adenylosuccinate synthase

Summary

Summary: A carbon-nitrogen ligase. During purine ribonucleotide biosynthesis, this enzyme catalyzes the synthesis of adenylosuccinate from GTP; IMP; and aspartate with the formation of orthophosphate and GDP. EC 6.3.4.4.

Top Publications

  1. Dong Q, Liu F, Myers A, Fromm H. Evidence for an arginine residue at the substrate binding site of Escherichia coli adenylosuccinate synthetase as studied by chemical modification and site-directed mutagenesis. J Biol Chem. 1991;266:12228-33 pubmed
    ..In addition, kcat of the R147L mutant decreased by a factor of 1.3 x 10(4). On the bases of these observations, it is suggested that Arg147 is critical for enzyme catalysis...
  2. Li X, Zhu Z, Mo D, Wang H, Yang S, Zhao S, et al. Comparative molecular characterization of ADSS1 and ADSS2 genes in pig (Sus scrofa). Comp Biochem Physiol B Biochem Mol Biol. 2007;147:271-7 pubmed
    ..Moreover, we found that one single nucleotide polymorphism (SNP, T/C(70)) in the ninth intron of ADSS2 gene was significantly associated with average daily gain trait (ADG, P<0.05) and loin muscle area trait (P<0.05). ..
  3. Kang C, Fromm H. Identification of an essential second metal ion in the reaction mechanism of Escherichia coli adenylosuccinate synthetase. J Biol Chem. 1995;270:15539-44 pubmed
    ..aspartate complex formation in the active site of adenylosuccinate synthetase may be important in activation of the protonated amino group of aspartate, enhancement of the enzyme's binding affinity, and its specificity for aspartate. ..
  4. Wang W, Gorrell A, Hou Z, Honzatko R, Fromm H. Ambiguities in mapping the active site of a conformationally dynamic enzyme by directed mutation. Role of dynamics in structure-function correlations in Escherichia coli adenylosuccinate synthetase. J Biol Chem. 1998;273:16000-4 pubmed
    ..The results underscore the difficulty of using directed mutations alone as a means of mapping the active site of an enzyme. ..
  5. Gallert K, Ohanjan T, Daignan Fornier B, Lottspeich F, Krauss G. Enzymatic properties and inhibition by single-stranded autonomously replicating sequences of adenylosuccinate synthase from Saccharomyces cerevisiae. Eur J Biochem. 1996;239:487-93 pubmed
    b>Adenylosuccinate synthase (ASS) from Saccharomyces cerevisiae has been shown to bind specifically to the T-rich side of the autonomously replicating sequence (ARS) core consensus sequence [Zeidler, R., Hobert, O., Johannes, L...
  6. Hitomi Y, Cirulli E, Fellay J, McHutchison J, Thompson A, Gumbs C, et al. Inosine triphosphate protects against ribavirin-induced adenosine triphosphate loss by adenylosuccinate synthase function. Gastroenterology. 2011;140:1314-21 pubmed publisher
    ..whether ITP can be used by adenosine triphosphatase (ATPase) in human erythrocytes or recombinant human adenylosuccinate synthase (ADSS)...
  7. Oshchepkova Nedosekina E, Likhoshvai V. A mathematical model for the adenylosuccinate synthetase reaction involved in purine biosynthesis. Theor Biol Med Model. 2007;4:11 pubmed
    ..35.10-3 mM/min, KmGTP = 0.023 mM, KmIMP = 0.02 mM, KmASP = 0.3 mM, KiGMP = 0.024 mM, KiGDP = 8.10-3 mM, KiAMP = 0.01 mM, KiASUC = 7.5.10-3 mM, KiSUCC = 8 mM, KmMg = 0.08 mM. ..
  8. Poland B, Silva M, Serra M, Cho Y, Kim K, Harris E, et al. Crystal structure of adenylosuccinate synthetase from Escherichia coli. Evidence for convergent evolution of GTP-binding domains. J Biol Chem. 1993;268:25334-42 pubmed
    ..We suggest that the similarities in the GTP-binding domains of the synthetase and the p21ras protein are an example of convergent evolution of two distinct families of GTP-binding proteins. ..
