氨基酸
尿素循环
生物化学
鸟氨酸转氨酶
谷氨酸脱氢酶
分解代谢
谷氨酰胺
化学
柠檬酸循环
高氨血症
新陈代谢
精氨酸
谷氨酸受体
受体
作者
Shimin Zhao,Songhua Hu,Yuan-Xin Yang,Huida Ma,Shuxian Zhou,Yanan Qiao,Kai-Hui Zhang,Lei Zhang,Luoxiu Huang,Yiyuan Yuan,Yan Lin,Wei Xu,Yao Li,Haitao Li,Jian‐Yuan Zhao
出处
期刊:Research Square - Research Square
日期:2022-04-26
被引量:1
标识
DOI:10.21203/rs.3.rs-1567510/v1
摘要
Abstract Ammonia production via glutamate dehydrogenase is inhibited by SIRT4, a sirtuin that displays both amidase and non-amidase activities. The processes underlying the regulation of ammonia removal by amino acids remain unclear. Here, we report that SIRT4 acts as a decarbamylase that responds to amino acid sufficiency and regulates ammonia removal. Amino acids promote lysine 307 carbamylation (CP-K307) of ornithine transcarbamylase (OTC), which activates OTC and the urea cycle. Proteomic and interactome screening identified OTC as a substrate of SIRT4. SIRT4 decarbamylates CP-K307 and inactivates OTC in a NAD+-dependent manner. SIRT4 expression was transcriptionally upregulated by the amino acid insufficiency-activated GCN2–eIF2a–ATF4 axis. SIRT4 knockout in cultured cells caused higher CP-K307 levels, activated OTC, elevated urea cycle intermediates, and urea production via amino acid catabolism. Sirt4 ablation decreased mouse blood ammonia levels and ameliorated CCl4-induced hepatic encephalopathy phenotypes. We reveal that SIRT4 safeguards cellular ammonia toxicity during amino acid catabolism.
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