National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), 113 Thailand Science Park, Phahonyothin Road, Khlong Nueng, Khlong Luang, Pathum Thani 12120, Thailand.
CAS-Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Chinese Academy of Sciences, Shanghai, 200032, China.
Mol Omics. 2024 Oct 28;20(9):584-594. doi: 10.1039/d4mo00088a.
The natural product 9-methoxystrobilurin G (9MG) from spp basidiomycetes is a potent and selective antimalarial. The mechanism of action of 9MG is unknown. We induced 9MG resistance in 3D7 and Dd2 strains and identified mutations associated with resistance by genome sequencing. All 9MG-resistant clones possessed missense mutations in the cytochrome b (CYTB) gene, a key component of mitochondrial complex III. The mutations map to the quinol oxidation site of CYTB, which is also the target of antimalarials such as atovaquone. In a complementary approach to identify protein targets of 9MG, a photoactivatable derivative of 9MG was synthesized and applied in chemoproteomic-based target profiling. Three components of mitochondrial complex III (QCR7, QCR9, and COX15) were specifically enriched consistent with 9MG targeting CYTB and complex III function in . Inhibition of complex III activity by 9MG was confirmed by ubiquinone cytochrome reductase assay using extract. The findings from this study may be useful for developing novel antimalarials targeting CYTB.
从 spp 担子菌中提取的天然产物 9-甲氧基曲古抑菌素 G（9MG）是一种强效且选择性的抗疟药。9MG 的作用机制尚不清楚。我们在 3D7 和 Dd2 株中诱导了 9MG 耐药性，并通过基因组测序鉴定了与耐药性相关的突变。所有 9MG 耐药克隆都在细胞色素 b（CYTB）基因中存在错义突变，该基因是线粒体复合物 III 的关键组成部分。突变位于 CYTB 的喹啉氧化位点，该位点也是阿托伐醌等抗疟药物的靶标。为了确定 9MG 的蛋白质靶标，我们合成了一种 9MG 的光活化衍生物，并应用于基于化学蛋白质组学的靶标分析。线粒体复合物 III 的三个成分（QCR7、QCR9 和 COX15）被特异性富集，这与 9MG 靶向 CYTB 和复合物 III 在 中的功能一致。用 提取物进行的 ubiquinone cytochrome reductase 测定证实了 9MG 对复合物 III 活性的抑制作用。这项研究的结果可能有助于开发针对 CYTB 的新型抗疟药物。
