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The structure of adenylosuccinate lyase, an enzyme with dual activity in the de novo purine biosynthetic pathway.

Toth EA, Yeates TO
Structure 8 163-74 (2000)
Cited: 49 times
EuropePMC logo PMID: 10673438

Abstract

Background

Adenylosuccinate lyase is an enzyme that plays a critical role in both cellular replication and metabolism via its action in the de novo purine biosynthetic pathway. Adenylosuccinate lyase is the only enzyme in this pathway to catalyze two separate reactions, enabling it to participate in the addition of a nitrogen at two different positions in adenosine monophosphate. Both reactions catalyzed by adenylosuccinate lyase involve the beta-elimination of fumarate. Enzymes that catalyze this type of reaction belong to a superfamily, the members of which are homotetramers. Because adenylosuccinate lyase plays an integral part in maintaining proper cellular metabolism, mutations in the human enzyme can have severe clinical consequences, including mental retardation with autistic features.

Results

The 1.8 A crystal structure of adenylosuccinate lyase from Thermotoga maritima has been determined by multiwavelength anomalous dispersion using the selenomethionine-substituted enzyme. The fold of the monomer is reminiscent of other members of the beta-elimination superfamily. However, its active tetrameric form exhibits striking differences in active-site architecture and cleft size.

Conclusion

This first structure of an adenylosuccinate lyase reveals that, along with the catalytic base (His141) and the catalytic acid (His68), Gln212 and Asn270 might play a vital role in catalysis by properly orienting the succinyl moiety of the substrates. We propose a model for the dual activity of adenylosuccinate lyase: a single 180 degrees bond rotation must occur in the substrate between the first and second enzymatic reactions. Modeling of the pathogenic human S413P mutation indicates that the mutation destabilizes the enzyme by disrupting the C-terminal extension.

Articles - 1c3c mentioned but not cited (4)

  1. The natural history of biocatalytic mechanisms. Nath N, Mitchell JB, Caetano-Anollés G. PLoS Comput Biol 10 e1003642 (2014)
  2. Structural studies of duck delta2 crystallin mutants provide insight into the role of Thr161 and the 280s loop in catalysis. Sampaleanu LM, Codding PW, Lobsanov YD, Tsai M, Smith GD, Horvatin C, Howell PL. Biochem J 384 437-447 (2004)
  3. Structure of Staphylococcus aureus adenylosuccinate lyase (PurB) and assessment of its potential as a target for structure-based inhibitor discovery. Fyfe PK, Dawson A, Hutchison MT, Cameron S, Hunter WN. Acta Crystallogr D Biol Crystallogr 66 881-888 (2010)
  4. The characterization of mutant Bacillus subtilis adenylosuccinate lyases corresponding to severe human adenylosuccinate lyase deficiencies. Palenchar JB, Crocco JM, Colman RF. Protein Sci 12 1694-1705 (2003)


Reviews citing this publication (9)

  1. Structural biology of the purine biosynthetic pathway. Zhang Y, Morar M, Ealick SE. Cell Mol Life Sci 65 3699-3724 (2008)
  2. From purines to purinergic signalling: molecular functions and human diseases. Huang Z, Xie N, Illes P, Di Virgilio F, Ulrich H, Semyanov A, Verkhratsky A, Sperlagh B, Yu SG, Huang C, Tang Y. Signal Transduct Target Ther 6 162 (2021)
  3. Microbial biochemistry, physiology, and biotechnology of hyperthermophilic Thermotoga species. Conners SB, Mongodin EF, Johnson MR, Montero CI, Nelson KE, Kelly RM. FEMS Microbiol Rev 30 872-905 (2006)
  4. Fumarate hydratase in cancer: A multifaceted tumour suppressor. Schmidt C, Sciacovelli M, Frezza C. Semin Cell Dev Biol 98 15-25 (2020)
  5. Fumaric aciduria: an overview and the first Brazilian case report. Allegri G, Fernandes MJ, Scalco FB, Correia P, Simoni RE, Llerena JC, de Oliveira ML. J Inherit Metab Dis 33 411-419 (2010)
  6. Optimizing therapy for argininosuccinic aciduria. Nagamani SC, Lee B, Erez A. Mol Genet Metab 107 10-14 (2012)
  7. Biochemical and molecular genetic correlation in adenylosuccinate lyase deficiency. Salerno C, Crifò C. Nucleosides Nucleotides Nucleic Acids 23 1253-1255 (2004)
  8. Fumarate hydratase (FH) and cancer: a paradigm of oncometabolism. Valcarcel-Jimenez L, Frezza C. Br J Cancer 129 1546-1557 (2023)
  9. The Pleiotropic Effects of Fumarate: From Mitochondrial Respiration to Epigenetic Rewiring and DNA Repair Mechanisms. Giallongo S, Costa F, Longhitano L, Giallongo C, Ferrigno J, Tropea E, Vicario N, Li Volti G, Parenti R, Barbagallo I, Bramanti V, Tibullo D. Metabolites 13 880 (2023)