  9. Schmitzer P, Graupner P, Chapin E, Fields S, Gilbert J, Gray J, et al. Ribofuranosyl triazolone: a natural product herbicide with activity on adenylosuccinate synthetase following phosphorylation. J Nat Prod. 2000;63:777-81 pubmed
    ..Metabolite reversal studies suggested the target site was adenylosuccinate synthetase, which was confirmed by direct measurement of the activity of the 5'-phosphorylated derivative on the isolated enzyme. ..

More Information

Publications62

  1. Sticht H, Gallert K, Krauss G, Rosch P. Homology modeling of adenylosuccinate synthetase from Saccharomyces cerevisiae reveals a possible binding region for single-stranded ARS sequences. J Biomol Struct Dyn. 1997;14:667-75 pubmed
    ..The mutant enzyme shows larger structural fluctuations than the wild-type protein according to the results of two independent molecular dynamics simulations. ..
  2. Zhang F, Xu Y, Liu P, Fan H, Huang X, Sun G, et al. Association analyses of the interaction between the ADSS and ATM genes with schizophrenia in a Chinese population. BMC Med Genet. 2008;9:119 pubmed publisher
    The blood-derived RNA levels of the adenylosuccinate synthase (ADSS) and ataxia telangiectasia mutated (ATM) genes were found to be down- and up-regulated, respectively, in schizophrenics compared with controls, and ADSS and ATM were ..
  3. Juang R, McCue K, Ow D. Two purine biosynthetic enzymes that are required for cadmium tolerance in Schizosaccharomyces pombe utilize cysteine sulfinate in vitro. Arch Biochem Biophys. 1993;304:392-401 pubmed
    ..These observations support the genetic data implicating a link among purine biosynthetic enzymes, sulfur metabolism, and cadmium tolerance. ..
  4. Marynissen G, Sener A, Malaisse W. Occurrence of the purine nucleotide cycle in rat pancreatic islets. Biochem Med Metab Biol. 1992;48:127-36 pubmed
  5. Wen H, Xia Y, Young M, Taegtmeyer H, Kellems R. The adenylosuccinate synthetase-1 gene is activated in the hypertrophied heart. J Cell Mol Med. 2002;6:235-43 pubmed
    ..We propose that ADSS1 plays a role in the development of cardiac hypertrophy through its function in adenine nucleotide biosynthesis. ..
  6. Oka J. [The second half of de novo synthetic pathway of IMP and conversion of IMP to AMP]. Nihon Rinsho. 2003;61 Suppl 1:52-8 pubmed
  7. Wang W, Hou Z, Honzatko R, Fromm H. Relationship of conserved residues in the IMP binding site to substrate recognition and catalysis in Escherichia coli adenylosuccinate synthetase. J Biol Chem. 1997;272:16911-6 pubmed
    ..Presented here is a mechanism for the synthetase, whereby Gln224 works in concert with Asp13 to stabilize the 6-oxyanion of IMP. ..
  8. Serra M, Bass M, Fromm H, Honzatko R. Preliminary X-ray crystallographic study of adenylosuccinate synthetase from Escherichia coli. J Mol Biol. 1988;200:753-4 pubmed
    ..16 A, b = 71.99 A, c = 82.95 A, and beta = 71.52 degrees. The asymmetric units of both crystal forms probably contain the entire dimeric enzyme. ..
  9. Datta S, Guicherit O, Kellems R. Adenylosuccinate synthetase: a dominant amplifiable genetic marker in mammalian cells. Somat Cell Mol Genet. 1994;20:381-9 pubmed
    ..We demonstrated that nonselectable genes can be cotransferred and coamplified with AdSS minigenes. These findings indicate that AdSS minigenes can be used as dominant amplifiable genetic markers in mammalian cells. ..
  10. Wang W, Poland B, Honzatko R, Fromm H. Identification of arginine residues in the putative L-aspartate binding site of Escherichia coli adenylosuccinate synthetase. J Biol Chem. 1995;270:13160-3 pubmed
  11. Walters E, Lee S, Niderman T, Bernasconi P, Subramanian M, Siehl D. Adenylosuccinate synthetase from maize. Purification, properties, and mechanism of inhibition by 5'-phosphohydantocidin. Plant Physiol. 1997;114:549-55 pubmed
    ..Inhibition of AdSS by 5'-PH was competitive with IMP, with an apparent Ki of 22 nM. Apparently, 5'-PH inhibits the enzyme by binding to the IMP site and forming a tight, dead-end complex. ..
