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Structure of aspartoacylase, the brain enzyme impaired in Canavan disease.

Bitto E, Bingman CA, Wesenberg GE, McCoy JG, Phillips GN
Proc Natl Acad Sci U S A 104 456-61 (2007)
Cited: 40 times
EuropePMC logo PMID: 17194761

Abstract

Aspartoacylase catalyzes hydrolysis of N-acetyl-l-aspartate to aspartate and acetate in the vertebrate brain. Deficiency in this activity leads to spongiform degeneration of the white matter of the brain and is the established cause of Canavan disease, a fatal progressive leukodystrophy affecting young children. We present crystal structures of recombinant human and rat aspartoacylase refined to 2.8- and 1.8-A resolution, respectively. The structures revealed that the N-terminal domain of aspartoacylase adopts a protein fold similar to that of zinc-dependent hydrolases related to carboxypeptidases A. The catalytic site of aspartoacylase shows close structural similarity to those of carboxypeptidases despite only 10-13% sequence identity between these proteins. About 100 C-terminal residues of aspartoacylase form a globular domain with a two-stranded beta-sheet linker that wraps around the N-terminal domain. The long channel leading to the active site is formed by the interface of the N- and C-terminal domains. The C-terminal domain is positioned in a way that prevents productive binding of polypeptides in the active site. The structures revealed that residues 158-164 may undergo a conformational change that results in opening and partial closing of the channel entrance. We hypothesize that the catalytic mechanism of aspartoacylase is closely analogous to that of carboxypeptidases. We identify residues involved in zinc coordination, and propose which residues may be involved in substrate binding and catalysis. The structures also provide a structural framework necessary for understanding the deleterious effects of many missense mutations of human aspartoacylase.

Articles - 2gu2 mentioned but not cited (3)

  1. Structure of aspartoacylase, the brain enzyme impaired in Canavan disease. Bitto E, Bingman CA, Wesenberg GE, McCoy JG, Phillips GN. Proc Natl Acad Sci U S A 104 456-461 (2007)
  2. Mouse aminoacylase 3: a metalloenzyme activated by cobalt and nickel. Tsirulnikov K, Abuladze N, Newman D, Ryazantsev S, Wolak T, Magilnick N, Koag MC, Kurtz I, Pushkin A. Biochim Biophys Acta 1794 1049-1057 (2009)
  3. Structures of aminoacylase 3 in complex with acetylated substrates. Hsieh JM, Tsirulnikov K, Sawaya MR, Magilnick N, Abuladze N, Kurtz I, Abramson J, Pushkin A. Proc Natl Acad Sci U S A 107 17962-17967 (2010)


Reviews citing this publication (6)

  1. Evidence that the tri-cellular metabolism of N-acetylaspartate functions as the brain's "operating system": how NAA metabolism supports meaningful intercellular frequency-encoded communications. Baslow MH. Amino Acids 39 1139-1145 (2010)
  2. Carboxypeptidases in disease: insights from peptidomic studies. Sapio MR, Fricker LD. Proteomics Clin Appl 8 327-337 (2014)
  3. Structural genomics and drug discovery: all in the family. Weigelt J, McBroom-Cerajewski LD, Schapira M, Zhao Y, Arrowsmith CH. Curr Opin Chem Biol 12 32-39 (2008)
  4. Large-scale structural biology of the human proteome. Edwards A. Annu Rev Biochem 78 541-568 (2009)
  5. Canavan disease: an Arab scenario. Zayed H. Gene 560 9-14 (2015)
  6. A thematic review of scientific and family interests in Canavan Disease: where are the developmentalists? Glicksman S, Borgen C, Blackstein M, Gordon A, Hanon I, Kusin D, Leibowitz B, Halle J. J Intellect Disabil Res 57 815-825 (2013)

Articles citing this publication (31)

