Treatment of Gaucher disease

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<StructureSection load='1ogs.pdb' size='500' frame='true' align='right' scene='1ogs/Rainbow/2' >
<StructureSection load='1ogs.pdb' size='500' frame='true' align='right' scene='1ogs/Rainbow/2' >
[http://en.wikipedia.org/wiki/Gaucher's_disease Gaucher disease], the most common [http://en.wikipedia.org/wiki/Lysosomal_storage_disease lysosomal storage disease], is caused by mutations in the gene that encoding the lysosomal enzyme, acid-β-glucosidase ([[acid-beta-glucosidase]], [http://en.wikipedia.org/wiki/Glucocerebrosidase glucocerebrosidase], GlcCerase, [http://www.expasy.org/cgi-bin/nicezyme.pl?3.2.1.45 E.C. 3.2.1.45]). The most common treatment for Gaucher disease is [http://en.wikipedia.org/wiki/Enzyme_replacement_therapy enzyme replacement therapy] (ERT), in which defective GlcCerase is supplemented with an active enzyme.
[http://en.wikipedia.org/wiki/Gaucher's_disease Gaucher disease], the most common [http://en.wikipedia.org/wiki/Lysosomal_storage_disease lysosomal storage disease], is caused by mutations in the gene that encoding the lysosomal enzyme, acid-β-glucosidase ([[acid-beta-glucosidase]], [http://en.wikipedia.org/wiki/Glucocerebrosidase glucocerebrosidase], GlcCerase, [http://www.expasy.org/cgi-bin/nicezyme.pl?3.2.1.45 E.C. 3.2.1.45]). The most common treatment for Gaucher disease is [http://en.wikipedia.org/wiki/Enzyme_replacement_therapy enzyme replacement therapy] (ERT), in which defective GlcCerase is supplemented with an active enzyme.
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The crystal structure of the human <scene name='1y7v/Active_site/9'>GlcCerase</scene> (colored <font color='yellow'><b>yellow</b></font>) with covalently bound irreversible inhibitor <scene name='1y7v/Bound_cyclohexitol/3'>cyclohexitol</scene> (<font color='cyan'><b>conduritol-B-epoxide; CBE; shown in cyan</b></font> with its <font color='red'><b>hydroxyl groups</b></font> are in <font color='red'><b>red</b></font>) was solved ([[1y7v]]). This structure reveals that binding of CBE to the active site does not induce a global conformational change in GlcCerase and confirms that Glu340 is the active-site catalytic nucleophile, because the <scene name='1y7v/Active_site1/2'>distance</scene> between the cyclohexitol C1 atom and Glu340 Oε2 is 1.43 Å. The comparison between the active sites of <scene name='1y7v/Active_site/7'>GlcCerase</scene> and another representative of the glycohydrolase family - plant <scene name='1y7v/Active_site_beta_glu_glyco/4'>β-D-glucan glucohydrolase</scene> ([[1iev]]), reveals that CBE bound with this plant enzyme adopted the "chair" conformation, while with human <scene name='1y7v/Active_site/8'>GlcCerase</scene>, it is observed in a "boat" conformation, with hydrogen bonds to Asn234 Oδ1 and Nδ2, Glu340 Oε1, Trp179 Nε1, and Asp127 Oδ1 and Oδ2 <ref name="Premkumar">PMID:15817452</ref>.
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The crystal structure of the human <scene name='1y7v/Active_site/9'>GlcCerase</scene> (colored <font color='yellow'><b>yellow</b></font>) with covalently bound irreversible inhibitor <scene name='1y7v/Bound_cyclohexitol/3'>cyclohexitol</scene> (<font color='cyan'><b>conduritol-B-epoxide; CBE; shown in cyan</b></font> with its <font color='red'><b>hydroxyl groups</b></font> are in <font color='red'><b>red</b></font>) was solved ([[1y7v]], <ref name="Premkumar">PMID:15817452</ref>). This structure reveals that binding of CBE to the active site does not induce a global conformational change in GlcCerase and confirms that Glu340 is the active-site catalytic nucleophile, because the <scene name='1y7v/Active_site1/2'>distance</scene> between the cyclohexitol C1 atom and Glu340 Oε2 is 1.43 Å. The comparison between the active sites of <scene name='1y7v/Active_site/7'>GlcCerase</scene> and another representative of the glycohydrolase family - plant <scene name='1y7v/Active_site_beta_glu_glyco/4'>β-D-glucan glucohydrolase</scene> ([[1iev]], <ref name="Hrmova">PMID:11709165</ref>), reveals that CBE bound with this plant enzyme adopted the "chair" conformation, while with human <scene name='1y7v/Active_site/8'>GlcCerase</scene>, it is observed in a "boat" conformation, with hydrogen bonds to Asn234 Oδ1 and Nδ2, Glu340 Oε1, Trp179 Nε1, and Asp127 Oδ1 and Oδ2 <ref name="Premkumar"/>.