  12. Boitz J, Strasser R, Yates P, Jardim A, Ullman B. Adenylosuccinate synthetase and adenylosuccinate lyase deficiencies trigger growth and infectivity deficits in Leishmania donovani. J Biol Chem. 2013;288:8977-90 pubmed publisher
    ..donovani, both ASL and ADSS are cytosolic enzymes. Overall, these data underscore the paramount importance of ASL to purine salvage by both life cycle stages of L. donovani and authenticate ASL as a potential drug target in Leishmania...
  13. Qian J, Cai X, Chu J, Zhuang Y, Zhang S. Nucleotide mutations in purA gene and pur operon promoter discovered in guanosine- and inosine-producing Bacillus subtilis strains. Biotechnol Lett. 2006;28:937-41 pubmed publisher
    ..These mutations may explain the purine accumulation in purine-producing strains and be helpful to the rational design of high-yield recombinant strains...
  14. Ribard C, Scazzocchio C, Oestreicher N. The oxpA5 mutation of Aspergillus nidulans is an allele of adB, the gene encoding adenylosuccinate synthetase. Mol Genet Genomics. 2001;266:701-10 pubmed
    ..The adB gene is located adjacent to helA, a newly identified gene coding for a putative RNA helicase. ..
  15. Yang T, Guo M, Yang H, Guo S, Dong C. The blue-light receptor CmWC-1 mediates fruit body development and secondary metabolism in Cordyceps militaris. Appl Microbiol Biotechnol. 2016;100:743-55 pubmed publisher
    ..CmWC-1 regulates adenylosuccinate synthase, an important enzyme for adenosine de novo synthesis, which could explain the reduction in cordycepin ..
  16. Clark S, Berry S, Ewing R, Rudolph F. Regulation of purine metabolism: a comparative study of the kinetic properties of adenylosuccinate synthetases from various sources. Comp Biochem Physiol B. 1977;58:63-5 pubmed
    ..3. The kinetic properties of the enzyme are generally consistent with proposed metabolic roles in various tissues. ..
  17. Manfredi J, Marquetant R, Magid A, Holmes E. Binding of adenylosuccinate synthetase to contractile proteins of muscle. Am J Physiol. 1989;257:C29-35 pubmed
    ..2 microM and binding maximum of 2.6 nmol enzyme/mg myofibrils indicate that binding of AdSS to myofibrils can be physiologically significant. The results suggest that AdSS in muscle may be associated with the thin filament of myofibrils. ..
  18. Barbour A, Putteet Driver A, Bunikis J. Horizontally acquired genes for purine salvage in Borrelia spp. causing relapsing fever. Infect Immun. 2005;73:6165-8 pubmed
    ..These were located among the rRNA genes. Phylogenetic analysis indicated that these genes had a different evolutionary history than those of orthologs in other spirochetes. ..
  19. Lai L, Hart I, Patterson D. A gene correcting the defect in the CHO mutant Ade -H, deficient in a branch point enzyme (adenylosuccinate synthetase) of de novo purine biosynthesis, is located on the long arm of chromosome 1. Genomics. 1991;9:322-8 pubmed
    ..In summary, we have shown by cytogenetics, segregant analysis, biochemical assay, and Southern blot analysis that human chromosome 1, most likely in the region 1cen-1q12, corrects the defect in ADSS-deficient mutant Ade-H cells. ..
  20. Wang X, Wang G, Li X, Fu J, Chen T, Wang Z, et al. Directed evolution of adenylosuccinate synthetase from Bacillus subtilis and its application in metabolic engineering. J Biotechnol. 2016;231:115-121 pubmed publisher
    ..This mutation may provide a promising application in purine-based product accumulation, like inosine, guanosine and folate which are directly stemming from purine pathway in B. subtilis. ..
  21. Operti M, Vincent M, Brucher J, Van den Berghe G. Enzymes of the purine nucleotide cycle in muscle of patients with exercise intolerance. Muscle Nerve. 1998;21:401-3 pubmed
    ..They also suggest that searches are warranted for primary deficiencies of adenylosuccinate synthetase as a cause of exercise intolerance. ..
