Disease relevance of ADSL

• CSF purines were grossly elevated compared with controls only in adenylosuccinate lyase (ADSL) deficiency and TB meningitis [1].
• ADSL deficiency is an inherited metabolic disease characterized by various degrees of psychomotor retardation and accumulation of dephosphorylated enzyme substrates 5-amino-4-imidazole-N-succinocarboxamide riboside (SAICAr) and succinyladenosine (SAdo) in body fluids [2].
• The equivalent positions are 62 and 69 in Bacillus subtilis ASL [3].
• Transfection of the replicated DNA into Escherichia coli gave Amps mutants [4].
• Although both the fold of the monomer and the architecture of the tetrameric assembly are similar to adenylosuccinate lyase from the thermophilic eubacterium Thermotoga maritima, the archaebacterial lyase contains unique features [5].

Psychiatry related information on ADSL

• Finally, although ADSL deficiency is a rare disorder, this diagnosis should be considered and assessed using a simple urinary screening method for the presence of succinylpurines in any patient with mental retardation of unexplained origin [6].
• Adenylosuccinate lyase (ADSL) and infantile autism: absence of previously reported point mutation [7].
• CONCLUSION: AMPS gives a different view of the patient's restitution than neuropsychological tests and may be a better indicator of the patients' ability to resume independent living [8].
• The Aachen List of Items for the Registration of Personality Disorders (AMPS) integrates the different types of disordered personality according to DSM-III-R, ICD-10, and four subaffective categories, which largely follow the typologies of Kraepelin, K [9].
• Furthermore, the Delayed sign language group performed significantly better than the ASL group on tests of speech perception and speech intelligibility [10].

High impact information on ADSL

• A point mutation in a purine nucleotide biosynthetic enzyme, adenylosuccinate lyase (ASL), segregates with the disorder [11].
• A mutation in adenylosuccinate lyase associated with mental retardation and autistic features [11].
• The point mutation results in a Ser413Pro substitution which leads to structural instability of the recombinant mutant enzyme, and this instability lowers ASL levels in lymphocytes [11].
• The compounds are dephosphorylated derivatives of the intracellular metabolites adenylosuccinate and succinylaminoimidazole carboxamide ribotide, the two substrates of adenylosuccinase (adenylosuccinate lyase, EC 4.3.2.2) [12].
• Mutation of a nuclear respiratory factor 2 binding site in the 5' untranslated region of the ADSL gene in three patients with adenylosuccinate lyase deficiency [13].

Chemical compound and disease context of ADSL

• Asn(276) of Bacillus subtilis adenylosuccinate lyase, a residue corresponding to the location of a human enzyme mutation, was replaced by Cys, Ser, Ala, Arg, and Glu [14].
• Characterization of a mutant Bacillus subtilis adenylosuccinate lyase equivalent to a mutant enzyme found in human adenylosuccinate lyase deficiency: asparagine 276 plays an important structural role [14].
• In adenylosuccinate lyase from Bacillus subtilis, Gln(212), Asn(270), and Arg(301) are conserved and located close to the succinyl moiety of docked adenylosuccinate [15].
• Site-directed mutagenesis was utilized to construct amino acid substitutions in B. subtilis adenylosuccinate lyase; Met(10), Ile(123), and Thr(367) were replaced by Leu, Trp, and Arg, respectively, and the altered enzymes were expressed in Escherichia coli [16].
• Therefore, in an attempt to produce surfaces which might diminish biomaterial-mediated thrombosis and inflammation, surface derivatization with 2-acrylamido-2-methylpropanesulphonic acid (AMPS) was carried out [17].

Biological context of ADSL

• Our findings indicate that a mutation of a regulatory region of the ADSL gene might be an unusually frequent cause of ADSL deficiency, and they suggest a role for NRF-2 in the gene regulation of the purine biosynthetic pathway [13].
• In the present study of 10 additional patients with ADSL deficiency, nine point mutations, among which seven unreported missense mutations, and the first splicing error reported in this disorder, have been identified [18].
• Up to now, nine missense mutations of the ADSL gene had been reported in six apparently unrelated sibships [18].
• Using both a somatic cell hybrid mapping panel and fluorescence in situ hybridization, we have precisely localized the human ADSL gene to chromosome 22q13.1-->q13.2 [19].
• By using a Chinese hamster ovary cell line deficient in ADSL activity, we have constructed a set of 17 somatic cell hybrids containing defined regions of human chromosome 22 [20].

