Argininosuccinate synthase
| Argininosuccinate synthetase | |||||||||
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ExPASy NiceZyme view | | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDB PDBe PDBsum | ||||||||
| Gene Ontology | AmiGO / QuickGO | ||||||||
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Chr. 9 q34.1 | |||||||
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| Argininosuccinate synthetase | |||||||||
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Argininosuccinate synthase or synthetase (ASS;
ASS is responsible for the third step of the urea cycle and one of the reactions of the citrulline-NO cycle.
Expression
The expressed ASS gene is at least 65 kb in length, including at least 12
.Mechanism
In the first step of the catalyzed reaction,
Thermodynamically, adenylation of the citrulline ureido group is more favorable than the analogous phosphorylation. Additionally, attack by citrulline at the α-phosphate of ATP produces an equivalent of pyrophosphate, which can be hydrolyzed in a thermodynamically favorable reaction to provide additional energy to drive the adenylation.[4]
Structure
Quaternary
Argininosuccinate synthetase is a homotetramer, with each subunit consisting of 412 residues.
Active site
Function
Argininosuccinate synthetase is involved in the synthesis of creatine, polyamines, arginine, urea, and nitric oxide.[9]
Arginine synthesis
The transformation of citrulline into argininosuccinate is the rate-limiting step in arginine synthesis. The activity of argininosuccinate synthetase in arginine synthesis occurs largely in at the outer
In
It is thought that regulation of argininosuccinate synthetase activity in arginine synthesis occurs primarily at the
Citrulline-NO cycle
The enzyme
In endothelial cells, it has been shown that ASS expression is increased by laminar shear stress due to pulsative blood flow.[11] Emerging evidence suggests that ASS may also be subject to regulation by phosphorylation at the Ser-328 residue by protein kinase C-α[12] and by nitrosylation at the Cys-132 residue by nitric oxide synthase.[7]
Role in disease
Citrullinemia
Citrullinemia is an inherited autosomal recessive disease.[13] At least 50 mutations that cause type I citrullinemia have been identified in the ASS gene. Most of these mutations substitute one amino acid for another in ASS. These mutations likely affect the structure of the enzyme and its ability to bind to citrulline, aspartate, and other molecules. A few mutations lead to the production of an abnormally short enzyme that cannot effectively play its role in the urea cycle.
Defects in ASS disrupt the third step of the urea cycle, preventing the liver from processing excess nitrogen into urea. As a result, nitrogen (in the form of ammonia) and other byproducts of the urea cycle (such as citrulline) build up in the bloodstream. Ammonia is toxic, particularly to the nervous system. An accumulation of ammonia during the first few days of life leads to poor feeding, vomiting, seizures, and the other signs and symptoms of type I citrullinemia.
Treatment for this defect includes a low-protein diet and dietary supplementation with arginine and phenylacetate. Arginine allows the urea cycle to complete itself, creating the substrates needed to originally fix ammonia. This will lower blood pH. Additionally, phenylacetate reacts with backed-up glutamine, resulting on phenylacetoglutamine, which can be excreted renally.[14]
Cancer
A lack of argininosuccinate synthetase expression has been observed in several types of cancer cells, including
See also
- Citrullinemia
- Urea cycle
- Synthetase