  22. Iancu C, Zhou Y, Borza T, Fromm H, Honzatko R. Cavitation as a mechanism of substrate discrimination by adenylosuccinate synthetases. Biochemistry. 2006;45:11703-11 pubmed
    ..At an approximate energy cost of 2.2 kcal/mol, the unfavorable thermodynamics of cavity formation may be the major factor in destabilizing ligands at the L-aspartate pocket. ..
  23. Vemparala S, Mehrotra S, Balaram H. Role of loop dynamics in thermal stability of mesophilic and thermophilic adenylosuccinate synthetase: a molecular dynamics and normal mode analysis study. Biochim Biophys Acta. 2011;1814:630-7 pubmed publisher
  24. Bønsdorff T, Gautier M, Farstad W, Rønningen K, Lingaas F, Olsaker I. Mapping of the bovine genes of the de novo AMP synthesis pathway. Anim Genet. 2004;35:438-44 pubmed
    ..ADSL), 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC) and adenylosuccinate synthase (ADSS)], were identified...
  25. Connolly J, Boldock E, Prince L, Renshaw S, Whyte M, Foster S. Identification of Staphylococcus aureus Factors Required for Pathogenicity and Growth in Human Blood. Infect Immun. 2017;85: pubmed publisher
    ..Our work highlights pabA and the pyrimidine salvage pathway as potential targets for novel therapeutics and suggests a previously undefined role for a human blood factor in the activity of sulfonamide antibiotics. ..
  26. Miller J, Blake D, Herzog C. Adenylosuccinate synthetase 1 gene is a novel target of deletion in lung adenocarcinoma. Mol Carcinog. 2009;48:1116-22 pubmed publisher
    ..These results implicate ADSS1 inactivation as a novel somatic alteration in lung carcinogenesis, and suggest that its selective deletion in LAC may be triggered by CIN. ..
  27. Suparmin A, Kato T, Dohra H, Park E. Insight into cordycepin biosynthesis of Cordyceps militaris: Comparison between a liquid surface culture and a submerged culture through transcriptomic analysis. PLoS ONE. 2017;12:e0187052 pubmed publisher
    ..Our analysis paves the way for unraveling the cordycepin biosynthesis pathway and for improving cordycepin production in C. militaris...
  28. Honzatko R, Stayton M, Fromm H. Adenylosuccinate synthetase: recent developments. Adv Enzymol Relat Areas Mol Biol. 1999;73:57-102, ix-x pubmed
    ..Finally, this review explores the current status of investigations on gene structure and gene expression in a number of organisms. ..
  29. Kang C, Fromm H. Characterization of the putative GTP-binding site residues of Escherichia coli adenylosuccinate synthetase by site-directed mutagenesis. Arch Biochem Biophys. 1994;310:475-80 pubmed
    ..These results suggest that the Lys331 of adenylosuccinate synthetase may play similar roles in the function and structure to that of GTP-binding proteins.(ABSTRACT TRUNCATED AT 400 WORDS) ..
  30. Cann I, Kanai S, Toh H, Ishino Y. Adenylosuccinate synthetase genes: molecular cloning and phylogenetic analysis of a highly conserved archaeal gene. Syst Appl Microbiol. 1998;21:478-86 pubmed
    ..The presence of two unique deletions in both euryarchaeal and crenarchaeal PurAs, but not in those of Bacteria and Eukarya, is a strong evidence confirming the common lineage of these two subdomains of Archaea. ..
  31. Becerra A, Lazcano A. The role of gene duplication in the evolution of purine nucleotide salvage pathways. Orig Life Evol Biosph. 1998;28:539-53 pubmed
    ..If this is the case, it implies that many purine salvage pathways appeared only after the evolution of phosphorylated sugar biosynthetic pathways made ribosides available. ..
  32. Blundell R, Williams S, Morrow C, Ericsson D, Kobe B, Fraser J. Purification, crystallization and preliminary X-ray analysis of adenylosuccinate synthetase from the fungal pathogen Cryptococcus neoformans. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2013;69:1033-6 pubmed publisher
    ..The crystals had the symmetry of space group P2(1)2(1)2(1) and diffracted to 2.2?Å resolution. ..
