N-Acetylglutamate synthase

N-Acetylglutamate synthase (NAGS) is an enzyme that catalyses the production of N-acetylglutamate (NAG) from glutamate and acetyl-CoA.

N-Acetylglutamate synthase
N-Acetylglutamate synthase/kinase tetramer, Maricaulis maris
Identifiers
SymbolNAGS
NCBI gene162417
HGNC17996
OMIM608300
RefSeqNM_153006
UniProtQ8N159
Other data
EC number2.3.1.1
LocusChr. 17 q21.31

Put simply NAGS catalyzes the following reaction:

acetyl-CoA + L-glutamate → CoA + N-acetyl-L-glutamate

NAGS, a member of the N-acetyltransferase family of enzymes, is present in both prokaryotes and eukaryotes, although its role and structure differ widely depending on the species. NAG can be used in the production of ornithine and arginine, two important amino acids, or as an allosteric cofactor for carbamoyl phosphate synthase (CPS1). In mammals, NAGS is expressed primarily in the liver and small intestine, and is localized to the mitochondrial matrix.[1]

Overall reaction scheme for N-acetylglutamate (NAG) synthesis via N-acetylglutamate synthase (NAGS)

Biological function

Most prokaryotes (bacteria) and lower eukaryotes (fungus, green algae, plants, and so on) produce NAG through ornithine acetyltransferase (OAT), which is part of a ‘cyclic’ ornithine production pathway. NAGS is therefore used in a supportive role, replenishing NAG reserves as required. In some plants and bacteria, however, NAGS catalyzes the first step in a ‘linear’ arginine production pathway.[2]

The protein sequences of NAGS between prokaryotes, lower eukaryotes and higher eukaryotes have shown a remarkable lack of similarity. Sequence identity between prokaryotic and eukaryotic NAGS is largely <30%,[3] while sequence identity between lower and higher eukaryotes is ~20%.[4]

Enzyme activity of NAGS is modulated by L-arginine, which acts as an inhibitor in plant and bacterial NAGS, but an effector in vertebrates.[5][6] While the role of arginine as an inhibitor of NAG in ornithine and arginine synthesis is well understood, there is some controversy as to the role of NAG in the urea cycle.[7][8] The currently accepted role of NAG in vertebrates is as an essential allosteric cofactor for CPS1, and therefore it acts as the primary controller of flux through the urea cycle. In this role, feedback regulation from arginine would act to signal NAGS that ammonia is plentiful within the cell, and needs to be removed, accelerating NAGS function. As it stands, the evolutionary journey of NAGS from essential synthetic enzyme to primary urea cycle controller is yet to be fully understood.[9]

Mechanism
A simplified reaction mechanism for N-acetylglutamate synthase (NAGS)

Two mechanisms for N-acetyltransferase function have been proposed: a two-step, ping-pong mechanism involving transfer of the relevant acetyl group to an activated cysteine residue[10] and a one-step mechanism through direct attack of the amino nitrogen on the carbonyl group.[11] Studies conducted using NAGS derived from Neisseria gonorrhoeae suggest that NAGS proceeds through the previously described one-step mechanism.[12] In this proposal, the carbonyl group of acetyl-CoA is attacked directly by the α-amino nitrogen of glutamate. This mechanism is supported by the activation of the carbonyl through hydrogen bond polarization, as well as the absence of a suitable cysteine within the active site to act as an intermediate acceptor of the acetyl group.[13][14]

Clinical significance

Inactivity of NAGS results in N-acetylglutamate synthase deficiency, a form of hyperammonemia.[15] In many vertebrates, N-acetylglutamate is an essential allosteric cofactor of CPS1, the enzyme that catalyzes the first step of the urea cycle.[16] Without NAG stimulation, CPS1 cannot convert ammonia to carbamoyl phosphate, resulting in toxic ammonia accumulation.[17] Carbamoyl glutamate has shown promise as a possible treatment for NAGS deficiency.[15] This is suspected to be a result of the structural similarities between NAG and carabamoyl glutamate, which allows carbamoyl glutamate to act as an effective agonist for CPS1.[14]

