Use of Activators and Inhibitors to Define the Properties of the Active Site of Normal and Gaucher Disease Lysosomal ß-Glucosidase

Enzyme ◽  
1985 ◽  
Vol 33 (2) ◽  
pp. 109-119 ◽  
Author(s):  
Shimon Gatt ◽  
Tama Dinur ◽  
Karen Osiecki ◽  
Robert J. Desnick ◽  
Gregory A. Grabowski
Keyword(s):  
Active Site ◽  
Gaucher Disease

N-Glycosylation and Gaucher Disease Mutation Allosterically Alter Active-Site Dynamics of Acid-β-Glucosidase

ACS Catalysis ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 1810-1820 ◽  
Author(s):  
Michael Gregory Souffrant ◽  
Xin-Qiu Yao ◽  
Mohamed Momin ◽  
Donald Hamelberg
Keyword(s):  
Active Site ◽  
Gaucher Disease ◽  
Disease Mutation

scholarly journals Binding of 3,4,5,6-Tetrahydroxyazepanes to the Acid-β-glucosidase Active Site: Implications for Pharmacological Chaperone Design for Gaucher Disease

Biochemistry ◽  
2011 ◽  
Vol 50 (49) ◽  
pp. 10647-10657 ◽  
Author(s):  
Susan D. Orwig ◽  
Yun Lei Tan ◽  
Neil P. Grimster ◽  
Zhanqian Yu ◽  
Evan T. Powers ◽  
...  
Keyword(s):  
Active Site ◽  
Gaucher Disease ◽  
Pharmacological Chaperone

New Derivatives of L-Idonojirimycin Working As Pharmacological Chaperones for the Treatment of Gaucher Disease

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3270-3270 ◽  
Author(s):  
Pilar Alfonso ◽  
Javier Gervas ◽  
Vanesa Andreu ◽  
Joaquin Navascues ◽  
Francisca Sanchez-Jimenez ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Active Site ◽  
Gaucher Disease ◽  
Research Funding ◽  
Neurological Involvement ◽  
Advisory Committees ◽  
Pharmacological Chaperones ◽  
Molecular Features ◽  
Derivatives Of

Abstract Abstract 3270 Introduction: Many of the mutations of the lysosomal acid b-glucosidase (b-glucocerebrosidase) associated with Gaucher disease (GD) translate into enzymes that retain partial catalytic activity in vitro but exhibit impaired cellular trafficking as a consequence of aberrant folding. Current investigational therapeutic strategies for include the development of ligands of the enzyme capable of promoting those conformational changes that are required for efficient folding, restoring trafficking. Although somewhat counter intuitive, competitive inhibitors of this b-glucocerebrosidase, at subinhibitory concentrations, can increase steady-state lysosomal levels of active enzyme through this rescuing mechanism, acting as “pharmacological chaperones”. At the massive lysosomal substrate concentration, the inhibitor would be replaced from the active site of the enzyme and the metabolic activity recovered. However, most of the pharmacological chaperones under study are iminosugars that behave as broad spectrum inhibitors, inhibiting simultaneously several glucosidases, which represents a serious inconvenient for clinical applications. An additional problem is that iminosugars and their derivatives are not active as pharmacological chaperones for glucocerebrosidase mutations located outside the domain containing the active site and are associated with neurological involvement, as the L444P mutation. Aim: The aim of this work is to present molecules with a high binding specificity towards b-glucocerebrosidase, with a high ratio of chaperone versus inhibitor activity and capable of producing an increased in the levels of mutant enzymes associated with Gaucher disease, including mutations located outside the catalytic domain. Methods: Different bicyclic derivatives of L-idonojirimycin were designed and chemically synthesized from D-glucose after in silico structural analysis and identification of the most favorable molecular features to interact with the active site of glucocerebrosidase. The chaperone potential of these compounds was evaluated at different concentrations in vitro using a cell model of GDcarrying the more frequent mutations in Gaucher disease, namely N370S and L444P. (P201230804). Results: The obtained results showed an increase in b-glucocerebrosidase activity at various chaperone concentrations, ranging from 1.96 to 4.98 folds for the L444P mutant and from 2.01 to 3.06 folds for the N370S mutation. Comments: The bicyclic derivatives of L-idonojirimycin could be considered as a therapeutic alternative for GD, mainly in patients with mutations located outside the active site of the enzyme and associated with neurologic involvement. Disclosures: Giraldo: Actelion: Membership on an entity's Board of Directors or advisory committees; Genzyme: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Locating Al in the DABCO catalyst before and after Al extraction

