Galactose Stabilizes Various Missense Mutants of α-Galactosidase in Fabry Disease

Okumiya, Toshika; Ishii, Satoshi; Takenaka, Toshihiro; Kase, Ryoichi; Kamei, Shigeru; Sakuraba, Hitoshi; Suzuki, Yoshiyuki

doi:10.1006/bbrc.1995.2416

Cited by 99 publications

(88 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…9,11,17,20 However, the clinical manifestations of patients with p.E66Q in the cited reports were not sufficiently convincing to confirm p.E66Q as a disease-causing mutation. For instance, Nakao et al 11 suggested that renal variants have a phenotype intermediate between cardiac variants and classical phenotypes.…”

Section: Discussionmentioning

confidence: 94%

“…8,17,19,20 Indeed, we have reported p.E66Q activities as high as 40% of mean normal activity in the transiently overexpressed COS-7 cells. 19 X-ray crystallography shows that GLA is a homodimeric glycoprotein in which each monomer is composed of two domains (Figure 2).…”

Section: Discussionmentioning

confidence: 99%

“…19 In this report, we found remarkably high residual enzyme activity of a protein with the p.E66Q mutation, previously known as a pathogenic mutation in patients with atypical Fabry disease. 9,11,17,20 p.E66Q synthesizes 40% of wild-type enzyme activity when overexpressed in COS-7 cells, indicating that p.E66Q might be a mild mutation or a functional single nucleotide polymorphism (SNP). 19 Herein, we report 25 distinct mutations in GLA, including six novel mutations, identified from 28 unrelated Korean families with Fabry disease.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Mutations of the GLA gene in Korean patients with Fabry disease and frequency of the E66Q allele as a functional variant in Korean newborns

et al. 2010

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Mutations of the GLA gene in Korean patients with Fabry disease and frequency of the E66Q allele as a functional variant in Korean newborns

et al. 2010

View full text Add to dashboard Cite

“…We analyzed amino acid substitutions including E59K, E66Q, M72V, I91T, A97V, R112H, F113L, A156V, L166V, N215S, G260A, Q279E, M296I, M296V, R301Q, R356W, and G373S, for which substrate analogues are effective for stabilization or transportation of mutant enzymes to lysosomes (Okumiya et al 1995b;Yam et al 2006;Ishii et al 2007).…”

Section: Discussionmentioning

confidence: 99%

Structural characterization of mutant α-galactosidases causing Fabry disease

et al. 2008

View full text Add to dashboard Cite

Fabry disease is an inborn error of glycolipid catabolism resulting from lesions in the gene encoding agalactosidase (GLA). To elucidate the basis of Fabry disease, we constructed structural models of mutant GLAs responsible for the disease and calculated indexes, i.e., the numbers of atoms affected in the main chain and side chain of each mutant GLA, the root-mean-square distance values, and the solvent-accessible surface-area values, based on 212 Fabry amino acid substitutions previously reported (196 classic and 16 variant). As two therapeutic options, enzyme replacement and enzyme enhancement, are now available for this disease, proper prediction of the natural outcome and therapeutic efficiency based on the molecular evidence for individual cases are critical for patients' quality of life. Our results revealed that structural changes in the classic Fabry group were generally large and tended to be in the core region of a protein or located in the functionally important region, including the active-site pocket. On the other hand, structural changes in the variant Fabry group were small or localized on the surface of the molecule far away from the active site. We focused on structural changes due to amino acid substitutions for which substrate analogues are effective for improving the stability or transportation of mutant GLAs, and the results of the study revealed that they are small or localized on the molecular surface, regardless of the phenotype. Coloring of affected atoms based on distances between wild type and mutant ones clearly showed the characteristic structural changes in the GLA protein geographically and subquantitatively. Structural investigation is useful for elucidation of the basis of Fabry disease and predicting disease outcome.

show abstract

“…1. In addition, mutated forms of the human lysosomal a-galactosidase gene have been isolated from Fabry's disease patients which encode enzymes with no or reduced activity (Ishii et al, 1992;Eng et al, 1993;Okumiya et al, 1995). Many of these genes contain point mutations involving a single amino acid substitution.…”

Section: Heapyp 515 Sdi-ys 490 Tni-gnmentioning

confidence: 99%

Three α‐Galactosidase Genes of Trichoderma reesei Cloned by Expression in Yeast

Margolles-Clark

Tenkanen

Luonteri

et al. 1996

European Journal of Biochemistry

View full text Add to dashboard Cite

Three cx-galactosidase genes, agll, ag12 and ag13, were isolated from a cDNA expression library of Trichoderma reesei RutC-30 constructed in the yeast Saccharomyces cerevisiae by screening the library on plates containing the substrate 5-bromo-4-chloro-3-indolyl-a-D-gnlactopyranoside. The genes ugll, ag12 and agl3 encode 444, 746 and 624 amino acids, respectively, including the signal sequences. The deduced amino acid sequences of AGLI and AGLIII showed similarity with the a-galactosidases of plant, animal, yeast and filamentous fungal origin classified into family 27 of glycosyl hydrolases whereas the deduced amino acid sequence of AGLII showed similarity with the bacterial a-galactosidases of family 36. The enzymes produced by yeast were analysed for enzymatic activity against different substrates. AGLI, AGLII and AGLIII were able to hydrolyse the synthetic substrate p-nitrophenyl-a-D-galactopyranoside and the small galactose-containing oligosaccharides, melibiose and raffinose. They liberated galactose from polymeric galacto(g1uco)mannan with different efficiencies. The action of AGLI towards polymeric substrates was enhanced by the presence of the endo-l,4-/?-mannanase of T reesei. AGLII and AGLIII showed synergy in galacto(g1uco)mannan hydrolysis with the endo-l,4-/?-mannanase of 7: reesei and a B-mannosidase of Aspergillus niger. The calculated molecular mass and the hydrolytic properties of AGLI indicate that it corresponds to the a-galactosidase previously purified from 7: reesei.

show abstract

Galactose Stabilizes Various Missense Mutants of α-Galactosidase in Fabry Disease

Cited by 99 publications

References 0 publications

Mutations of the GLA gene in Korean patients with Fabry disease and frequency of the E66Q allele as a functional variant in Korean newborns

Mutations of the GLA gene in Korean patients with Fabry disease and frequency of the E66Q allele as a functional variant in Korean newborns

Structural characterization of mutant α-galactosidases causing Fabry disease

Three α‐Galactosidase Genes of Trichoderma reesei Cloned by Expression in Yeast

Contact Info

Product

Resources

About