N-Acetylglutamate synthase explained

N-Acetylglutamate synthase
Symbol:NAGS
Hgncid:17996
Chromosome:17
Arm:q
Band:21.31
Ecnumber:2.3.1.1
Omim:608300
Entrezgene:162417
Refseq:NM_153006
Uniprot:Q8N159

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

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]

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

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. This is suspected to be a result of the structural similarities between NAG and carbamoyl glutamate, which allows carbamoyl glutamate to act as an effective agonist for CPS1.

External links

Notes and References

  1. Meijer AJ, Lof C, Ramos IC, Verhoeven AJ . Control of ureogenesis . European Journal of Biochemistry . 148 . 1 . 189–96 . April 1985 . 3979393 . 10.1111/j.1432-1033.1985.tb08824.x. free .
  2. Cunin R, Glansdorff N, Piérard A, Stalon V . Biosynthesis and metabolism of arginine in bacteria . Microbiological Reviews . 50 . 3 . 314–52 . September 1986 . 3534538 . 373073 . 10.1128/MMBR.50.3.314-352.1986.
  3. Yu YG, Turner GE, Weiss RL . Acetylglutamate synthase from Neurospora crassa: structure and regulation of expression . Molecular Microbiology . 22 . 3 . 545–54 . November 1996 . 8939437 . 10.1046/j.1365-2958.1996.1321494.x . 38149253 .
  4. Caldovic L, Ah Mew N, Shi D, Morizono H, Yudkoff M, Tuchman M . N-Acetylglutamate synthase: structure, function and defects . Molecular Genetics and Metabolism . 100 . Suppl 1 . S13–9 . 2010 . 20303810 . 2876818 . 10.1016/j.ymgme.2010.02.018.
  5. Cybis J, Davis RH . Organization and control in the arginine biosynthetic pathway of Neurospora . Journal of Bacteriology . 123 . 1 . 196–202 . July 1975 . 166979 . 235707 . 10.1128/JB.123.1.196-202.1975.
  6. Sonoda T, Tatibana M . 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 . August 1983 . 10.1016/S0021-9258(17)44574-1 . 6885773 . free .
  7. Meijer AJ, Verhoeven AJ . N-Acetylglutamate and urea synthesis . The Biochemical Journal . 223 . 2 . 559–60 . October 1984 . 6497864 . 1144333 . 10.1042/bj2230559.
  8. Lund P, Wiggins D . Is N-acetylglutamate a short-term regulator of urea synthesis? . The Biochemical Journal . 218 . 3 . 991–4 . March 1984 . 6721845 . 1153434 . 10.1042/bj2180991.
  9. Caldovic L, Tuchman M . N-Acetylglutamate and its changing role through evolution . The Biochemical Journal . 372 . Pt 2 . 279–90 . June 2003 . 12633501 . 1223426 . 10.1042/BJ20030002 .
  10. Wong LJ, Wong SS . Kinetic mechanism of the reaction catalyzed by nuclear histone acetyltransferase from calf thymus . Biochemistry . 22 . 20 . 4637–41 . September 1983 . 6626521 . 10.1021/bi00289a004.
  11. Dyda F, Klein DC, Hickman AB . GCN5-related N-acetyltransferases: a structural overview . Annual Review of Biophysics and Biomolecular Structure . 29 . 81–103 . 2000 . 10940244 . 4782277 . 10.1146/annurev.biophys.29.1.81 .
  12. Shi D, Sagar V, Jin Z, Yu X, Caldovic L, Morizono H, Allewell NM, Tuchman M . 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 . March 2008 . 18184660 . 4099063 . 10.1074/jbc.M707678200 . free .
  13. Min L, Jin Z, Caldovic L, Morizono H, Allewell NM, Tuchman M, Shi D . Mechanism of allosteric inhibition of N-acetyl-L-glutamate synthase by L-arginine . The Journal of Biological Chemistry . 284 . 8 . 4873–80 . February 2009 . 19095660 . 2643497 . 10.1074/jbc.M805348200 . free .
  14. Morizono H, Caldovic L, Shi D, Tuchman M . Mammalian N-acetylglutamate synthase . Molecular Genetics and Metabolism . 81 . S4–11 . April 2004 . Suppl 1 . 15050968 . 3031861 . 10.1016/j.ymgme.2003.10.017 .
  15. Caldovic L, Morizono H, Panglao MG, Cheng SF, Packman S, Tuchman M . Null mutations in the N-acetylglutamate synthase gene associated with acute neonatal disease and hyperammonemia . Human Genetics . 112 . 4 . 364–8 . April 2003 . 12594532 . 10.1007/s00439-003-0909-5 . 27479847 .
  16. McCudden CR, Powers-Lee SG . Required allosteric effector site for N-acetylglutamate on carbamoyl-phosphate synthetase I . The Journal of Biological Chemistry . 271 . 30 . 18285–94 . July 1996 . 8663466 . 10.1074/jbc.271.30.18285. free .
  17. Caldovic L, Morizono H, Daikhin Y, Nissim I, McCarter RJ, Yudkoff M, Tuchman M . Restoration of ureagenesis in N-acetylglutamate synthase deficiency by N-carbamylglutamate . The Journal of Pediatrics . 145 . 4 . 552–4 . October 2004 . 15480384 . 10.1016/j.jpeds.2004.06.047 .

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