Adenylosuccinate lyase deficiency
Encyclopedia
Adenylosuccinate lyase deficiency, also called adenylosuccinase deficiency, is a rare autosomal recessive
metabolic disorder characterized by the appearance of succinylaminoimidazolecarboxamide riboside
(SAICA riboside
) and succinyladenosine (S-Ado) in cerebrospinal fluid
, urine
, and to a lesser extent in plasma
.
These two succinylpurines are the dephosphorylated
derivatives of SAICA ribotide (SAICAR
) and adenylosuccinate (S-AMP), the two substrates
of adenylosuccinate lyase (ASL), which catalyzes an important reaction in the de novo pathway of purine biosynthesis. ASL catalyzes two distinct reactions in the synthesis of purine nucleotides, both of which involve the β-elimination of fumarate
to produce either aminoimidazole carboxamide ribotide (AICAR) from SAICAR or adenosine monophosphate
(AMP) from S-AMP.
The deficiency is responsible for a range of symptoms that involve psychomotor retardation, often accompanied by epileptic seizures, and autistic features. Most patients suffer from moderate to severe retardation, while rare patients display only mild psychomotor retardation
. Two common theories were proposed to account for these effects. The first is that they result from decreased concentrations of purine nucleotides needed for purine biosynthesis. Decreased concentrations, however, could not be found in various tissues taken from ASL-deficient patients, probably because purines are furnished via the purine salvage pathway and some residual activity of ASL. The second is the buildup of accumulating succinylpurines causes neurotoxic effects. In the severely affected patients, the concentration levels of SAICA riboside
and S-Ado are comparable, whereas in patients with milder forms of the disease, the ratio of S-Ado is more than double that of those more severely affected, while SAICA riboside
concentration levels remain comparable. This suggests SAICA riboside is the major contributor, while S-Ado may protect against SAICA riboside’s toxic effects.
Biochemical studies of the enzyme have focused on proteins of ASL from nonhuman species. The ASL structure from the crystallized protein of Thermotoga maritima has been used, along with DNA sequencing data, to construct homology models for a variety of other organisms, including human ASL. A variety of studies have been done using the equivalent enzyme from Bacillus subtilis
, which shares 27% identity along with about 17% similarity in amino acid sequence with the human enzyme. Homology models overlaid on each other show a high degree of overlap between the enzymes. The family of enzymes to which ASL belongs and that catalyze β-eliminations in which fumarate is one of the products are homotetramers with four active sites composed of amino acid residues from three distinct subunits. Much is known about the active site of human ASL due to studies of the active site in the B. subtilis ASL through affinity labeling and site-directed mutagenesis. While there is quite a bit of variability among species in the sequencing of ASL, the active site of the enzyme contains many residues that are conserved across species and have been shown to be critical to the enzyme’s function. His
68 and His141 seem to serve as the general acid and general base catalysts, respectively, and are critical to the catalyzing reaction of the substrate. His89 seems to enhance the binding of the substrate’s phosphoryl group and orient adenylosuccinate for catalysis. All three histidines are conserved throughout the 28 species for which the structure of ASL is known. Glu275 and Lys
268 have also been shown to contribute to the active site, indicating there are four active sites, each of which is formed from regions of three subunits. ASL deficiency in different patients is often caused by different mutations to the enzyme. More than 30 different mutations in the ASL gene have been discovered worldwide. The mutations resulting in this deficiency are spread throughout the enzyme, with the majority located far from the active site, suggesting thermal instability, rather than catalytic impairment of the active site, is the most frequent cause of the deficiency.
. ASL deficiency rose to prominence in the well documented case of Michael Dignan, a developmentally challenged youth. There is yet no cure for this deficiency.
Recessive
In genetics, the term "recessive gene" refers to an allele that causes a phenotype that is only seen in a homozygous genotype and never in a heterozygous genotype. Every person has two copies of every gene on autosomal chromosomes, one from mother and one from father...
metabolic disorder characterized by the appearance of succinylaminoimidazolecarboxamide riboside
Riboside
A riboside is any glycoside of ribose. Ribosides in the form of ribonucleosides and ribonucleotides play an important role in biochemistry....
(SAICA riboside
Riboside
A riboside is any glycoside of ribose. Ribosides in the form of ribonucleosides and ribonucleotides play an important role in biochemistry....
) and succinyladenosine (S-Ado) in cerebrospinal fluid
Cerebrospinal fluid
Cerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...
, urine
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...
, and to a lesser extent in plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
.
These two succinylpurines are the dephosphorylated
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
derivatives of SAICA ribotide (SAICAR
SAICAR
SAICAR is an intermediate in the formation of purines....
