The RFK catalytic cycle of the pathogen Streptococcus pneumoniae shows species-specific features in prokaryotic FMN synthesis.
Maria Sebastian-ValverdeAdrián Velázquez-CampoyMilagros MedinaPublished in: Journal of enzyme inhibition and medicinal chemistry (2018)
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.
Keyphrases
- multidrug resistant
- electronic health record
- big data
- endothelial cells
- healthcare
- small molecule
- fatty acid
- candida albicans
- transcription factor
- genetic diversity
- molecular dynamics simulations
- high throughput
- molecular dynamics
- escherichia coli
- acinetobacter baumannii
- artificial intelligence
- machine learning
- intensive care unit
- klebsiella pneumoniae
- highly efficient
- dna binding
- aqueous solution
- pluripotent stem cells