Computational and Functional Genomics Group, Centre for DNA Fingerprinting and Diagnostics, Uppal, Hyderabad, 500039, Telangana, India; Graduate studies, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India.
Computational and Functional Genomics Group, Centre for DNA Fingerprinting and Diagnostics, Uppal, Hyderabad, 500039, Telangana, India.
Neurotoxicology. 2020 Mar;77:169-180. doi: 10.1016/j.neuro.2020.01.006. Epub 2020 Jan 24.
Malaria is an infectious disease that is caused by different species of Plasmodium. Several antimalarial drugs are used to counter the spread and infectivity of Plasmodium species. However, humans are also vulnerable to many of the antimalarial drugs, including the quinoline-based drugs. In particular, the antimalarial mefloquine has been reported to show adverse neuropsychiatric effects in humans. Though mefloquine is known to be neurotoxic, the molecular mechanisms associated with this phenomenon are still obscure. In this study, we show that mefloquine binds to and inactivates the human acyl-CoA binding protein (hACBP), potentially inducing redox stress in human neuroblastoma cells (IMR-32). Mefloquine occupies the acyl-CoA binding pocket of hACBP by interacting with several of the critical acyl-CoA binding amino acids. This leads to the competitive inhibition of acyl-CoA(s) binding to hACBP and to the accumulation of lipid droplets inside the IMR-32 cells. The accumulation of cytosolic lipid globules and oxidative stress finally correlates with the apoptotic death of cells. Taken together, our study deciphers a mechanistic detail of how mefloquine leads to the death of human cells by perturbing the activity of hACBP and lipid homeostasis.
疟疾是一种由不同种疟原虫引起的传染病。有几种抗疟药物被用于阻止疟原虫的传播和感染。然而，人类也容易受到许多抗疟药物的影响，包括喹啉类药物。特别是，抗疟药甲氟喹已被报道在人类中表现出不良的神经精神影响。尽管甲氟喹已知具有神经毒性，但与之相关的分子机制仍不清楚。在这项研究中，我们表明甲氟喹与人类酰基辅酶 A 结合蛋白（hACBP）结合并使其失活，可能在人神经母细胞瘤细胞（IMR-32）中诱导氧化应激。甲氟喹通过与几个关键的酰基辅酶 A 结合氨基酸相互作用，占据 hACBP 的酰基辅酶 A 结合口袋。这导致酰基辅酶 A（s）与 hACBP 的结合被竞争性抑制，并导致 IMR-32 细胞内的脂滴积累。细胞质脂滴的积累和氧化应激最终与细胞凋亡死亡相关。总之，我们的研究揭示了甲氟喹通过干扰 hACBP 的活性和脂质动态平衡导致人类细胞死亡的机制细节。
