RESUMEN
Aspartate kinase (AK), an enzyme from the Wolbachia endosymbiont of Brugia malayi (WBm), plays a pivotal role in the bacterial cell wall and amino acid biosynthesis, rendering it an attractive candidate for therapeutic intervention. Allosteric inhibition of aspartate kinase is a prevalent mode of regulation across microorganisms and plants, often modulated by end products such as lysine, threonine, methionine, or meso-diaminopimelate. The intricate and diverse nature of microbial allosteric regulation underscores the need for rigorous investigation. This study employs a combined experimental and computational approach to decipher the allosteric regulation of WBmAK. Molecular Dynamics (MD) simulations elucidate that ATP (cofactor) and ASP (substrate) binding induce a closed conformation, promoting enzymatic activity. In contrast, the binding of lysine (allosteric inhibitor) leads to enzyme inactivation and an open conformation. The enzymatic assay demonstrates the optimal activity of WBmAK at 28 °C and a pH of 8.0. Notably, the allosteric inhibition study highlights lysine as a more potent inhibitor compared to threonine. Importantly, this investigation sheds light on the allosteric mechanism governing WBmAK and imparts novel insights into structure-based drug discovery, paving the way for the development of effective inhibitors against filarial pathogens.
