Lysine 88 Acetylation Negatively Regulates Ornithine Carbamoyltransferase Activity in Response to Nutrient Signals

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 peptide...

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Bibliographic Details
Published in:The Journal of biological chemistry 2009-05, Vol.284 (20), p.13669-13675
Main Authors: Yu, Wei, Lin, Yan, Yao, Jun, Huang, Wei, Lei, Qunying, Xiong, Yue, Zhao, Shimin, Guan, Kun-Liang
Format: Article
Language:English
Subjects:
Acetylation
Carbamyl Phosphate - metabolism
Cell Line
Humans
Infant, Newborn
Kinetics
Lysine - genetics
Lysine - metabolism
Mutation
Ornithine Carbamoyltransferase - genetics
Ornithine Carbamoyltransferase - metabolism
Ornithine Carbamoyltransferase Deficiency Disease - enzymology
Ornithine Carbamoyltransferase Deficiency Disease - genetics
Protein Synthesis, Post-Translational Modification, and Degradation
Signal Transduction - physiology
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Summary: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 Lys88, which is also mutated in OTC-deficient patients. OTC acetylation was confirmed to occur under physiological conditions. Biochemical characterizations revealed that OTC Lys88 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, Lys88 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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M901921200