Disease relevance of Adenylosuccinic acid

• Purine oversecretion in cultured murine lymphoma cells deficient in adenylosuccinate synthetase: genetic model for inherited hyperuricemia and gout [1].
• Adenylosuccinate synthetase (EC 6.3.4.4), encoded by the purA gene of Escherichia coli K12, catalyzes the synthesis of adenylosuccinate (SAMP) from IMP, the first committed step in AMP biosynthesis [2].
• Tetrameric adenylosuccinate lyase (ASL) of Bacillus subtilis catalyzes the cleavage of adenylosuccinate to form AMP and fumarate [3].
• Adenylosuccinate concentrations fell from a control value of 4.5 +/- 0.9nmol/g of kidney to 1.2 +/- 0.3nmol/g (P less than 0.005) by day 5 of acidosis and continued to fall to undetectable values by 48h after recovery [4].
• 4. Adenylosuccinate content rose to 36 nmol/g in phosphorylase kinase-deficient muscle and to 9 nmol/g in normal muscle at 45s tetanus, but then fell [5].

High impact information on Adenylosuccinic acid

• Disruption of the purine nucleotide cycle during muscle stimulation was evidenced by a greater accumulation of adenylosuccinate, the substrate for adenylosuccinate lyase, in the animals receiving AICAriboside (0.60 +/- 0.10 vs. 0.05 +/- 0.01 nmol/mumol total creatine, P less than 0.0001) [6].
• 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) [7].
• The nucleotide sequence of this gene and the physical map of the 1475-base-pair fragment on which it was cloned are identical to those of purB, which encodes the adenylosuccinate lyase (adenylosuccinate AMP-lyase, EC 4.3.2.2), an enzyme involved in the de novo synthesis of purines [8].
• Recombinant mouse muscle adenylosuccinate synthetase: overexpression, kinetics, and crystal structure [9].
• Electrical stimulation of neonatal cardiac myocytes activates the NFAT3 and GATA4 pathways and up-regulates the adenylosuccinate synthetase 1 gene [10].

Chemical compound and disease context of Adenylosuccinic acid

• The biological activity of L-alanosine AICO ribonucleoside was tested in vitro on whole tumor cells and on the isolated enzyme adenylosuccinate synthetase and in vivo on murine experimental leukemia [11].

Biological context of Adenylosuccinic acid

• Specificity of adenylosuccinate synthetase and adenylosuccinate lyase from Leishmania donovani. Selective amination of an antiprotozoal agent [12].
• Three subunits contribute amino acids to the active site of tetrameric adenylosuccinate lyase: Lys268 and Glu275 are required [3].
• These results indicate that after the initial phosphorylation of ara-M by the VZV-coded thymidine kinase, the monophosphate is demethoxylated by AMP deaminase to form ara-IMP, which is converted to ara-ATP by the sequential actions of the cellular adenylosuccinate synthetase, adenylosuccinate lyase, and nucleotide kinases [13].
• Implication of His68 in the substrate site of Bacillus subtilis adenylosuccinate lyase by mutagenesis and affinity labeling with 2-[(4-bromo-2,3-dioxobutyl)thio]adenosine 5'-monophosphate [14].
• Distribution of the other enzymes of the PNC, that is, adenylosuccinate synthetase and adenylosuccinate lyase, in the cytosol of cortex and medulla correlated with that observed for AMP deamination and IMP reamination potentials [15].

