Allen Adam M B, Maxwell Anthony
Department of Molecular Microbiology, John Innes Centre, Norwich Research Park, Norwich NR4 7UH, UK.
NAR Genom Bioinform. 2024 Aug 6;6(3):lqae085. doi: 10.1093/nargab/lqae085. eCollection 2024 Sep.
DNA topoisomerases (topos) are major targets for antimicrobial and chemotherapeutic drugs due to their fundamental roles in regulating DNA topology. Type II topos are essential for chromosome segregation and relaxing positive DNA supercoils, and are exemplified by topo II in eukaryotes, topo IV and DNA gyrase in bacteria, and topo VI in archaea. Topo VI occurs ubiquitously in plants and sporadically in bacteria, algae, and other protists and is highly homologous to Spo11, which initiates eukaryotic homologous recombination. This homology makes the two complexes difficult to distinguish by sequence and leads to discrepancies such as the identity of the putative topo VI in malarial species. A lack of understanding of the role and distribution of topo VI outside of archaea hampers its pursuit as a potential drug target, and the present study addresses this with an up-to-date and extensive phylogenetic analysis. We show that the A and B subunits of topo VI and Spo11 can be distinguished using phylogenetics and structural modelling, and that topo VI is not present in nor other members of the phylum Apicomplexa. These findings provide insights into the evolutionary relationships between topo VI and Spo11, and their adoption alongside other type II topos.
DNA拓扑异构酶（拓扑酶）是抗菌药物和化疗药物的主要靶点，因为它们在调节DNA拓扑结构中起着重要作用。II型拓扑酶对于染色体分离和松弛正超螺旋DNA至关重要，真核生物中的拓扑酶II、细菌中的拓扑酶IV和DNA促旋酶以及古细菌中的拓扑酶VI均为例证。拓扑酶VI普遍存在于植物中，在细菌、藻类和其他原生生物中偶尔出现，并且与启动真核生物同源重组的Spo11高度同源。这种同源性使得这两种复合物在序列上难以区分，并导致了诸如疟原虫物种中假定的拓扑酶VI的身份等差异。对古细菌以外的拓扑酶VI的作用和分布缺乏了解阻碍了将其作为潜在药物靶点的研究，而本研究通过最新的广泛系统发育分析解决了这一问题。我们表明，使用系统发育学和结构建模可以区分拓扑酶VI和Spo11的A和B亚基，并且在顶复门的疟原虫或其他成员中不存在拓扑酶VI。这些发现为拓扑酶VI和Spo11之间的进化关系以及它们与其他II型拓扑酶的共同存在提供了见解。