Only one of two <scene name='1y7v/Loops/2'>alternative conformations</scene> of a pair of flexible loops (L1: Ser345–Glu349, and L2: Val394–Asp399) located at the entrance to the active site in native GlcCerase ([[1ogs]]) is observed in the GlcCerase-CBE structure ([[1y7v]]), a conformation in which the active site is accessible to CBE (<font color='blue'><b>colored blue</b></font>), while these loops in <font color='magenta'><b>the second (closed) conformation are colored magenta</b></font>. In <scene name='1y7v/L2/3'>loop 2</scene>, a major structural change is observed in the positions of <scene name='1y7v/L2/4'>Asn396 and Phe397</scene>, and in <scene name='1y7v/L1/4'>loop 1</scene> a more limited difference is observed in the conformations of <scene name='1y7v/L1/5'>Lys346 and Glu349</scene>. Analysis of the dynamics of these two alternative conformations suggests that the two loops act as a lid at the entrance to the active site. The movies [http://www.jbc.org/content/vol0/issue2005/images/data/M502799200/DC1/mov.mov 1] and [http://www.jbc.org/content/vol0/issue2005/images/data/M502799200/DC1/mov2.mov 2] illustrate the dynamics of the movement of these two loops <ref name="Premkumar"/><ref name="Zeev-Ben-Mordehai">PMID:12601798</ref>.
Only one of two <scene name='1y7v/Loops/2'>alternative conformations</scene> of a pair of flexible loops (L1: Ser345–Glu349, and L2: Val394–Asp399) located at the entrance to the active site in native GlcCerase ([[1ogs]]) is observed in the GlcCerase-CBE structure ([[1y7v]]), a conformation in which the active site is accessible to CBE (<font color='blue'><b>colored blue</b></font>), while these loops in <font color='magenta'><b>the second (closed) conformation are colored magenta</b></font>. In <scene name='1y7v/L2/3'>loop 2</scene>, a major structural change is observed in the positions of <scene name='1y7v/L2/4'>Asn396 and Phe397</scene>, and in <scene name='1y7v/L1/4'>loop 1</scene> a more limited difference is observed in the conformations of <scene name='1y7v/L1/5'>Lys346 and Glu349</scene>. Analysis of the dynamics of these two alternative conformations suggests that the two loops act as a lid at the entrance to the active site. The movies [http://www.jbc.org/content/vol0/issue2005/images/data/M502799200/DC1/mov.mov 1] and [http://www.jbc.org/content/vol0/issue2005/images/data/M502799200/DC1/mov2.mov 2] illustrate the dynamics of the movement of these two loops <ref name="Premkumar"/><ref name="Zeev-Ben-Mordehai">PMID:12601798</ref>.
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Three-dimensional structure of recombinant plant-derived glucocerebrosidase (prGCD, [[2v3f]]) consists of <scene name='2v3f/Cv/7'>3 domains</scene>. Domain I (residues 1–27 and 384–414, colored <font color='pink'><b>pink</b></font>) comprises a 3-stranded anti-parallel β-sheet flanked by a perpendicular amino-terminal strand. <font color='lime'><b>Domain II (residues 30–75 and 431–497, colored lime)</b></font> consists of two β-sheets. <font color='red'><b>Domain III (residues 76–381 and 416–430, colored red)</b></font> is a (β/α) 8 TIM barrel. <scene name='2v3f/Cv/8'>The catalytic site</scene> with molecule BTB is shown <ref name="Shaaltiel">PMID:17524049</ref>.
Three-dimensional structure of recombinant plant-derived glucocerebrosidase (prGCD, [[2v3f]]) consists of <scene name='2v3f/Cv/7'>3 domains</scene>. Domain I (residues 1–27 and 384–414, colored <font color='pink'><b>pink</b></font>) comprises a 3-stranded anti-parallel β-sheet flanked by a perpendicular amino-terminal strand. <font color='lime'><b>Domain II (residues 30–75 and 431–497, colored lime)</b></font> consists of two β-sheets. <font color='red'><b>Domain III (residues 76–381 and 416–430, colored red)</b></font> is a (β/α) 8 TIM barrel. <scene name='2v3f/Cv/8'>The catalytic site</scene> with molecule BTB is shown <ref name="Shaaltiel">PMID:17524049</ref>.
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<scene name='2v3f/Align/2'>Structural alignment</scene> of <font color='red'><b>prGCD</b></font> ([[2v3f]]) with both <font color='cyan'><b>Cerezyme®</b></font> ([[1ogs]]) and Cerezyme® covalently modified by an irreversible inhibitor, conduritol-B-epoxide ([[1y7v]], colored <font color='yellow'><b>yellow</b></font>), revealed highly significant structural identity. The RMSD values for Cα atoms of these structures were of 0.64 and 0.60 Å, respectively. Moreover, there was strict conservation of the <scene name='2v3f/Align/3'>active site residues</scene> <ref name="Shaaltiel"/>.
<scene name='2v3f/Align/2'>Structural alignment</scene> of <font color='red'><b>prGCD</b></font> ([[2v3f]]) with both <font color='cyan'><b>Cerezyme®</b></font> ([[1ogs]]) and Cerezyme® covalently modified by an irreversible inhibitor, conduritol-B-epoxide ([[1y7v]], colored <font color='yellow'><b>yellow</b></font>), revealed highly significant structural identity. The RMSD values for Cα atoms of these structures were of 0.64 and 0.60 Å, respectively. Moreover, there was strict conservation of the <scene name='2v3f/Align/3'>active site residues</scene> <ref name="Shaaltiel"/>.

