N-Acetylglutamate synthase

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N-Acetylglutamate synthase
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N-Acetylglutamate synthase/kinase tetramer, Maricaulis maris
Identifiers
SymbolNAGS
NCBI gene 162417
HGNC 17996
OMIM 608300
RefSeq NM_153006
UniProt Q8N159
Other data
EC number 2.3.1.1
Locus Chr. 17 q21.31
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Structures Swiss-model
Domains InterPro

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

Contents

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) N-Acetylglutamate Synthase Chemical Equation.png
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) Reaction mechanism for N-acetylglutamate synthase.png
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 carbamoyl glutamate, which allows carbamoyl glutamate to act as an effective agonist for CPS1. [14]

Related Research Articles

The urea cycle (also known as the ornithine cycle) is a cycle of biochemical reactions that produces urea (NH2)2CO from ammonia (NH3). Animals that use this cycle, mainly amphibians and mammals, are called ureotelic.

<span class="mw-page-title-main">Ornithine</span> Chemical compound

Ornithine is a non-proteinogenic amino acid that plays a role in the urea cycle. Ornithine is abnormally accumulated in the body in ornithine transcarbamylase deficiency. The radical is ornithyl.

<span class="mw-page-title-main">Citrulline</span> Chemical compound

The organic compound citrulline is an α-amino acid. Its name is derived from citrullus, the Latin word for watermelon. Although named and described by gastroenterologists since the late 19th century, it was first isolated from watermelon in 1914 by Japanese researchers Yotaro Koga and Ryo Odake and further codified by Mitsunori Wada of Tokyo Imperial University in 1930. It has the formula H2NC(O)NH(CH2)3CH(NH2)CO2H. It is a key intermediate in the urea cycle, the pathway by which mammals excrete ammonia by converting it into urea. Citrulline is also produced as a byproduct of the enzymatic production of nitric oxide from the amino acid arginine, catalyzed by nitric oxide synthase.

<span class="mw-page-title-main">Ornithine transcarbamylase</span> Mammalian protein found in Homo sapiens

Ornithine transcarbamylase (OTC) is an enzyme that catalyzes the reaction between carbamoyl phosphate (CP) and ornithine (Orn) to form citrulline (Cit) and phosphate (Pi). There are two classes of OTC: anabolic and catabolic. This article focuses on anabolic OTC. Anabolic OTC facilitates the sixth step in the biosynthesis of the amino acid arginine in prokaryotes. In contrast, mammalian OTC plays an essential role in the urea cycle, the purpose of which is to capture toxic ammonia and transform it into urea, a less toxic nitrogen source, for excretion.

<span class="mw-page-title-main">Carbamoyl phosphate</span> Chemical compound

Carbamoyl phosphate is an anion of biochemical significance. In land-dwelling animals, it is an intermediary metabolite in nitrogen disposal through the urea cycle and the synthesis of pyrimidines. Its enzymatic counterpart, carbamoyl phosphate synthetase I, interacts with a class of molecules called sirtuins, NAD dependent protein deacetylases, and ATP to form carbamoyl phosphate. CP then enters the urea cycle in which it reacts with ornithine to form citrulline.

<span class="mw-page-title-main">Hyperammonemia</span> Medical condition

Hyperammonemia is a metabolic disturbance characterised by an excess of ammonia in the blood. It is a dangerous condition that may lead to brain injury and death. It may be primary or secondary.

Biosynthesis is a multi-step, enzyme-catalyzed process where substrates are converted into more complex products in living organisms. In biosynthesis, simple compounds are modified, converted into other compounds, or joined to form macromolecules. This process often consists of metabolic pathways. Some of these biosynthetic pathways are located within a single cellular organelle, while others involve enzymes that are located within multiple cellular organelles. Examples of these biosynthetic pathways include the production of lipid membrane components and nucleotides. Biosynthesis is usually synonymous with anabolism.

