Sappati Subrahmanyam, Kondaka Kavya, Gabriel Iwona, Baginski Maciej
Department of Pharmaceutical Technology and Biochemistry, Gdansk University of Technology, Narutowicza St 11/12, 80-233, Gdansk, Poland.
Sci Rep. 2025 Mar 19;15(1):9467. doi: 10.1038/s41598-025-93122-1.
Topoisomerases are essential enzymes regulating DNA supercoiling and disentanglement, critical for genomic integrity. While topoisomerase inhibitors are well-established in anticancer and antibacterial chemotherapy, their potential as antifungal agents remains underexplored or even not proofed. This study investigates structural distinctions between Saccharomyces cerevisiae topoisomerase II (ScTopoII) and human topoisomerase IIα (hTopoIIα), aiming to identify if ScTopoII can be a selective target for antifungal drug development. A comprehensive sequence analysis, extending to various fungal strains and evolutionary ancient organisms, reveals dissimilarities in the transducer and transducer linker domains of these proteins, as well as in the lysine-rich K-loop region. Molecular dynamics simulations emphasize structural differences in the K-loop, α-helix (or helix-like region), and helix supporting loop region, as well as show unique patterns in hydrophilic and hydrophobic intramolecular interactions in ScTopoII. Moreover, phylogenetic comparisons support the importance of specific regions studied. The study includes topos from different organisms, highlighting discrepancies in helix stability near the K-loop and the role of helix supporting loop region. This broad analysis provides insights into the structural basis of human and fungal enzymes presenting potential pharmacophore "hot spots" in ScTopoII which may give hope for developing selective antifungal agents.
拓扑异构酶是调节DNA超螺旋和解缠结的必需酶，对基因组完整性至关重要。虽然拓扑异构酶抑制剂在抗癌和抗菌化疗中已得到充分确立，但其作为抗真菌剂的潜力仍未得到充分探索甚至尚未得到证实。本研究调查了酿酒酵母拓扑异构酶II（ScTopoII）和人类拓扑异构酶IIα（hTopoIIα）之间的结构差异，旨在确定ScTopoII是否可以成为抗真菌药物开发的选择性靶点。一项涵盖各种真菌菌株和进化古老生物的全面序列分析揭示了这些蛋白质的转导结构域和转导连接结构域以及富含赖氨酸的K环区域存在差异。分子动力学模拟强调了K环、α螺旋（或螺旋样区域）和螺旋支撑环区域的结构差异，并展示了ScTopoII中亲水和疏水分子内相互作用的独特模式。此外，系统发育比较支持所研究特定区域的重要性。该研究包括来自不同生物的拓扑异构酶，突出了K环附近螺旋稳定性的差异以及螺旋支撑环区域的作用。这一广泛分析为人类和真菌酶的结构基础提供了见解，揭示了ScTopoII中潜在的药效团“热点”，这可能为开发选择性抗真菌剂带来希望。
