Shishikura Kyosuke, Li Jiasong, Chen Yiming, McKnight Nate R, Bustin Katelyn A, Barr Eric W, Chilkamari Snehil R, Ayub Mahaa, Kim Sun Woo, Lin Zongtao, Hu Ren-Ming, Hicks Kelly, Wang Xie, O'Rourke Donald M, Bollinger J Martin, Binder Zev A, Parsons William H, Martemyanov Kirill A, Liu Aimin, Matthews Megan L
Department of Chemistry, University of Pennsylvania, Philadelphia, PA, USA.
Department of Chemistry, The University of Texas at San Antonio, TX, USA.
bioRxiv. 2024 Dec 21:2024.12.19.629450. doi: 10.1101/2024.12.19.629450.
The vasodilator hydralazine (HYZ) has been used clinically for ~ 70 years and remains on the World Health Organization's List of Essential Medicines as a therapy for preeclampsia. Despite its longstanding use and the concomitant progress toward a general understanding of vasodilation, the target and mechanism of HYZ have remained unknown. We show that HYZ selectively targets 2-aminoethanethiol dioxygenase (ADO) by chelating its metal cofactor and alkylating one of its ligands. This covalent inactivation slows entry of proteins into the Cys/N-degron pathway that ADO initiates. HYZ's capacity to stabilize regulators of G-protein signaling (RGS4/5) normally marked for degradation by ADO explains its effect on blood vessel tension and comports with prior associations of insufficient RGS levels with human preeclampsia and analogous symptoms in mice. The established importance of ADO in glioblastoma led us to test HYZ in these cell types. Indeed, a single treatment induced senescence, suggesting a potential new HYZ-based therapy for this deadly brain cancer.
血管扩张剂肼屈嗪（HYZ）已在临床上使用约70年，并且仍在世界卫生组织的基本药物清单中，作为子痫前期的一种治疗药物。尽管其长期使用以及在对血管扩张的总体理解方面取得了相应进展，HYZ的靶点和作用机制仍不清楚。我们发现，HYZ通过螯合其金属辅因子并烷基化其一个配体，选择性地靶向2-氨基乙硫醇双加氧酶（ADO）。这种共价失活减缓了蛋白质进入由ADO启动的半胱氨酸/N-降解子途径的速度。HYZ稳定通常被ADO标记为降解的G蛋白信号调节剂（RGS4/5）的能力，解释了其对血管张力的影响，并且与先前RGS水平不足与人类子痫前期及小鼠类似症状的关联相一致。ADO在胶质母细胞瘤中的既定重要性促使我们在这些细胞类型中测试HYZ。事实上，单次治疗即可诱导衰老，这表明HYZ可能成为治疗这种致命性脑癌的新疗法。