<span class="mw-page-title-main">Mitochondrial matrix</span> Space within the inner membrane of the mitochondrion

In the mitochondrion, the matrix is the space within the inner membrane. The word "matrix" stems from the fact that this space is viscous, compared to the relatively aqueous cytoplasm. The mitochondrial matrix contains the mitochondrial DNA, ribosomes, soluble enzymes, small organic molecules, nucleotide cofactors, and inorganic ions.[1] The enzymes in the matrix facilitate reactions responsible for the production of ATP, such as the citric acid cycle, oxidative phosphorylation, oxidation of pyruvate, and the beta oxidation of fatty acids.

<i>N</i>-Acetylglutamic acid Chemical compound

N-Acetylglutamic acid (also referred to as N-acetylglutamate, abbreviated NAG, chemical formula C7H11NO5) is biosynthesized from glutamate and acetylornithine by ornithine acetyltransferase, and from glutamic acid and acetyl-CoA by the enzyme N-acetylglutamate synthase. The reverse reaction, hydrolysis of the acetyl group, is catalyzed by a specific hydrolase. It is the first intermediate involved in the biosynthesis of arginine in prokaryotes and simple eukaryotes and a regulator in the process known as the urea cycle that converts toxic ammonia to urea for excretion from the body in vertebrates.

Carbamoyl phosphate synthetase I is a ligase enzyme located in the mitochondria involved in the production of urea. Carbamoyl phosphate synthetase I transfers an ammonia molecule to a molecule of bicarbonate that has been phosphorylated by a molecule of ATP. The resulting carbamate is then phosphorylated with another molecule of ATP. The resulting molecule of carbamoyl phosphate leaves the enzyme.

<span class="mw-page-title-main">N-Acetylglutamate synthase deficiency</span> Medical condition

N-Acetylglutamate synthase deficiency is an autosomal recessive urea cycle disorder.

<span class="mw-page-title-main">Carbamoyl phosphate synthetase</span> Class of enzymes

Carbamoyl phosphate synthetase catalyzes the ATP-dependent synthesis of carbamoyl phosphate from glutamine or ammonia and bicarbonate. This enzyme catalyzes the reaction of ATP and bicarbonate to produce carboxy phosphate and ADP. Carboxy phosphate reacts with ammonia to give carbamic acid. In turn, carbamic acid reacts with a second ATP to give carbamoyl phosphate plus ADP.

In enzymology, a N-acetylornithine carbamoyltransferase (EC 2.1.3.9) is an enzyme that catalyzes the chemical reaction

In enzymology, an aminoacylase (EC 3.5.1.14) is an enzyme that catalyzes the chemical reaction

In enzymology, a glutamate N-acetyltransferase (EC 2.3.1.35) is an enzyme that catalyzes the chemical reaction

In enzymology, an acetylornithine transaminase (EC 2.6.1.11) is an enzyme that catalyzes the chemical reaction

In enzymology, an acetylglutamate kinase is an enzyme that catalyzes the chemical reaction:

<span class="mw-page-title-main">ATCase/OTCase family</span>

In molecular biology, the ATCase/OTCase family is a protein family which contains two related enzymes: aspartate carbamoyltransferase EC 2.1.3.2 and ornithine carbamoyltransferase EC 2.1.3.3. It has been shown that these enzymes are evolutionary related. The predicted secondary structure of both enzymes is similar and there are some regions of sequence similarities. One of these regions includes three residues which have been shown, by crystallographic studies to be implicated in binding the phosphoryl group of carbamoyl phosphate and may also play a role in trimerisation of the molecules. The N-terminal domain is the carbamoyl phosphate binding domain. The C-terminal domain is an aspartate/ornithine-binding domain.

N-succinylornithine carbamoyltransferase (EC 2.1.3.11, succinylornithine transcarbamylase, N-succinyl-L-ornithine transcarbamylase, SOTCase) is an enzyme with systematic name carbamoyl phosphate:N2-succinyl-L-ornithine carbamoyltransferase. This enzyme catalyses the following chemical reaction

Carbamoyl Phosphate synthetase III is one of the three isoforms of the Carbamoyl Phosphate Synthetase, en enzyme that catalyzes the active production of carbamoyl phosphate in many organisms.

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. doi: 10.1016/S0021-9258(17)44574-1 . 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. 1 2 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. 1 2 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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