  33. Zeidler R, Hobert O, Johannes L, Faulhammer H, Krauss G. Characterization of two novel single-stranded DNA-specific autonomously replicating sequence-binding proteins from Saccharomyces cerevisiae, one of which is adenylosuccinate synthetase. J Biol Chem. 1993;268:20191-7 pubmed
    ..Partial amino acid sequencing and enzymatic assays identify the 45-kDa protein as adenylosuccinate synthetase, an enzyme necessary for the de novo synthesis of adenylate. ..
  34. Wiesmuller L, Wittbrodt J, Noegel A, Schleicher M. Purification and cDNA-derived sequence of adenylosuccinate synthetase from Dictyostelium discoideum. J Biol Chem. 1991;266:2480-5 pubmed
    ..The deduced amino acid sequence shows 43% identity to adenylosuccinate synthetase from Escherichia coli. Homologous regions include short sequence motifs, such as the glycine-rich loop which is typical for GTP-binding proteins. ..
  35. Wang J, Liu Y, Tang L, Qi S, Mi Y, Liu D, et al. Identification of candidate substrates of ubiquitin-specific protease 13 using 2D-DIGE. Int J Mol Med. 2017;40:47-56 pubmed publisher
    ..However, sufficient follow-up validation studies are required in order to determine whether vinculin protein directly interacts with USP13. ..
  36. Pang J, Du R, Bingham H, Juranka P, Chan V. Imbalance of purine nucleotides in alanosine-resistant baby hamster kidney cells. Somat Cell Mol Genet. 1989;15:101-11 pubmed
    ..By including erthyro-9-(2-hydroxy-3-nonyl)adenine in the AAU medium (renamed as AAUE medium) to block deamination of adenosine, AK+ BHK cells were isolated. ..
  37. Wolfe S, Smith J. Nucleotide sequence and analysis of the purA gene encoding adenylosuccinate synthetase of Escherichia coli K12. J Biol Chem. 1988;263:19147-53 pubmed
    ..The purA control region did not resemble the control regions of the other known pur loci. ..
  38. Lee P, Gorrell A, Fromm H, Colman R. 8-(4-Bromo-2,3-dioxobutylthio)guanosine 5'-triphosphate: a new affinity label for purine nucleotide sites in proteins. Arch Biochem Biophys. 1999;372:205-13 pubmed
    ..coli adenylosuccinate synthetase may accommodate 8-BDB-TGTP as a GTP analog. The new affinity label may be useful for identifying catalytic amino acid residues of protein proximal to the guanosine ring. ..
  39. Guicherit O, Rudolph F, Kellems R, Cooper B. Molecular cloning and expression of a mouse muscle cDNA encoding adenylosuccinate synthetase. J Biol Chem. 1991;266:22582-7 pubmed
    ..The availability of antibodies and cDNA clones specific for the basic isozyme of adenylosuccinate synthetase from muscle will facilitate future genetic and biochemical analysis of this protein and its role in muscle physiology. ..
  40. Nelson S, Binkowski D, Honzatko R, Fromm H. Mechanism of action of Escherichia coli phosphoribosylaminoimidazolesuccinocarboxamide synthetase. Biochemistry. 2005;44:766-74 pubmed
    ..Inhibition by IMP and maleate is consistent with a chemical mechanism for SAICAR synthetase that parallels that of adenylosuccinate synthetase. ..
  41. Moe O, Baker Malcolm J, Wang W, Kang C, Fromm H, Colman R. Involvement of arginine 143 in nucleotide substrate binding at the active site of adenylosuccinate synthetase from Escherichia coli. Biochemistry. 1996;35:9024-33 pubmed
    ..These results indicate that both subunits of dimeric adenylosuccinate synthetase contribute to each active site and that Arg-143 plays an important role in nucleotide binding. ..
  42. Mehrotra S, Bopanna M, Bulusu V, Balaram H. Adenine metabolism in Plasmodium falciparum. Exp Parasitol. 2010;125:147-51 pubmed publisher
    ..Our results implicate the role of an APRT like activity that enables parasite survival when the flux through the HGPRT pathway is blocked. ..
