Structural and biochemical studies on Pompe disease and a “pseudodeficiency of acid α-glucosidase”

Tajima, Youichi; Matsuzawa, Fumiko; Aikawa, Sei Ichi; Okumiya, Toshika; Yoshimizu, Michiru; Tsukimura, Takahiro; Ikekita, Masahiko; Tsujino, Seiichi; Tsuji, Akihiko; Edmunds, Tim; Sakuraba, Hitoshi

doi:10.1007/s10038-007-0191-9

Cited by 55 publications

(55 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Figure 1 shows the sequence alignment of these enzymes, human acid a-glucosidase (LYAG) and human intestinal maltaseglucoamylase (PDB: 2QLY), completed with a-glucosidase MalA from S. solfataricus (PDB: 2G3N) that was earlier used for threedimensional modeling. 11 The amino acid identity between human acid a-glucosidase and the N-terminal subunit of human intestinal maltaseglucoamylase was 41%, this being sufficiently high to model the entire structure, whereas the homology with S. solfatarics MalA was only 28 %, this being too low to construct the entire model. The residues responsible for the catalytic activity (D518 and D616) and sequence motifs of family 31 glycosyl hydrolases were well conserved.…”

Section: Resultsmentioning

confidence: 99%

“…A simpler three-dimensional model not covering the entire length of the protein has already shown its value for predicting the location of amino acid residues that are involved in catalytic function. 11 We have used this new model, encompassing the entire structure of acid a-glucosidase, to gain an impression of the structural changes brought about by amino acid substitutions that affect the posttranslational processing and transport of the enzyme en route from the ER to lysosomes and causing Pompe disease.…”

Section: Discussionmentioning

confidence: 99%

“…11 However, the investigations were restricted to a limited region of the enzyme protein because the amino acid sequence identity between the human acid a-glucosidase and the template was low.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Structural modeling of mutant α-glucosidases resulting in a processing/transport defect in Pompe disease

et al. 2009

Self Cite

View full text Add to dashboard Cite

To elucidate the mechanism underlying transport and processing defects from the viewpoint of enzyme folding, we constructed three-dimensional models of human acid a-glucosidase encompassing 27 relevant amino acid substitutions by means of homology modeling. Then, we determined in each separate case the number of affected atoms, the root-mean-square distance value and the solvent-accessible surface area value. The analysis revealed that the amino acid substitutions causing a processing or transport defect responsible for Pompe disease were widely spread over all of the five domains comprising the acid a-glucosidase. They were distributed from the core to the surface of the enzyme molecule, and the predicted structural changes varied from large to very small. Among the structural changes, we paid particular attention to G377R and G483R. These two substitutions are predicted to cause electrostatic changes in neighboring small regions on the molecular surface. The quality control system of the endoplasmic reticulum apparently detects these very small structural changes and degrades the mutant enzyme precursor (G377R), but also the cellular sorting system might be misled by these minor changes whereby the precursor is secreted instead of being transported to lysosomes (G483R).

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Structural modeling of mutant α-glucosidases resulting in a processing/transport defect in Pompe disease

et al. 2009

Self Cite

View full text Add to dashboard Cite

show abstract

“…19 Briefly, 10 ml of a cell homogenate was added to 40 ml of a substrate solution comprising 4 mM 4-methylumbelliferyl-a-D-glucopyranoside in 0.2 M citrate buffer, pH 4.0. The reaction mixture was incubated at 371C for 30 min, and then the reaction was stopped by the addition of 950 ml of 0.…”

Section: Primary Pompe Fibroblast Cell Lines and Culturementioning

confidence: 99%

“…After 72 h, the cells were collected with 0.125% trypsin-EDTA and washed with PBS, and then the cell pellets were sonicated in 50 mM 2-(N-morpholino) ethanesulfonic acid buffer, pH 6.0, as described previously. 19 The cell homogenates were used for protein determination, GAA assaying and western blotting analysis.…”

Section: Preparation Of Mutant Gaa Constructsmentioning

confidence: 99%

Biochemical and structural study on a S529V mutant acid α-glucosidase responsive to pharmacological chaperones

et al. 2011

Self Cite

View full text Add to dashboard Cite

The genotype–phenotype correlation in Pompe disease

Kroos¹,

Hoogeveen‐Westerveld²,

Ploeg³

et al. 2012

American J of Med Genetics Pt C

117

111

View full text Add to dashboard Cite

Pompe disease is an autosomal recessive lysosomal glycogen storage disorder that is caused by acid α-glucosidase (GAA) deficiency and is due to pathogenic sequence variations in the corresponding GAA gene. The correlation between genotypes and phenotypes is strict, in that patients with the most severe phenotype, classic infantile Pompe disease, have two pathogenic mutations, one in each GAA allele, that prevent the formation of GAA or totally obliterates its function. All patients with less progressive phenotypes have at least one sequence variation that allows normal or low level synthesis of GAA leading to the formation of analytically measurable, low level GAA activity in most cases. There is an overall trend of finding higher GAA enzyme levels in patients with onset of symptoms in adulthood when compared to patients who show clinical manifestations in early childhood, aged 0-5 years, with a rapidly progressive course, but who lack the severe characteristics of classic infantile Pompe disease. However, several cases have been reported of adult-onset disease with very low GAA activity, which in all those cases corresponds with the GAA genotype. The clinical diversity observed within a large group of patients with functionally the same GAA genotype and the same c.-32-13C > T haplotype demonstrates that modifying factors can have a substantial effect on the clinical course of Pompe disease, disturbing the GAA genotype-phenotype correlation. The present day challenge is to identify these factors and explore them as therapeutic targets.

show abstract

Structural and biochemical studies on Pompe disease and a “pseudodeficiency of acid α-glucosidase”

Abstract: We constructed structural models of the catalytic domain and the surrounding region of human wildtype acid a-glucosidase and the enzyme with amino acid substitutions by means of homology modeling, and exam-

Cited by 55 publications

References 26 publications

Structural modeling of mutant α-glucosidases resulting in a processing/transport defect in Pompe disease

Structural modeling of mutant α-glucosidases resulting in a processing/transport defect in Pompe disease

Biochemical and structural study on a S529V mutant acid α-glucosidase responsive to pharmacological chaperones

The genotype–phenotype correlation in Pompe disease

Contact Info

Product

Resources

About