Anatomical context of Adenylosuccinic acid

• The products of the two enzyme reactions, threo-beta-fluoro-SAICAR and threo-beta-fluoroadenylosuccinate, are inhibitors of adenylosuccinate lyase purified from rat skeletal muscle [16].
• In order to determine whether this nucleobase transport system was bidirectional, mutant cell lines possessing this high affinity base transport capability were derived from a nucleoside transport-deficient derivative of an adenylosuccinate synthetase-deficient S49 cell line [17].
• Earlier studies [J. Biol. Chem. 263:15354 (1988)] showed that anabolism of ddlno in human lymphoid cells is mediated via an initial step of phosphorylation and subsequent amination to dideoxy-AMP via adenylosuccinate synthetase/lyase [18].
• These results show that the efficiency of PNC is about twice as high in the medulla cytosol as in the cortex cytosol, and that the activity of PNC in kidney is mainly limited by the activity of adenylosuccinate synthetase and supply of AMP [15].
• In contrast, in type II fibroblasts, the activity with adenylosuccinate is only 3% of normal, whereas that with succinyl-AICAR is also 30% of normal [19].

Associations of Adenylosuccinic acid with other chemical compounds

• Amplification of an adenylosuccinate synthetase gene in alanosine-resistant murine T-lymphoma cells. Molecular cloning of a cDNA encoding the "non-muscle" isozyme [20].
• The increase in IMP pool levels may result from (i) a direct inhibitory effect of ribavirin 5'-monophosphate on IMP dehydrogenase (which converts IMP to XMP) and (ii) an indirect inhibition of adenylosuccinate synthetase by the decreased GTP and dGTP pools (since GTP is an obligatory cofactor in the conversion of IMP to succinyl AMP) [21].
• In crude extracts, the molecular form of adenylosuccinate lyase is pH-dependent as studied by gel filtration and sucrose gradient centrifugation [22].
• Hydantocidin itself did not inhibit adenylosuccinate synthetase or adenylosuccinate lyase isolated from Zea mays [23].
• Active-site ligands, either adenylosuccinate or IMP and GTP, completely prevent inactivation of the enzyme by 6-BDB-TAMP, whereas IMP or IMP and aspartate is much less effective in protection [24].

Gene context of Adenylosuccinic acid

• Five MCL cell lines were analyzed for MTAP expression and for the in vitro sensitivity to L-alanosine, an inhibitor of adenylosuccinate synthetase, and hence de novo AMP synthesis [25].
• The Ade -H mutant is defective in the enzyme adenylosuccinate (AMPS) synthetase (ADSS; EC 6.3.4.4), which carries out the first of a two-step sequence in the biosynthesis of AMP from IMP, and therefore requires exogenous adenine for growth [26].
• We conclude that 6-BDB-TAMP functions as a reactive adenylosuccinate analog in modifying His141 in the substrate-binding site of adenylosuccinate lyase, where it may serve as a general base accepting a proton from the succinyl group during catalysis [27].
• AdSSL1 is 98% identical to mouse muscle type AdSS1 and contains conserved sequence and structural features of adenylosuccinate synthetase [28].
• Adenylosuccinate synthetase (AdSS) catalyses the Mg(2+) dependent formation of adenylosuccinate from IMP and aspartate, the reaction being driven by the hydrolysis of GTP to GDP [29].

Analytical, diagnostic and therapeutic context of Adenylosuccinic acid

• Mutant adenylosuccinate lyases of Bacillus subtilis were prepared by site-directed mutagenesis with replacements for His141, previously identified by affinity labeling as being in the active site [Lee, T. T., Worby, C., Dixon, J. E., and Colman, R. F. (1997) J. Biol. Chem. 272, 458-465] [30].
• High-performance liquid chromatography of proteins: purification of the acidic isozyme of adenylosuccinate synthetase from rat liver [31].
• The enzyme adenylosuccinate (sAMP) synthetase has been partially purified from Dictyostelium discoideum using hadacidin-Sepharose 4B affinity chromatography, anion-exchange high-performance liquid chromatography (HPLC), and gel-filtration HPLC, resulting in a 2600-fold purification [32].
• Purification, crystallization, and properties of adenylosuccinate synthetase from rat skeletal muscle [33].
• This review describes how the balanced application of X-ray crystallography and enzyme kinetics has advanced the comprehension of the catalytic and regulatory properties of adenylosuccinate synthetase [34].

References