1990 ◽  
Vol 48 (4) ◽  
pp. 265-267
Author(s):  
Kathleen B. Reuter
Keyword(s):  
Active Site ◽  
Inverse Relationship ◽  
Transverse Direction ◽  
Reaction Rate ◽  
Acid Phosphate ◽  
Fracture Surfaces ◽  
Al Content ◽  
Before And After ◽  
Relationship Of

The reaction rate and efficiency of piperazine to 1,4-diazabicyclo-octane (DABCO) depends on the Si/Al ratio of the MFI topology catalysts. The Al was shown to be the active site, however, in the Si/Al range of 30-200 the reaction rate increases as the Si/Al ratio increases. The objective of this work was to determine the location and concentration of Al to explain this inverse relationship of Al content with reaction rate.Two silicalite catalysts in the form of 1/16 inch SiO2/Al2O3 bonded extrudates were examined: catalyst A with a Si/Al of 83; and catalyst B, the acid/phosphate Al extracted form of catalyst A, with a Si/Al of 175. Five extrudates from each catalyst were fractured in the transverse direction and particles were obtained from the fracture surfaces near the center of the extrudate diameter. Particles were also obtained from the outside surfaces of five extrudates.

Structures of c-di-GMP/cGAMP degrading phosphodiesterase VcEAL: identification of a novel conformational switch and its implication

2019 ◽  
Vol 476 (21) ◽  
pp. 3333-3353 ◽  
Author(s):  
Malti Yadav ◽  
Kamalendu Pal ◽  
Udayaditya Sen
Keyword(s):  
Active Site ◽  
Metal Binding ◽  
Metal Ion ◽  
Triosephosphate Isomerase ◽  
Catalytic Mechanism ◽  
Degradation Mechanism ◽  
Structural Basis ◽  
Conserved Residues ◽  
Phosphodiester Bond ◽  
Cyclic Dinucleotides

Cyclic dinucleotides (CDNs) have emerged as the central molecules that aid bacteria to adapt and thrive in changing environmental conditions. Therefore, tight regulation of intracellular CDN concentration by counteracting the action of dinucleotide cyclases and phosphodiesterases (PDEs) is critical. Here, we demonstrate that a putative stand-alone EAL domain PDE from Vibrio cholerae (VcEAL) is capable to degrade both the second messenger c-di-GMP and hybrid 3′3′-cyclic GMP–AMP (cGAMP). To unveil their degradation mechanism, we have determined high-resolution crystal structures of VcEAL with Ca2+, c-di-GMP-Ca2+, 5′-pGpG-Ca2+ and cGAMP-Ca2+, the latter provides the first structural basis of cGAMP hydrolysis. Structural studies reveal a typical triosephosphate isomerase barrel-fold with substrate c-di-GMP/cGAMP bound in an extended conformation. Highly conserved residues specifically bind the guanine base of c-di-GMP/cGAMP in the G2 site while the semi-conserved nature of residues at the G1 site could act as a specificity determinant. Two metal ions, co-ordinated with six stubbornly conserved residues and two non-bridging scissile phosphate oxygens of c-di-GMP/cGAMP, activate a water molecule for an in-line attack on the phosphodiester bond, supporting two-metal ion-based catalytic mechanism. PDE activity and biofilm assays of several prudently designed mutants collectively demonstrate that VcEAL active site is charge and size optimized. Intriguingly, in VcEAL-5′-pGpG-Ca2+ structure, β5–α5 loop adopts a novel conformation that along with conserved E131 creates a new metal-binding site. This novel conformation along with several subtle changes in the active site designate VcEAL-5′-pGpG-Ca2+ structure quite different from other 5′-pGpG bound structures reported earlier.

Ten years’ experience of enzyme infusion therapy of Norrbottnian (type 3) Gaucher disease

2006 ◽  
Vol 95 (3) ◽  
pp. 312-317 ◽  
Author(s):  
Anders Erikson ◽  
Håkan Forsberg ◽  
Magnus Nilsson ◽  
Marianne Åström ◽  
Jan-Eric Månsson
Keyword(s):  
Gaucher Disease ◽  
Infusion Therapy ◽  
Type 3 ◽  
Enzyme Infusion
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