  1. Long-term follow-up after gene therapy for canavan disease. Leone P, Shera D, McPhee SW, Francis JS, Kolodny EH, Bilaniuk LT, Wang DJ, Assadi M, Goldfarb O, Goldman HW, Freese A, Young D, During MJ, Samulski RJ, Janson CG. Sci Transl Med 4 165ra163 (2012)
  2. Linking mechanistic and behavioral responses to sublethal esfenvalerate exposure in the endangered delta smelt; Hypomesus transpacificus (Fam. Osmeridae). Connon RE, Geist J, Pfeiff J, Loguinov AV, D'Abronzo LS, Wintz H, Vulpe CD, Werner I. BMC Genomics 10 608 (2009)
  3. Aspartoacylase-lacZ knockin mice: an engineered model of Canavan disease. Mersmann N, Tkachev D, Jelinek R, Röth PT, Möbius W, Ruhwedel T, Rühle S, Weber-Fahr W, Sartorius A, Klugmann M. PLoS One 6 e20336 (2011)
  4. Mutational analysis of aspartoacylase: implications for Canavan disease. Hershfield JR, Pattabiraman N, Madhavarao CN, Namboodiri MA. Brain Res 1148 1-14 (2007)
  5. N-acetylaspartate (NAA) and N-acetylaspartylglutamate (NAAG) promote growth and inhibit differentiation of glioma stem-like cells. Long PM, Moffett JR, Namboodiri AMA, Viapiano MS, Lawler SE, Jaworski DM. J Biol Chem 288 26188-26200 (2013)
  6. Examination of the mechanism of human brain aspartoacylase through the binding of an intermediate analogue. Le Coq J, Pavlovsky A, Malik R, Sanishvili R, Xu C, Viola RE. Biochemistry 47 3484-3492 (2008)
  7. The molecular mechanisms affecting N-acetylaspartate homeostasis following experimental graded traumatic brain injury. Di Pietro V, Amorini AM, Tavazzi B, Vagnozzi R, Logan A, Lazzarino G, Signoretti S, Lazzarino G, Belli A. Mol Med 20 147-157 (2014)
  8. A structural and functional analysis of Nna1 in Purkinje cell degeneration (pcd) mice. Wu HY, Wang T, Li L, Correia K, Morgan JI. FASEB J 26 4468-4480 (2012)
  9. Are astrocytes the missing link between lack of brain aspartoacylase activity and the spongiform leukodystrophy in Canavan disease? Baslow MH, Guilfoyle DN. Neurochem Res 34 1523-1534 (2009)
  10. Carboxypeptidase O is a glycosylphosphatidylinositol-anchored intestinal peptidase with acidic amino acid specificity. Lyons PJ, Fricker LD. J Biol Chem 286 39023-39032 (2011)
  11. Two patients with Canavan disease and structural modeling of a novel mutation. Zaki OK, Krishnamoorthy N, El Abd HS, Harche SA, Mattar RA, Al Disi RS, Nofal MY, El Bekay R, Ahmed KA, George Priya Doss C, Zayed H. Metab Brain Dis 32 171-177 (2017)
  12. Expression and localization of myosin-1d in the developing nervous system. Benesh AE, Fleming JT, Chiang C, Carter BD, Tyska MJ. Brain Res 1440 9-22 (2012)
  13. Genome-wide gene expression profiling and mutation analysis of Saudi patients with Canavan disease. Kaya N, Imtiaz F, Colak D, Al-Sayed M, Al-Odaib A, Al-Zahrani F, Al-Mubarak BR, Al-Owain M, Al-Dhalaan H, Chedrawi A, Al-Hassnan Z, Coskun S, Sakati N, Ozand P, Meyer BF. Genet Med 10 675-684 (2008)
  14. Modification of aspartoacylase for potential use in enzyme replacement therapy for the treatment of Canavan disease. Zano S, Malik R, Szucs S, Matalon R, Viola RE. Mol Genet Metab 102 176-180 (2011)
  15. Comparative computational assessment of the pathogenicity of mutations in the Aspartoacylase enzyme. George Priya Doss C, Zayed H. Metab Brain Dis 32 2105-2118 (2017)
  16. Stimulation-induced transient changes in neuronal activity, blood flow and N-acetylaspartate content in rat prefrontal cortex: a chemogenetic fMRS-BOLD study. Baslow MH, Cain CK, Sears R, Wilson DA, Bachman A, Gerum S, Guilfoyle DN. NMR Biomed 29 1678-1687 (2016)
