N-Acetylglutamate synthetase deficiency
Encyclopedia
N-Acetylglutamate synthase deficiency is an autosomal recessive urea cycle disorder
.
and it catalyzes the very first reaction of the Urea cycle
, in which carbamoyl phosphate
is produced.
Carbamoyl Phosphate Synthase 1, abbreviated as CPS1, is activated by its natural activator N-Acetyl glutamate, which in turn is synthesized from acetyl-CoA
and glutamic acid
in the reaction catalyzed by N-Acetyl glutamate synthase, commonly called NAGS. N-Acetyl Glutamate is required for the Urea cycle
to take place.
Deficiency in N-Acetyl Glutamate Synthase or a genetic mutation in the gene coding for the enzyme, will lead to urea cycle failure in which ammonia
is not converted to urea
, but rather accumulated in blood leading to the condition called Type I Hyperammonemia. This is a severe neonatal disorder with fatal consequences, if not detected immediately upon birth.
The chromosome
found to be carrying the gene
encoding for N-Acetyl Glutamate synthetase is chromosome 17q (q stands for longer arm of the chromosome
) in humans and chromosome 11 in mice. In both organisms, the chromosome consists of seven exons and six introns and non-coding sequence
.
The cause for this disorder is a single base
deletion that led to frameshift mutation
, and thus the error in gene's coding for this specific enzyme
.
Although there is currently no cure, treatment includes injections of structurally similar compound, N-Carbamoyl-L-glutamate, an analogue of N-Acetyl Glutamate. This analogue likewise activates CPS1
. This treatment mitigates the intensity of the disorder.
If symptoms are detected early enough and the patient is injected with this compound, levels of severe mental retardation
can be slightly lessened, but brain damage
is irreversible.
Early symptoms include lethargy, vomiting
, and deep coma
.
Urea cycle disorder
An urea cycle disorder or urea cycle defect is a genetic disorder caused by a deficiency of one of the enzymes in the urea cycle which is responsible for removing ammonia from the blood stream. The urea cycle involves a series of biochemical steps in which nitrogen, a waste product of protein...
.
Mechanism
Carbamoyl phosphate synthase I is an enzyme found in mitochondrial matrixMitochondrial matrix
In the mitochondrion, the matrix contains soluble enzymes that catalyze the oxidation of pyruvate and other small organic molecules.The mitochondrial matrix also contains the mitochondria's DNA and ribosomes. The word "matrix" stems from the fact that this space is viscous, compared to the...
and it catalyzes the very first reaction of the Urea cycle
Urea cycle
The urea cycle is a cycle of biochemical reactions occurring in many animals that produces urea from ammonia . This cycle was the first metabolic cycle discovered , five years before the discovery of the TCA cycle...
, in which carbamoyl phosphate
Carbamoyl phosphate
Carbamoyl phosphate is an anion of biochemical significance. In land-dwelling animals it is an intermediary metabolite participating in the nitrogen disposal through in the urea cycle and the synthesis of pyrimidines....
is produced.
Carbamoyl Phosphate Synthase 1, abbreviated as CPS1, is activated by its natural activator N-Acetyl glutamate, which in turn is synthesized from acetyl-CoA
Acetyl-CoA
Acetyl coenzyme A or acetyl-CoA is an important molecule in metabolism, used in many biochemical reactions. Its main function is to convey the carbon atoms within the acetyl group to the citric acid cycle to be oxidized for energy production. In chemical structure, acetyl-CoA is the thioester...
and glutamic acid
Glutamic acid
Glutamic acid is one of the 20 proteinogenic amino acids, and its codons are GAA and GAG. It is a non-essential amino acid. The carboxylate anions and salts of glutamic acid are known as glutamates...
in the reaction catalyzed by N-Acetyl glutamate synthase, commonly called NAGS. N-Acetyl Glutamate is required for the Urea cycle
Urea cycle
The urea cycle is a cycle of biochemical reactions occurring in many animals that produces urea from ammonia . This cycle was the first metabolic cycle discovered , five years before the discovery of the TCA cycle...
to take place.
Deficiency in N-Acetyl Glutamate Synthase or a genetic mutation in the gene coding for the enzyme, will lead to urea cycle failure in which ammonia
Ammonia
Ammonia is a compound of nitrogen and hydrogen with the formula . It is a colourless gas with a characteristic pungent odour. Ammonia contributes significantly to the nutritional needs of terrestrial organisms by serving as a precursor to food and fertilizers. Ammonia, either directly or...
is not converted to urea
Urea
Urea or carbamide is an organic compound with the chemical formula CO2. The molecule has two —NH2 groups joined by a carbonyl functional group....
, but rather accumulated in blood leading to the condition called Type I Hyperammonemia. This is a severe neonatal disorder with fatal consequences, if not detected immediately upon birth.
Genetics
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
found to be carrying the gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
encoding for N-Acetyl Glutamate synthetase is chromosome 17q (q stands for longer arm of the chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
) in humans and chromosome 11 in mice. In both organisms, the chromosome consists of seven exons and six introns and non-coding sequence
Sequence
In mathematics, a sequence is an ordered list of objects . Like a set, it contains members , and the number of terms is called the length of the sequence. Unlike a set, order matters, and exactly the same elements can appear multiple times at different positions in the sequence...
.
Base pair
In molecular biology and genetics, the linking between two nitrogenous bases on opposite complementary DNA or certain types of RNA strands that are connected via hydrogen bonds is called a base pair...
deletion that led to frameshift mutation
Frameshift mutation
A frameshift mutation is a genetic mutation caused by indels of a number of nucleotides that is not evenly divisible by three from a DNA sequence...
, and thus the error in gene's coding for this specific enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
.
Presentation and treatment
The symptoms are visible within the first week of life and if not detected and diagnosed correctly immediately consequences are fatal.Although there is currently no cure, treatment includes injections of structurally similar compound, N-Carbamoyl-L-glutamate, an analogue of N-Acetyl Glutamate. This analogue likewise activates CPS1
Carbamoyl phosphate synthetase I
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 from glutamine to a molecule of bicarbonate that has been phosphorylated by a molecule of ATP. The resulting carbamate is...
. This treatment mitigates the intensity of the disorder.
If symptoms are detected early enough and the patient is injected with this compound, levels of severe mental retardation
Mental retardation
Mental retardation is a generalized disorder appearing before adulthood, characterized by significantly impaired cognitive functioning and deficits in two or more adaptive behaviors...
can be slightly lessened, but brain damage
Brain damage
"Brain damage" or "brain injury" is the destruction or degeneration of brain cells. Brain injuries occur due to a wide range of internal and external factors...
is irreversible.
Early symptoms include lethargy, vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
, and deep coma
Coma
In medicine, a coma is a state of unconsciousness, lasting more than 6 hours in which a person cannot be awakened, fails to respond normally to painful stimuli, light or sound, lacks a normal sleep-wake cycle and does not initiate voluntary actions. A person in a state of coma is described as...
.