Deoxyhypusine hydroxylase as a novel pharmacological target for ischemic stroke via inducing a unique post-translational hypusination modification

• Published in: Pharmacological research 2022-02, Vol.176, p.106046-106046, Article 106046
• Main Authors: Guo, Qiang, Zhang, Yi-Chi, Wang, Wei, Wang, Yu-Qi, Liu, Yang, Yang, Zhuo, Zhao, Mei-Mei, Feng, Na, Wang, Yan-Hang, Zhang, Xiao-Wen, Yang, Heng, Liu, Ting-Ting, Shi, Lun-Yong, Shi, Xiao-Meng, Liu, Dan, Tu, Peng-Fei, Zeng, Ke-Wu
• Format: Article
• Language: English
• Subjects: Allosteric activator; Animals; Benzopyrans - pharmacology; Benzopyrans - therapeutic use; Brain - drug effects; Brain - metabolism; Brain - pathology; Brazilin; Cells, Cultured; Deoxyhypusine hydroxylase; Female; Humans; Hypusination; Infarction, Middle Cerebral Artery - drug therapy; Infarction, Middle Cerebral Artery - metabolism; Infarction, Middle Cerebral Artery - pathology; Ischemic stroke; Ischemic Stroke - drug therapy; Ischemic Stroke - metabolism; Ischemic Stroke - pathology; Male; Mice; Mice, Inbred ICR; Mitophagy; Mixed Function Oxygenases - metabolism; Neurons - drug effects; Neurons - metabolism; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Pregnancy; Protein Processing, Post-Translational; Rats; Rats, Wistar; Zebrafish
• ISSN: 1043-6618; 1096-1186
• DOI: 10.1016/j.phrs.2021.106046

Ischemic stroke remains one of the leading causes of death worldwide, thereby highlighting the urgent necessary to identify new therapeutic targets. Deoxyhypusine hydroxylase (DOHH) is a fundamental enzyme catalyzing a unique posttranslational hypusination modification of eukaryotic translation initiation factor 5A (eIF5A) and is highly involved in the progression of several human diseases, including HIV-1 infection, cancer, malaria, and diabetes. However, the potential therapeutic role of pharmacological regulation of DOHH in ischemic stroke is still poorly understood. Our study first discovered a natural small-molecule brazilin (BZ) with an obvious neuroprotective effect against oxygen-glucose deprivation/reperfusion insult. Then, DOHH was identified as a crucial cellular target of BZ using HuProt™ human proteome microarray. By selectively binding to the Cys232 residue, BZ induced a previously undisclosed allosteric effect to significantly increase DOHH catalytic activity. Furthermore, BZ-mediated DOHH activation amplified mitophagy for mitochondrial function and morphology maintenance via DOHH/eIF5A hypusination signaling pathway, thereby protecting against ischemic neuronal injury in vitro and in vivo. Collectively, our study first identified DOHH as a previously unreported therapeutic target for ischemic stroke, and provided a future drug design direction for DOHH allosteric activators using BZ as a novel molecular template. Small-molecule brazilin shows significant neuroprotective effect against ischemic cerebral injury in vitro and in vivo. DOHH is identified as a crucial cellular target of brazilin via directly binding to Cys232. Brazilin allosterically activates DOHH conformation to promote a unique eIF5A hypusination and further induces mitophagy to exert neuroprotective effect. [Display omitted] •Brazilin is the first DOHH allosteric activator for ischemic cerebral injury.•Cys232 is a crucial small-molecule binding site for DOHH allosteric activation.•DOHH/eIF5A hypusination signaling promotes mitophagy for neuronal cell protection.•DOHH is a promising pharmacological therapeutic target against ischemic stroke.