References
  1. Meijer AJ, Lof C, Ramos IC, Verhoeven AJ (April 1985). "Control of ureogenesis". European Journal of Biochemistry. 148 (1): 189–96. doi:10.1111/j.1432-1033.1985.tb08824.x. PMID 3979393.
  2. Cunin R, Glansdorff N, Piérard A, Stalon V (September 1986). "Biosynthesis and metabolism of arginine in bacteria". Microbiological Reviews. 50 (3): 314–52. doi:10.1128/MMBR.50.3.314-352.1986. PMC 373073. PMID 3534538.
  3. Yu YG, Turner GE, Weiss RL (November 1996). "Acetylglutamate synthase from Neurospora crassa: structure and regulation of expression". Molecular Microbiology. 22 (3): 545–54. doi:10.1046/j.1365-2958.1996.1321494.x. PMID 8939437. S2CID 38149253.
  4. Caldovic L, Ah Mew N, Shi D, Morizono H, Yudkoff M, Tuchman M (2010). "N-Acetylglutamate synthase: structure, function and defects". Molecular Genetics and Metabolism. 100 (Suppl 1): S13–9. doi:10.1016/j.ymgme.2010.02.018. PMC 2876818. PMID 20303810.
  5. Cybis J, Davis RH (July 1975). "Organization and control in the arginine biosynthetic pathway of Neurospora". Journal of Bacteriology. 123 (1): 196–202. doi:10.1128/JB.123.1.196-202.1975. PMC 235707. PMID 166979.
  6. Sonoda T, Tatibana M (August 1983). "Purification of N-acetyl-L-glutamate synthetase from rat liver mitochondria and substrate and activator specificity of the enzyme". The Journal of Biological Chemistry. 258 (16): 9839–44. PMID 6885773.
  7. Meijer AJ, Verhoeven AJ (October 1984). "N-Acetylglutamate and urea synthesis". The Biochemical Journal. 223 (2): 559–60. doi:10.1042/bj2230559. PMC 1144333. PMID 6497864.
  8. Lund P, Wiggins D (March 1984). "Is N-acetylglutamate a short-term regulator of urea synthesis?". The Biochemical Journal. 218 (3): 991–4. doi:10.1042/bj2180991. PMC 1153434. PMID 6721845.
  9. Caldovic L, Tuchman M (June 2003). "N-Acetylglutamate and its changing role through evolution". The Biochemical Journal. 372 (Pt 2): 279–90. doi:10.1042/BJ20030002. PMC 1223426. PMID 12633501.
  10. Wong LJ, Wong SS (September 1983). "Kinetic mechanism of the reaction catalyzed by nuclear histone acetyltransferase from calf thymus". Biochemistry. 22 (20): 4637–41. doi:10.1021/bi00289a004. PMID 6626521.
  11. Dyda F, Klein DC, Hickman AB (2000). "GCN5-related N-acetyltransferases: a structural overview". Annual Review of Biophysics and Biomolecular Structure. 29: 81–103. doi:10.1146/annurev.biophys.29.1.81. PMC 4782277. PMID 10940244.
  12. Shi D, Sagar V, Jin Z, Yu X, Caldovic L, Morizono H, Allewell NM, Tuchman M (March 2008). "The crystal structure of N-acetyl-L-glutamate synthase from Neisseria gonorrhoeae provides insights into mechanisms of catalysis and regulation". The Journal of Biological Chemistry. 283 (11): 7176–84. doi:10.1074/jbc.M707678200. PMC 4099063. PMID 18184660.
  13. Min L, Jin Z, Caldovic L, Morizono H, Allewell NM, Tuchman M, Shi D (February 2009). "Mechanism of allosteric inhibition of N-acetyl-L-glutamate synthase by L-arginine". The Journal of Biological Chemistry. 284 (8): 4873–80. doi:10.1074/jbc.M805348200. PMC 2643497. PMID 19095660.
  14. Morizono H, Caldovic L, Shi D, Tuchman M (April 2004). "Mammalian N-acetylglutamate synthase". Molecular Genetics and Metabolism. 81 Suppl 1: S4–11. doi:10.1016/j.ymgme.2003.10.017. PMC 3031861. PMID 15050968.
  15. Caldovic L, Morizono H, Panglao MG, Cheng SF, Packman S, Tuchman M (April 2003). "Null mutations in the N-acetylglutamate synthase gene associated with acute neonatal disease and hyperammonemia". Human Genetics. 112 (4): 364–8. doi:10.1007/s00439-003-0909-5. PMID 12594532. S2CID 27479847.
  16. McCudden CR, Powers-Lee SG (July 1996). "Required allosteric effector site for N-acetylglutamate on carbamoyl-phosphate synthetase I". The Journal of Biological Chemistry. 271 (30): 18285–94. doi:10.1074/jbc.271.30.18285. PMID 8663466.
  17. Caldovic L, Morizono H, Daikhin Y, Nissim I, McCarter RJ, Yudkoff M, Tuchman M (October 2004). "Restoration of ureagenesis in N-acetylglutamate synthase deficiency by N-carbamylglutamate". The Journal of Pediatrics. 145 (4): 552–4. doi:10.1016/j.jpeds.2004.06.047. PMID 15480384.

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