  43. Mehrotra S, B Ningappa M, Raman J, Anand R, Balaram H. Mutational analysis of cysteine 328 and cysteine 368 at the interface of Plasmodium falciparum adenylosuccinate synthetase. Biochim Biophys Acta. 2012;1824:589-97 pubmed publisher
    ..These observations suggest that cysteines at the dimer interface of PfAdSS may indeed be charged and exist as thiolate anion. ..
  44. Kang C, Sun N, Honzatko R, Fromm H. Replacement of Asp333 with Asn by site-directed mutagenesis changes the substrate specificity of Escherichia coli adenylosuccinate synthetase from guanosine 5'-triphosphate to xanthosine 5'-triphosphate. J Biol Chem. 1994;269:24046-9 pubmed
    ..These results demonstrate that Asp333 in the (N/T)KXD consensus sequence of adenylosuccinate synthetase from E. coli is a determinant for GTP-specificity. ..
  45. Matsui H, Kawasaki H, Shimaoka M, Kurahashi O. Investigation of various genotype characteristics for inosine accumulation in Escherichia coli W3110. Biosci Biotechnol Biochem. 2001;65:570-8 pubmed
    ..Although we investigated the effects of purR disruption and purF gene improvement, unexpectedly an increase in the inosine productivity could not be found with this mutant. ..
  46. Poland B, Hou Z, Bruns C, Fromm H, Honzatko R. Refined crystal structures of guanine nucleotide complexes of adenylosuccinate synthetase from Escherichia coli. J Biol Chem. 1996;271:15407-13 pubmed
  47. Wang W, Gorrell A, Honzatko R, Fromm H. A study of Escherichia coli adenylosuccinate synthetase association states and the interface residues of the homodimer. J Biol Chem. 1997;272:7078-84 pubmed
    ..Our results suggest that IMP binding induces enzyme dimerization and that two residues in the interface region, Arg143 and Asp231, play significant roles in IMP and GTP binding. ..
  48. Song Y, Cai X, Chu J, Zhuang Y, Zhang S. [Relationship between key enzyme activities of inosine-producing pathway and inosine accumulation]. Wei Sheng Wu Xue Bao. 2003;43:361-5 pubmed
    ..Enzymology study is believed to be an effective way to make screening of high-yield strains more efficient. ..
  49. Fonn Pfister R, Chemla P, Ward E, Girardet M, Kreuz K, Honzatko R, et al. The mode of action and the structure of a herbicide in complex with its target: binding of activated hydantocidin to the feedback regulation site of adenylosuccinate synthetase. Proc Natl Acad Sci U S A. 1996;93:9431-6 pubmed
    ..This work provides the first crystal structure of a herbicide-target complex reported to date...
  50. Downs S. High performance liquid chromatography analysis of hypoxanthine metabolism in mouse oocyte-cumulus cell complexes: effects of purine metabolic perturbants. Biol Reprod. 1994;50:1403-12 pubmed
    ..In addition, whereas metabolism favors conversion of IMP to adenyl nucleotides, synthesis of adenyl nucleotides by this route during the culture period is apparently not required for hypoxanthine-maintained meiotic arrest in vitro. ..
  51. Honzatko R, Fromm H. Structure-function studies of adenylosuccinate synthetase from Escherichia coli. Arch Biochem Biophys. 1999;370:1-8 pubmed
    ..Following the formation of 6-phosphoryl-IMP, the enzyme then catalyzes the nucleophilic displacement of the 6-phosphoryl group by the alpha-amino group of l-aspartate in a transition state, which requires two metal cations. ..
  52. Mehrotra S, Balaram H. Kinetic characterization of adenylosuccinate synthetase from the thermophilic archaea Methanocaldococcus jannaschii. Biochemistry. 2007;46:12821-32 pubmed
    ..Regulation of enzyme activity by the glycolytic intermediate, fructose 1,6 bisphosphate, was also observed with the inhibition being competitive with IMP and noncompetitive against GTP. ..
  53. Lipps G, Krauss G. Adenylosuccinate synthase from Saccharomyces cerevisiae: homologous overexpression, purification and characterization of the recombinant protein. Biochem J. 1999;341 ( Pt 3):537-43 pubmed
    b>Adenylosuccinate synthase (EC 6.3.4.4) catalyses the first committed step in the synthesis of adenosine. We have overexpressed the cloned gene of Saccharomyces cerevisiae (ADE12) in S. cerevisiae...