Abstract:
Comprehending the molecular strategies employed by Mycobacterium tuberculosis (Mtb) in FAS-II regulation is of paramount significance for curbing tuberculosis progression. Mtb employs two sets of dehydratases, namely HadAB and HadBC (β-hydroxyacyl acyl carrier protein dehydratase), for the regulation of the fatty acid synthase (FAS-II) pathway. We utilized a sequence similarity network to discern the basis for the presence of two copies of the dehydratase gene in Mtb. This analysis groups HadC and HadA in different clusters, which could be attributed to the variability in their physiological role with respect to the acyl chain uptake. Our study reveals structural details pertaining to the crystal structure of the last remaining enzyme of the FAS-II pathway. It also provides insights into the highly flexible hot-dog helix and substrate regulatory loop. Additionally, mutational studies assisted in establishing the role of the C-terminal end in HadC of HadBC in the regulation of acyl carrier protein from Mtb-mediated interactions. Complemented with surface plasmon resonance and molecular dynamics simulation studies, the present study provides the first evidence of the molecular mechanisms involved in the differential binding affinity of the acyl carrier protein from Mtb towards both mtbHadAB and mtbHadBC.
摘要:
了解结核分枝杆菌(Mtb)在FAS-II调节中采用的分子策略对于遏制结核病进展至关重要。Mtb使用两套脱水酶,即HadAB和HadBC(β-羟酰基酰基载体蛋白脱水酶),用于调节脂肪酸合成酶(FAS-II)途径。我们利用序列相似性网络来辨别Mtb中存在两个拷贝的脱水酶基因的基础。此分析将HadC和HadA分为不同的簇,这可能归因于它们在酰基链摄取方面的生理作用的变异性。我们的研究揭示了与FAS-II途径的最后剩余酶的晶体结构有关的结构细节。它还提供了对高度灵活的热狗螺旋和底物调节环的见解。此外,突变研究有助于确定HadBC的HadC中C末端在调节Mtb介导的相互作用中的酰基载体蛋白中的作用。辅以表面等离子体共振和分子动力学模拟研究,本研究提供了有关Mtb酰基载体蛋白对mtbHadAB和mtbHadBC的差异结合亲和力的分子机制的第一个证据。