Lysine 88 Acetylation Negatively Regulates Ornithine Carbamoyltransferase Activity in Response to Nutrient Signals
Lysine 88 Acetylation Negatively Regulates Ornithine Carbamoyltransferase Activity in Response to Nutrient Signals
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DOI：
10.1074/jbc.m901921200
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发表时间：
2009-05-15
影响因子：
4.8
通讯作者：
Guan, Kun-Liang
中科院分区：
文献类型：
--
作者：
Yu, Wei;Lin, Yan;Guan, Kun-Liang
鸟氨酸氨基甲酰转移酶 (OTC) 是尿素循环中的关键酶，可对氨基酸分解代谢产生的铵进行解毒。 OTC 缺乏症是一种 X 连锁遗传性疾病，其范围从新生儿的致命性到成人的高氨血症和厌食症。通过乙酰化肽的亲和纯化和质谱分析，我们发现 OTC 在赖氨酸残基上被乙酰化，包括 Lys(88)，它在 OTC 缺陷患者中也发生突变。 OTC乙酰化被证实在生理条件下发生。生化特征表明，OTC Lys(88) 乙酰化会降低对氨基甲酰磷酸（两种 OTC 底物之一）的亲和力以及最大速度，而鸟氨酸（另一种 OTC 底物）的 Km 不受影响。此外，Lys(88) 乙酰化受到细胞外葡萄糖和氨基酸可用性的调节，表明 OTC 活性可能受到细胞代谢状态的调节。我们的结果提供了通过蛋白质乙酰化调节代谢酶活性的新机制的例子。
Ornithine carbamoyltransferase (OTC) is a key enzyme in the urea cycle to detoxify ammonium produced from amino acid catabolism. OTC deficiency is an X-linked genetic disorder ranging from fatal in newborns to hyperammonemia and anorexia in adults. Through affinity purification of acetylated peptides and mass spectrometry, we identified that OTC is acetylated on lysine residues, including Lys(88), which is also mutated in OTC-deficient patients. OTC acetylation was confirmed to occur under physiological conditions. Biochemical characterizations revealed that OTC Lys(88) acetylation decreases the affinity for carbamoyl phosphate, one of the two OTC substrates, and the maximum velocity, whereas the Km for ornithine, the other OTC substrate, is not affected. Furthermore, Lys(88) acetylation is regulated by both extracellular glucose and amino acid availability, indicating that OTC activity may be regulated by cellular metabolic status. Our results provide an example of the novel mechanism of regulating metabolic enzyme activity through protein acetylation.