  17. Clinically Distinct Phenotypes of Canavan Disease Correlate with Residual Aspartoacylase Enzyme Activity. Mendes MI, Smith DE, Pop A, Lennertz P, Fernandez Ojeda MR, Kanhai WA, van Dooren SJ, Anikster Y, Barić I, Boelen C, Campistol J, de Boer L, Kariminejad A, Kayserili H, Roubertie A, Verbruggen KT, Vianey-Saban C, Williams M, Salomons GS. Hum Mutat 38 524-531 (2017)
  18. Multi-omic rejuvenation of human cells by maturation phase transient reprogramming. Gill D, Parry A, Santos F, Okkenhaug H, Todd CD, Hernando-Herraez I, Stubbs TM, Milagre I, Reik W. Elife 11 e71624 (2022)
  19. New T530C mutation in the aspartoacylase gene caused Canavan disease with no correlation between severity and N-acetylaspartate excretion. Di Pietro V, Cavallari U, Amorini AM, Lazzarino G, Longo S, Poggiani C, Cavalli P, Tavazzi B. Clin Biochem 46 1902-1904 (2013)
  20. Novel mutation in an Egyptian patient with infantile Canavan disease. Zaki OK, El Abd HS, Mohamed SA, Zayed H. Metab Brain Dis 31 573-577 (2016)
  21. Detection of Differentially Expressed Cleavage Site Intervals Within 3' Untranslated Regions Using CSI-UTR Reveals Regulated Interaction Motifs. Harrison BJ, Park JW, Gomes C, Petruska JC, Sapio MR, Iadarola MJ, Chariker JH, Rouchka EC. Front Genet 10 182 (2019)
  22. Computational analysis of deleterious missense mutations in aspartoacylase that cause Canavan's disease. Sreevishnupriya K, Chandrasekaran P, Senthilkumar A, Sethumadhavan R, Shanthi V, Daisy P, Nisha J, Ramanathan K, Rajasekaran R. Sci China Life Sci 55 1109-1119 (2012)
  23. A new T677C mutation of the aspartoacylase gene encodes for a protein with no enzymatic activity. Di Pietro V, Gambacurta A, Amorini AM, Finocchiaro A, D'Urso S, Ceccarelli L, Tavazzi B, Giardina B, Lazzarino G. Clin Biochem 41 611-615 (2008)
  24. Structural modeling of p.V31F variant in the aspartoacylase gene. Krishnamoorthy N, Zayed H. Metab Brain Dis 31 723-726 (2016)
  25. Letter Chasing N-acetyl-L-aspartate, a shiny NMR object in the brain. Baslow MH. NMR Biomed 31 e3895 (2018)
  26. Mapping the degradation pathway of a disease-linked aspartoacylase variant. Gersing SK, Wang Y, Grønbæk-Thygesen M, Kampmeyer C, Clausen L, Willemoës M, Andréasson C, Stein A, Lindorff-Larsen K, Hartmann-Petersen R. PLoS Genet 17 e1009539 (2021)
  27. Myelination Deficits in the Auditory Brainstem of a Mouse Model of Fragile X Syndrome. Lucas A, Poleg S, Klug A, McCullagh EA. Front Neurosci 15 772943 (2021)
  28. Reexamination of aspartoacylase: is this human enzyme really a glycoprotein? Wang Q, Viola RE. Arch Biochem Biophys 548 66-73 (2014)
  29. Structure and computational analysis of a novel protein with metallopeptidase-like and circularly permuted winged-helix-turn-helix domains reveals a possible role in modified polysaccharide biosynthesis. Das D, Murzin AG, Rawlings ND, Finn RD, Coggill P, Bateman A, Godzik A, Aravind L. BMC Bioinformatics 15 75 (2014)
  30. Aspartoacylase suppresses prostate cancer progression by blocking LYN activation. Weng H, Xiong KP, Wang W, Qian KY, Yuan S, Wang G, Yu F, Luo J, Lu MX, Yang ZH, Liu T, Huang X, Zheng H, Wang XH. Mil Med Res 10 25 (2023)
  31. The impact of structural biology on neurobiology. Viola RE. Proc Natl Acad Sci U S A 104 399-400 (2007)


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