Zaragoza)

Resumen: Emergence of multidrug-resistant bacteria forces us to explore new therapeutic strategies, and proteins involved in key metabolic pathways are promising anti-bacterial targets. Bifunctional flavin-adenine dinucleotide (FAD) synthetases (FADS) are prokaryotic enzymes that synthesise the flavin mononucleotide (FMN) and FAD cofactors. The FADS from the human pathogen Streptococcus pneumoniae (SpnFADS)–causative agent of pneumonia in humans - shows relevant catalytic dissimilarities compared to other FADSs. Here, by integrating thermodynamic and kinetic data, we present a global description of the riboflavin kinase activity of SpnFADS, as well as of the inhibition mechanisms regulating this activity. Our data shed light on biophysical determinants that modulate species-specific conformational changes leading to catalytically competent conformations, as well as binding rates and affinities of substrates versus products. This knowledge paves the way for the development of tools - that taking advantage of the regulatory dissimilarities during FMN biosynthesis in different species - might be used in the discovery of specific anti-pneumococcal drugs.

Idioma: Inglés

DOI: 10.1080/14756366.2018.1461857

Año: 2018

Publicado en: Journal of Enzyme Inhibition and Medicinal Chemistry 33, 1 (2018), 842-849
ISSN: 1475-6366

Factor impacto JCR: 4.027 (2018)

Categ. JCR: CHEMISTRY, MEDICINAL rank: 9 / 61 = 0.148 (2018) - Q1 - T1
Categ. JCR: BIOCHEMISTRY & MOLECULAR BIOLOGY rank: 82 / 294 = 0.279 (2018) - Q2 - T1

Factor impacto SCIMAGO: 0.781 - Drug Discovery (Q2) - Pharmacology (Q2) - Medicine (miscellaneous) (Q2)

Financiación: info:eu-repo/grantAgreement/ES/MINECO/BIO2016-75183-P

Tipo y forma: Article (Published version)

Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)