) and adenylosuccinate (S-AMP), the two substrates
Substrate (biochemistry)
In biochemistry, a substrate is a molecule upon which an enzyme acts. Enzymes catalyze chemical reactions involving the substrate. In the case of a single substrate, the substrate binds with the enzyme active site, and an enzyme-substrate complex is formed. The substrate is transformed into one or...
of adenylosuccinate lyase (ASL), which catalyzes an important reaction in the de novo pathway of purine biosynthesis. ASL catalyzes two distinct reactions in the synthesis of purine nucleotides, both of which involve the β-elimination of fumarate
Fumaric acid
Fumaric acid or trans-butenedioic acid is the chemical compound with the formula HO2CCH=CHCO2H. This white crystalline compound is one of two isomeric unsaturated dicarboxylic acids, the other being maleic acid. In fumaric acid the carboxylic acid groups are trans and in maleic acid they are cis...
to produce either aminoimidazole carboxamide ribotide (AICAR) from SAICAR or adenosine monophosphate
Adenosine monophosphate
Adenosine monophosphate , also known as 5'-adenylic acid, is a nucleotide that is used as a monomer in RNA. It is an ester of phosphoric acid and the nucleoside adenosine. AMP consists of a phosphate group, the sugar ribose, and the nucleobase adenine...
(AMP) from S-AMP.
Pathophysiology
Retardation
Retardation is the act or result of delaying; the extent to which anything is retarded or delayed; that which retards or delays. In particular, it can mean:-In engineering:* Negative acceleration in mechanics Retardation is the act or result of delaying; the extent to which anything is retarded...
. Two common theories were proposed to account for these effects. The first is that they result from decreased concentrations of purine nucleotides needed for purine biosynthesis. Decreased concentrations, however, could not be found in various tissues taken from ASL-deficient patients, probably because purines are furnished via the purine salvage pathway and some residual activity of ASL. The second is the buildup of accumulating succinylpurines causes neurotoxic effects. In the severely affected patients, the concentration levels of SAICA riboside
Riboside
A riboside is any glycoside of ribose. Ribosides in the form of ribonucleosides and ribonucleotides play an important role in biochemistry....
and S-Ado are comparable, whereas in patients with milder forms of the disease, the ratio of S-Ado is more than double that of those more severely affected, while SAICA riboside
Riboside
A riboside is any glycoside of ribose. Ribosides in the form of ribonucleosides and ribonucleotides play an important role in biochemistry....
concentration levels remain comparable. This suggests SAICA riboside is the major contributor, while S-Ado may protect against SAICA riboside’s toxic effects.
Biochemical studies of the enzyme have focused on proteins of ASL from nonhuman species. The ASL structure from the crystallized protein of Thermotoga maritima has been used, along with DNA sequencing data, to construct homology models for a variety of other organisms, including human ASL. A variety of studies have been done using the equivalent enzyme from Bacillus subtilis
Bacillus subtilis
Bacillus subtilis, known also as the hay bacillus or grass bacillus, is a Gram-positive, catalase-positive bacterium commonly found in soil. A member of the genus Bacillus, B. subtilis is rod-shaped, and has the ability to form a tough, protective endospore, allowing the organism to tolerate...
, which shares 27% identity along with about 17% similarity in amino acid sequence with the human enzyme. Homology models overlaid on each other show a high degree of overlap between the enzymes. The family of enzymes to which ASL belongs and that catalyze β-eliminations in which fumarate is one of the products are homotetramers with four active sites composed of amino acid residues from three distinct subunits. Much is known about the active site of human ASL due to studies of the active site in the B. subtilis ASL through affinity labeling and site-directed mutagenesis. While there is quite a bit of variability among species in the sequencing of ASL, the active site of the enzyme contains many residues that are conserved across species and have been shown to be critical to the enzyme’s function. His
Histidine
Histidine Histidine, an essential amino acid, has a positively charged imidazole functional group. It is one of the 22 proteinogenic amino acids. Its codons are CAU and CAC. Histidine was first isolated by German physician Albrecht Kossel in 1896. Histidine is an essential amino acid in humans...
68 and His141 seem to serve as the general acid and general base catalysts, respectively, and are critical to the catalyzing reaction of the substrate. His89 seems to enhance the binding of the substrate’s phosphoryl group and orient adenylosuccinate for catalysis. All three histidines are conserved throughout the 28 species for which the structure of ASL is known. Glu275 and Lys
Lysine
Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
268 have also been shown to contribute to the active site, indicating there are four active sites, each of which is formed from regions of three subunits. ASL deficiency in different patients is often caused by different mutations to the enzyme. More than 30 different mutations in the ASL gene have been discovered worldwide. The mutations resulting in this deficiency are spread throughout the enzyme, with the majority located far from the active site, suggesting thermal instability, rather than catalytic impairment of the active site, is the most frequent cause of the deficiency.
History
As of 2004, about 60 patients had been diagnosed with ASL deficiency, but many more are thought to be undiagnosed, due to the heterogeneity of the disease and a paucity of general screening. Patients have been diagnosed from a number of areas around the world, although a large number of them are from the Low CountriesLow Countries
The Low Countries are the historical lands around the low-lying delta of the Rhine, Scheldt, and Meuse rivers, including the modern countries of Belgium, the Netherlands, Luxembourg and parts of northern France and western Germany....
. ASL deficiency rose to prominence in the well documented case of Michael Dignan, a developmentally challenged youth. There is yet no cure for this deficiency.