The pupylation pathway marks proteins for prokaryotic ubiquitin-like protein (Pup)-proteasomal degradation and survival strategy of mycobacteria inside of the host macrophages. Deamidase of Pup (Dop) plays a central role in the pupylation pathway. It is still a matter of investigation to know the function of Dop in virulence of mycobacterial lineage. Hence, the present study was intended to describe the sequence–structure–function–virulence link of Dop for understanding the molecular virulence mechanism of Mycobacterium tuberculosis H37Rv (Mtb). Phylogenetic analysis of this study indicated that Dop has extensively diverged across the proteasome-harboring bacteria. The functional part of Dop was converged across the pathogenic mycobacterial lineage. The genome-wide analysis pointed out that the pupylation gene locus was identical to each other, but its genome neighborhood differed from species to species. Molecular modeling and dynamic studies proved that the predicted structure of Mtb Dop was energetically stable and low conformational freedom. Moreover, evolutionary constraints in Mtb Dop were intensively analyzed for inferring its sequence–structure–function relationships for the full virulence of Mtb. It indicated that evolutionary optimization was extensively required to stabilize its local structural environment at the side chains of mutable residues. The sequence–structure–function–virulence link of Dop might have retained in Mtb by reordering hydrophobic and hydrogen bonding patterns in the local structural environment. Thus, the results of our study provide a quest to understand the molecular virulence and pathogenesis mechanisms of Mtb during the infection process.

中文翻译：

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基于序列-结构-功能连接的结核分枝杆菌Dop异肽酶分子毒性机理的研究。

pupylation途径标记了宿主巨噬细胞内部原核泛素样蛋白（Pup）-蛋白酶体降解和分枝杆菌生存策略的蛋白。Pup（Dop）的脱酰胺酶在pupylation途径中起着核心作用。了解Dop在分枝杆菌谱系毒力中的功能仍是一个调查问题。因此，本研究旨在描述Dop的序列-结构-功能-毒力联系，以了解结核分枝杆菌的分子毒力机制。H37Rv（Mtb）。这项研究的系统发育分析表明，Dop在携带蛋白酶体的细菌中广泛分布。Dop的功能部分在致病性分枝杆菌谱系中汇聚。全基因组分析指出，pupylation基因位点彼此相同，但其基因组邻域因物种而异。分子建模和动力学研究证明，Mtb Dop的预测结构在能量上稳定且构象自由度低。此外，对Mtb Dop的进化限制进行了深入分析，以推断其对Mtb完全毒性的序列-结构-功能关系。它表明进化优化被广泛地需要以稳定其在可变残基侧链的局部结构环境。通过在局部结构环境中重新排列疏水和氢键模式，Dop的序列-结构-功能-毒力链接可能保留在Mtb中。因此，我们的研究结果为了解Mtb在感染过程中的分子毒力和发病机理提供了一个探索。