Anatomical context of ADSL

• Adenylosuccinate lyase (ADSL) deficiency (MIM 103050) is an autosomal recessive inborn error of purine synthesis characterized by the accumulation in body fluids of succinylaminoimidazolecarboxamide (SAICA) riboside and succinyladenosine (S-Ado), the dephosphorylated derivatives of the two substrates of the enzyme [21].
• Patients homozygous for one of these mutations, R426H, displayed similarly decreased ADSL activities in their fibroblasts, S-Ado:SAICA riboside ratios of approximately 1 in their cerebrospinal fluid and were profoundly retarded [21].
• Delta-crystallin, the major soluble protein component in the avian eye lens, is homologous to argininosuccinate lyase (ASL) [22].
• 8. Of the two PKA inhibitors tested, H-89 (10 microM) and Rp cyclic AMPS (10 microM), the more effective inhibitor of PGE2-induced inhibition of neutrophil superoxide anion generation was H-89 (EC50s for PGE2 were 0.36 +/- 0.1 and > 10 microM, respectively) [23].
• However, AMPS derivatization unexpectedly increases the recruitment of macrophages to implanted material and promotes the formation of adherent sleeve thrombi on central venous catheters indwelling in non-anticoagulated canine femoral veins [17].

Associations of ADSL with chemical compounds

• Adenylosuccinate lyase (ADSL; also called "adenylosuccinase") catalyzes two steps in the synthesis of purine nucleotides: (1) the conversion of succinylaminoimidazolecarboxamide ribotide into aminoimidazolecarboxamide ribotide and (2) the conversion of adenylosuccinate into adenosine monophosphate [13].
• These results suggest that, in some cases, the genetic lesion of ADSL determines the ratio of its activities with S-AMP versus SAICAR, which in turn defines the S-Ado:SAICA riboside ratio and the patients' mental status [21].
• A point mutation in the ADSL gene, resulting in a predicted serine-to-proline substitution and conferring structural instability to the mutant enzyme, has been reported previously in 3 affected siblings [7].
• Such studies require availability of both ADSL substrates, 5-amino-4-imidazole-N-succinocarboxamide ribotide (SAICAR) and succinyladenosine 5'-monophosphate (SAMP) and their dephosphorylated products in sufficient amounts and purity [2].
• Although both human and B. subtilis enzymes normally have Asp at position 87 (or 69), the B. subtilis ASL has Ile and Asp at 62 and 65, respectively, whereas human ASL has Glu and Arg at the equivalent positions [3].

Enzymatic interactions of ADSL

• Adenylosuccinase (ASase) catalyses both the conversion of succinyl-aminoimidazole carboxamide ribotide (succinyl-AICAR) into AICAR and that of adenylosuccinate into AMP in the synthesis of purine nucleotides [24].

Other interactions of ADSL

• ADSL deficiency, a recessively inherited disorder, causes variable-but most often severe-mental retardation, frequently accompanied by epilepsy and/or autism [13].
• Because ADSL-deficient patients display widely variable degrees of psychomotor retardation, we have expressed eight mutated ADSL enzymes as thioredoxin fusions and compared their properties with the clinical and biochemical characteristics of 10 patients [21].
• The present study investigated three candidate genes located in this segment: GPR24, ADSL, and ST13 [25].
• Three enzymes of purine metabolism, adenylosuccinate synthetase, adenylosuccinate lyase and AMP deaminase, have been proposed to form a functional unit, termed the purine nucleotide cycle [26].
• Comparative analyses, using HPCE, high-performance liquid chromatography (HPLC) and an automated amino acid analyser, were carried out on urine and blood samples from patients with homocystinuria, cystinuria, glutathione synthetase deficiency and adenylosuccinase deficiency [27].

Analytical, diagnostic and therapeutic context of ADSL

• Rehabilitation services to four remote sites in New Brunswick were delivered via PC-based videoconferencing equipment, using ADSL connections to the Internet. Approximately 40 people used the equipment over 18 months [28].
• Using the differential display RT-PCR technology we identified the gene encoding adenylosuccinate lyase [EC 4.3.2.2] as a novel KGF-regulated gene [29].
• Capillary electrophoresis for screening of adenylosuccinate lyase deficiency [30].
• LCGreen I-based real-time PCR assays for detecting common ASL and HMGCL variants [31].
• Regional brain glucose utilization in adenylosuccinase-deficient patients measured by positron emission tomography [32].

References