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  1. Analysis of catalytic residues in enzyme active sites. Bartlett GJ, Porter CT, Borkakoti N, Thornton JM. J Mol Biol 324 105-121 (2002)
  2. Adenosine nucleotide biosynthesis and AMPK regulate adult life span and mediate the longevity benefit of caloric restriction in flies. Stenesen D, Suh JM, Seo J, Yu K, Lee KS, Kim JS, Min KJ, Graff JM. Cell Metab 17 101-112 (2013)
  3. The crystal structure of adenylosuccinate lyase from Pyrobaculum aerophilum reveals an intracellular protein with three disulfide bonds. Toth EA, Worby C, Dixon JE, Goedken ER, Marqusee S, Yeates TO. J Mol Biol 301 433-450 (2000)
  4. The Dual Activity Responsible for the Elongation and Branching of β-(1,3)-Glucan in the Fungal Cell Wall. Aimanianda V, Simenel C, Garnaud C, Clavaud C, Tada R, Barbin L, Mouyna I, Heddergott C, Popolo L, Ohya Y, Delepierre M, Latge JP. mBio 8 e00619-17 (2017)
  5. CO2 -dependent metabolic modulation in red blood cells stored under anaerobic conditions. Dumont LJ, D'Alessandro A, Szczepiorkowski ZM, Yoshida T. Transfusion 56 392-403 (2016)
  6. Transcriptome and proteome exploration to provide a resource for the study of Agrocybe aegerita. Wang M, Gu B, Huang J, Jiang S, Chen Y, Yin Y, Pan Y, Yu G, Li Y, Wong BH, Liang Y, Sun H. PLoS One 8 e56686 (2013)
  7. Lethal fetal and early neonatal presentation of adenylosuccinate lyase deficiency: observation of 6 patients in 4 families. Mouchegh K, Zikánová M, Hoffmann GF, Kretzschmar B, Kühn T, Mildenberger E, Stoltenburg-Didinger G, Krijt J, Dvoráková L, Honzík T, Zeman J, Kmoch S, Rossi R. J Pediatr 150 57-61.e2 (2007)
  8. Fumaric acid production by Torulopsis glabrata: engineering the urea cycle and the purine nucleotide cycle. Chen X, Wu J, Song W, Zhang L, Wang H, Liu L. Biotechnol Bioeng 112 156-167 (2015)
  9. Substrate and product complexes of Escherichia coli adenylosuccinate lyase provide new insights into the enzymatic mechanism. Tsai M, Koo J, Yip P, Colman RF, Segall ML, Howell PL. J Mol Biol 370 541-554 (2007)
  10. Biosynthesis of fluopsin C, a copper-containing antibiotic from Pseudomonas aeruginosa. Patteson JB, Putz AT, Tao L, Simke WC, Bryant LH, Britt RD, Li B. Science 374 1005-1009 (2021)
  11. Phylogenetic analysis of the genus Plasmodium based on the gene encoding adenylosuccinate lyase. Kedzierski L, Escalante AA, Isea R, Black CG, Barnwell JW, Coppel RL. Infect Genet Evol 1 297-301 (2002)
  12. Adenylosuccinate lyase of Schistosoma mansoni: gene structure, mRNA expression, and analysis of the predicted peptide structure of a potential chemotherapeutic target. Foulk BW, Pappas G, Hirai Y, Hirai H, Williams DL. Int J Parasitol 32 1487-1495 (2002)
  13. Homology Modelling and Molecular Docking Studies of Selected Substituted Benzo[d]imidazol-1-yl)methyl)benzimidamide Scaffolds on Plasmodium falciparum Adenylosuccinate Lyase Receptor. Oduselu GO, Ajani OO, Ajamma YU, Brors B, Adebiyi E. Bioinform Biol Insights 13 1177932219865533 (2019)
  14. Conformational changes upon ligand binding in the essential class II fumarase Rv1098c from Mycobacterium tuberculosis. Mechaly AE, Haouz A, Miras I, Barilone N, Weber P, Shepard W, Alzari PM, Bellinzoni M. FEBS Lett 586 1606-1611 (2012)
  15. Proteome scale comparative modeling for conserved drug and vaccine targets identification in Corynebacterium pseudotuberculosis. Hassan SS, Tiwari S, Guimarães LC, Jamal SB, Folador E, Sharma NB, de Castro Soares S, Almeida S, Ali A, Islam A, Póvoa FD, de Abreu VA, Jain N, Bhattacharya A, Juneja L, Miyoshi A, Silva A, Barh D, Turjanski A, Azevedo V, Ferreira RS. BMC Genomics 15 Suppl 7 S3 (2014)
  16. Crystal structure of thermostable aspartase from Bacillus sp. YM55-1: structure-based exploration of functional sites in the aspartase family. Fujii T, Sakai H, Kawata Y, Hata Y. J Mol Biol 328 635-654 (2003)
  17. Expression, purification, and characterization of stable, recombinant human adenylosuccinate lyase. Lee P, Colman RF. Protein Expr Purif 51 227-234 (2007)
