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N-Acetylglutamate synthase

Introduction

N-Acetylglutamate synthase (NAGS) is a mitochondrial enzyme involved in the Urea Cycle. The urea cycle is responsible for producing urea from toxic ammonium. NAGS is most directly used in the conversion of glutamate (glutamic acid) and Coenzyme A into N-Acetylglutamate (NAG). N-Acetylglutamate synthase was first discovered as a mammalian liver enzyme but has very low rate of conservation across phyla.

In mammals, N-Acetylglutamate synthase produces the enzyme cofactor N-Acetylglutamate which modulates Carbamoyl phosphate synthetase I activity. Carbamoyl phosphate synthetase is the first rate limiting enzyme in the Urea cycle. L-arginine, ammonium, and nutrients up-taken through the diet can regulate NAG production through NAGS. L-argninie up regulates the activity of NAGS in mammals. Between vertebral species, 197 amino acids are identical in the current NAGS alignment. In humans, NAGS is synthesized by 534 amino acids that make up a pre-protein but between humans and mice this sequence is only 63% identical.

Unlike mammalian NAGS, in bacteria and fungi NAGS is inhibited by arginine.

Structure

Mechanism of action

Implications or possible application

Because of the nature of N-Acetylglutamate synthase, symptoms of NAGS deficiency present similarly to a CPSI deficiency. Both present with elevated plasma ammonia and glutamine, reduced or absent citrulline, and normal urinary orotate [1]. To tell the difference between the two, an enzyme assay with CPSI and NAG is done. Patients with NAGS deficiency will show normal CPS activity.

It is possible to treat NAGS deficiencies with a structural analog to NAG. For many patients, N-carbamylglutamate can be used to restore proper CPSI activity.

References

Heibel, Sandra Kirsch . "PLOS." PLOS. 7.2 (2012): n. page. Web. 11 Nov. 2012. <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3287996/>.

Morizono, Hiroki, et. al. "Molecular Genetics and Metabolism." Molecular Genetics and Metabolism. 81.April (2004): 4-11. Web. 11 Nov. 2012. <http://www.sciencedirect.com.prox.lib.ncsu.edu/science/article/pii/S1096719204000046>.

Footnotes