Revision as of 08:04, 19 December 2010

PDB ID 1ogs.pdb

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Additional Resources

For additional information, see: Metabolic Disorders

References

  1. Dvir H, Harel M, McCarthy AA, Toker L, Silman I, Futerman AH, Sussman JL. X-ray structure of human acid-beta-glucosidase, the defective enzyme in Gaucher disease. EMBO Rep. 2003 Jul;4(7):704-9. PMID:12792654 doi:10.1038/sj.embor.embor873
  2. 2.0 2.1 2.2 Premkumar L, Sawkar AR, Boldin-Adamsky S, Toker L, Silman I, Kelly JW, Futerman AH, Sussman JL. X-ray structure of human acid-beta-glucosidase covalently bound to conduritol-B-epoxide. Implications for Gaucher disease. J Biol Chem. 2005 Jun 24;280(25):23815-9. Epub 2005 Apr 6. PMID:15817452 doi:M502799200
  3. Hrmova M, Varghese JN, De Gori R, Smith BJ, Driguez H, Fincher GB. Catalytic mechanisms and reaction intermediates along the hydrolytic pathway of a plant beta-D-glucan glucohydrolase. Structure. 2001 Nov;9(11):1005-16. PMID:11709165
  4. Zeev-Ben-Mordehai T, Silman I, Sussman JL. Acetylcholinesterase in motion: visualizing conformational changes in crystal structures by a morphing procedure. Biopolymers. 2003 Mar;68(3):395-406. PMID:12601798 doi:10.1002/bip.10287
  5. 5.0 5.1 5.2 5.3 Shaaltiel Y, Bartfeld D, Hashmueli S, Baum G, Brill-Almon E, Galili G, Dym O, Boldin-Adamsky SA, Silman I, Sussman JL, Futerman AH, Aviezer D. Production of glucocerebrosidase with terminal mannose glycans for enzyme replacement therapy of Gaucher's disease using a plant cell system. Plant Biotechnol J. 2007 Sep;5(5):579-90. Epub 2007 May 24. PMID:17524049 doi:10.1111/j.1467-7652.2007.00263.x
  6. Brumshtein B, Greenblatt HM, Butters TD, Shaaltiel Y, Aviezer D, Silman I, Futerman AH, Sussman JL. Crystal structures of complexes of N-butyl- and N-nonyl-deoxynojirimycin bound to acid beta-glucosidase: insights into the mechanism of chemical chaperone action in Gaucher disease. J Biol Chem. 2007 Sep 28;282(39):29052-8. Epub 2007 Jul 31. PMID:17666401 doi:10.1074/jbc.M705005200
  7. Lieberman RL, Wustman BA, Huertas P, Powe AC Jr, Pine CW, Khanna R, Schlossmacher MG, Ringe D, Petsko GA. Structure of acid beta-glucosidase with pharmacological chaperone provides insight into Gaucher disease. Nat Chem Biol. 2007 Feb;3(2):101-7. Epub 2006 Dec 24. PMID:17187079 doi:http://dx.doi.org/10.1038/nchembio850
  8. Brumshtein B, Wormald MR, Silman I, Futerman AH, Sussman JL. Structural comparison of differently glycosylated forms of acid-beta-glucosidase, the defective enzyme in Gaucher disease. Acta Crystallogr D Biol Crystallogr. 2006 Dec;62(Pt 12):1458-65. Epub 2006, Nov 23. PMID:17139081 doi:S0907444906038303
  9. Brumshtein B, Salinas P, Peterson B, Chan V, Silman I, Sussman JL, Savickas PJ, Robinson GS, Futerman AH. Characterization of gene-activated human acid-beta-glucosidase: crystal structure, glycan composition, and internalization into macrophages. Glycobiology. 2010 Jan;20(1):24-32. Epub 2009 Sep 9. PMID:19741058 doi:10.1093/glycob/cwp138

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