  18. Structural and biochemical characterization of human adenylosuccinate lyase (ADSL) and the R303C ADSL deficiency-associated mutation. Ray SP, Deaton MK, Capodagli GC, Calkins LA, Sawle L, Ghosh K, Patterson D, Pegan SD. Biochemistry 51 6701-6713 (2012)
  19. Evaluation of global gene expression during cold shock in the human pathogen Vibrio vulnificus. Wood RR, Arias CR. Mar Biotechnol (NY) 13 942-954 (2011)
  20. Inhibition of defective adenylosuccinate lyase by HNE: a neurological disease that may be affected by oxidative stress. Crifò C, Siems W, Soro S, Salerno C. Biofactors 24 131-136 (2005)
  21. Structural and kinetic analysis of Schistosoma mansoni Adenylosuccinate Lyase (SmADSL). Romanello L, Serrão VHB, Torini JR, Bird LE, Nettleship JE, Rada H, Reddivari Y, Owens RJ, DeMarco R, Brandão-Neto J, Pereira HD. Mol Biochem Parasitol 214 27-35 (2017)
  22. Structural and kinetic studies on adenylosuccinate lyase from Mycobacterium smegmatis and Mycobacterium tuberculosis provide new insights on the catalytic residues of the enzyme. Banerjee S, Agrawal MJ, Mishra D, Sharan S, Balaram H, Savithri HS, Murthy MR. FEBS J 281 1642-1658 (2014)
  23. Crystal structure of the nitrosuccinate lyase CreD in complex with fumarate provides insights into the catalytic mechanism for nitrous acid elimination. Katsuyama Y, Sato Y, Sugai Y, Higashiyama Y, Senda M, Senda T, Ohnishi Y. FEBS J 285 1540-1555 (2018)
  24. Effect of a new non-cleavable substrate analog on wild-type and serine mutants in the signature sequence of adenylosuccinate lyase of Bacillus subtilis and Homo sapiens. Sivendran S, Colman RF. Protein Sci 17 1162-1174 (2008)
  25. Targeted urine metabolomics with a graphical reporting tool for rapid diagnosis of inborn errors of metabolism. Steinbusch LKM, Wang P, Waterval HWAH, Stassen FAPM, Coene KLM, Engelke UFH, Habets DDJ, Bierau J, Körver-Keularts IMLW. J Inherit Metab Dis 44 1113-1123 (2021)
  26. Proteomic analysis of sulfur-nitrogen-carbon removal by Pseudomonas sp. C27 under micro-aeration condition. Guo H, Chen C, Lee DJ, Wang A, Ren N. Enzyme Microb Technol 56 20-27 (2014)
  27. Important roles of hydroxylic amino acid residues in the function of Bacillus subtilis adenylosuccinate lyase. Segall ML, Cashman MA, Colman RF. Protein Sci 16 441-448 (2007)
  28. Purine signaling pathway dysfunction in autism spectrum disorders: Evidence from multiple omics data. Dai S, Lin J, Hou Y, Luo X, Shen Y, Ou J. Front Mol Neurosci 16 1089871 (2023)
  29. Molecular cloning, characterization and expression analysis of adenylosuccinate lyase gene in grass carp (Ctenopharyngodon idella). Yuan T, Gu JR, Gu WB, Wu J, Ge SR, Xu H. Mol Biol Rep 38 2059-2065 (2011)
  30. Coenzyme M biosynthesis in bacteria involves phosphate elimination by a functionally distinct member of the aspartase/fumarase superfamily. Partovi SE, Mus F, Gutknecht AE, Martinez HA, Tripet BP, Lange BM, DuBois JL, Peters JW. J Biol Chem 293 5236-5246 (2018)
  31. Effect of Sea Buckthorn Leaves on Inosine Monophosphate and Adenylosuccinatelyase Gene Expression in Broilers during Heat Stress. Zhao W, Chen X, Yan C, Liu H, Zhang Z, Wang P, Su J, Li Y. Asian-Australas J Anim Sci 25 92-97 (2012)
  32. Effect of toyF on wuyiencin and toyocamycin production by Streptomyces albulus CK-15. Liu B, Wei Q, Yang M, Shi L, Zhang K, Ge B. World J Microbiol Biotechnol 38 65 (2022)
  33. Identification of a S-(2-succino)cysteine breakdown pathway that uses a novel S-(2-succino) lyase. Hillmann KB, Goethel ME, Erickson NA, Niehaus TD. J Biol Chem 298 102639 (2022)
  34. Crystallization and preliminary X-ray analysis of argininosuccinate lyase from Streptococcus mutans. Cao YL, Li GL, Wang KT, Zhang HY, Li LF. Acta Crystallogr Sect F Struct Biol Cryst Commun 67 682-684 (2011)
  35. Effect of Asp69 and Arg310 on the pK of His68, a key catalytic residue of adenylosuccinate lyase. Sivendran S, Segall ML, Rancy PC, Colman RF. Protein Sci 16 1700-1707 (2007)
  36. Crystal structure of adenylosuccinate lyase from the thermophilic bacterium Thermus thermophilus HB8. Nemoto N, Kawai G, Sampei GI. Acta Crystallogr F Struct Biol Commun 79 278-284 (2023)


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