DBPW00000001

O75746

DBPW00000001

P00367

DBPW00000001

P00480

DBPW00000001

P00505

DBPW00000001

P00966

DBPW00000001

smpdb

SMP0000001

Citrullinemia Type I

Disease

Citrullinemia Type 1, also called argininosuccinate synthetase deficiency, argininosuccinic acid synthetase deficiency or ASS deficiency, is a rare inborn error of metabolism (IEM) and autosomal recessive disorder of the urea cycle caused by a deficiency of argininosuccinate synthetase. Argininosuccinate synthetase is an important enzyme in the process of removing nitrogen from the body. This disorder is characterized by a large accumulation of ammonia in the blood as well as other bodily fluids . Symptoms of the disorder include vomiting, lethargy and intracranial pressure. Treatment with protein restriction and intravenous administration of arginine can help manage symptoms, and diet management throughout the patient’s life can also show improvement. It is estimated that citrullinemia type 1 affects 1 in 57,000 individuals.

DBPW00000002

smpdb

SMP0000002

Carbamoyl Phosphate Synthetase Deficiency

Disease

CCarbamoyl Phosphate Synthetase Deficiency, also called hyperammonemia due to carbamoyl phosphate synthetase 1 deficiency, is a rare inborn error of metabolism (IEM) and autosomal recessive disorder of the urea cycle caused by a defective CPS1 gene. The CPS1 gene codes for the protein carbamoyl phosphate synthetase I, which plays a role in the urea cycle. This disorder is characterized by a large accumulation of ammonia in the blood. Symptoms of the disorder include unusual movements, seizures, unusual sleeping or coma. Treatment with citrulline or arginine, which maintains a regular rate of protein creation. It is estimated that carbamoyl phosphate synthetase deficiency affects 1 in 800,000 individuals in Japan.

DBPW00000003

smpdb

SMP0000003

Argininosuccinic Aciduria

Disease

Argininosuccinic Aciduria, (Argininosuccinase Deficiency, Argininosuccinate Lyase Deficiency, ASL Deficiency) is an autosomal recessive disorder caused by a mutation in the ASL gene which codes for argininosuccinate lyase. It results in accumulation of citrulline, arginosuccinic acid, L-arginine, and L-glutamic acid in plasma as well as ammonia in blood. Infants are lethargic and unwilling to eat. They may develop seizures, coma, and failure to thrive as toxic ammonia accumulates.

DBPW00000004

smpdb

SMP0000004

Glycine and Serine Metabolism

Metabolic

This pathway describes the synthesis and breakdown of several small amino acids, including glycine, serine, and cysteine. All of these compounds share common intermediates and almost all can be biosynthesized from one another. Serine and glycine are not essential amino acids and can be synthesized from several routes. On the other hand, cysteine is a conditionally essential amino acid, meaning that it can be endogenously synthesized but insufficient quantities may be produced due to certain diseases or conditions. Serine is central to the synthesis and breakdown of the other two amino acids. Serine can be synthesized via glycerate, which can be converted into glycerate 3-phosphate (via glycerate kinase), which in turn is converted into phosphohydroxypyruvate by phosphoglycerate dehydrogenase and then phosphoserine (via phosphoserine transaminase) and finally to serine (via phosphoserine phosphatase). The serine synthesized via this route can be used to create cysteine and glycine through the homocysteine cycle. In the homocysteine cycle, cystathionine beta-synthase catalyzes the condensation of homocysteine and serine to give cystathionine. Cystathionine beta-lyase then converts this double amino acid to cysteine, ammonia, and alpha-ketoglutarate. Glycine is biosynthesized in the body from the amino acid serine. In most organisms, the enzyme serine hydroxymethyltransferase (SHMT) catalyzes this transformation using tetrahydrofolate (THF), leading to methylene THF and glycine. Glycine can be degraded via three pathways. The predominant pathway in animals involves the glycine cleavage system, also known as the glycine decarboxylase complex or GDC. This system is usually triggered in response to high concentrations of glycine. The system is sometimes referred to as glycine synthase when it runs in the reverse direction to produce glycine. The glycine cleavage system consists of four weakly interacting proteins: T, P, L and H-proteins. The glycine cleavage system leads to the degradation of glycine into ammonia and CO2. In the second pathway, glycine is degraded in two steps. The first step in this degradation pathway is the reverse of glycine biosynthesis from serine with serine hydroxymethyltransferase (SHMT). The serine generated via glycine is then converted into pyruvate by the enzyme known as serine dehydratase. In the third route to glycine degradation, glycine is converted into glyoxylate by D-amino acid oxidase. Glyoxylate is then oxidized by hepatic lactate dehydrogenase into oxalate in an NAD+-dependent reaction.

DBPW00000005

smpdb

SMP0000005

Pterine Biosynthesis

Metabolic

Folates are very important cofactors that provide support for many biosynthetic reactions. The reactions depicted in this pathway include reactions that are paired with transports, within the cell, travelling intracellularly, which allows folate to be absorbed by cells, as well as the synthesis of pterines, which are used in folate synthesis. Two branches are depicted: Pterin synthesis and Folate biosynthesis. In pterin synthesis, GTP is the precursor for pterin biosynthesis. In the first reaction, GTP cyclohydrolase acts to create formamidopyrimidine nucleoside triphosphate from guanosine triphosphate, which is provided from the purine metabolism pathway. Formamidopyrimidine nucleoside triphosphate then uses GTP cyclohydrolase again to create 2,5-diaminopyrimidine nucleoside triphosphate. GTP cyclohydrolase then works with 2,5-diaminopyrimidine nucleoside triphosphate to produce 2,3-diamino-6-(5’-triphosphoryl-3’,4’-trihydroxy-2’-oxopentyl)-amino-4-oxopyrimidine, which is then converted by GTP cyclohydrolase to dihydroneopterin triphosphate. Dihydroneopterin is then transported to the mitochondria and subsequently catalyzed into dyspropterin, which then exits the mitochondria to continue pterin biosynthesis. Once having been transported from the mitochondria, dyspropterin uses sepiapterin reductase, aldose reductase and carbonyl reductase [NADPH] 1 to create 6-lactoyltetrahydropterin. This compound then undergoes 2 reactions, the first being sepiapterin reductase converting 6-lactoyltetrahydropterin into tetrahydrobiopterin, the second being 6-lactoyltetrahydropterin being converted to sepiapterin. Both branches of pterin reactions then respectively end in the creation of neopterin and dihydrobiopterin.