Alpha-galactosidase is a glycoside hydrolase enzyme that hydrolyses the terminal alpha-galactosyl moieties from glycolipids and glycoproteins. It is encoded by the GLA gene. Two recombinant forms of alpha-galactosidase are called agalsidase alpha (INN) and agalsidase beta (INN).
This enzyme is a homodimeric glycoprotein that hydrolyses the terminal alpha-galactosyl moieties from glycolipids and glycoproteins. It predominantly hydrolyzes ceramide trihexoside, and it can catalyze the hydrolysis of melibiose into galactose and glucose.
A variety of mutations in this gene affect the synthesis, processing, and stability of this enzyme, which causes Fabry disease, a rare lysosomal storage disorder and sphingolipidosis that results from a failure to catabolize alpha-D-galactosyl glycolipid moieties.
Two enzyme replacement therapies are available to functionally compensate for alpha-galactosidase deficiency. Agalsidase alpha and beta are both recombinant forms of the human α-galactosidase A enzyme and both have the same amino acid sequence as the native enzyme. Agalsidase alpha and beta differ in the structures of their oligosaccharide side chains.
The pharmaceutical company Shire manufactures agalsidase alfa (INN) under the trade name Replagal as a treatment for Fabry disease, and was granted marketing approval in the EU in 2001. FDA approval was applied for the United States. However, in 2012, Shire withdrew their application for approval in the United States citing that the agency will require additional clinical trials before approval.
The pharmaceutical company Genzyme produces synthetic agalsidase beta (INN) under the trade name Fabrazyme for treatment of Fabry disease. In 2009, contamination at Genzyme's Allston, Massachusetts plant caused a worldwide shortage of Fabrazyme, and supplies were rationed to patients at one-third the recommended dose. Some patients have petitioned to break the company's patent on the drug under the "march-in" provisions of the Bayh–Dole Act.
Over-the-counter brand names
Alpha-galactosidase is an active ingredient in Beano, CVS BeanAid, Enzymedica's BeanAssist. These products are marketed to reduce stomach gas production after eating foods known to cause gas. There are dozens of generic brands containing the enzyme in the United States. It is optimally active at 55 degrees C, after which its half-life is 120 minutes.
- Migalastat, a drug targeting alpha-galactosidase
- Classification of α-galactosidases (according to CAZy)
- Calhoun DH, Bishop DF, Bernstein HS, Quinn M, Hantzopoulos P, Desnick RJ (1985). "Fabry disease: isolation of a cDNA clone encoding human alpha-galactosidase A". Proceedings of the National Academy of Sciences of the United States of America. 82 (21): 7364–8. Bibcode:1985PNAS...82.7364C. PMC . PMID 2997789. doi:10.1073/pnas.82.21.7364.
- "Entrez Gene: GLA galactosidase, alpha".
- Fervenza FC, Torra R, Warnock DG (December 2008). "Safety and efficacy of enzyme replacement therapy in the nephropathy of Fabry disease". Biologics. 2 (4): 823–43. PMC . PMID 19707461. doi:10.2147/btt.s3770.
- Keating GM (October 2012). "Agalsidase alfa: a review of its use in the management of Fabry disease". BioDrugs. 26 (5): 335–54. PMID 22946754. doi:10.2165/11209690-000000000-00000.
- "Shire Submits Biologics License Application (BLA) for REPLAGAL with the U.S. Food and Drug Administration (FDA)". FierceBiotech.
- "With A Life-Saving Medicine In Short Supply, Patients Want Patent Broken". 2010-08-04. Archived from the original on 14 September 2010. Retrieved 2010-09-02.
- Grogan K (2012-03-15). "Shire withdraws Replagal in USA as FDA wants more trials". PharmaTimes. Archived from the original on 2014-08-19.
- Patil AG, K PK, Mulimani VH, Veeranagouda Y, Lee K (2010). "alpha-Galactosidase from Bacillus megaterium VHM1 and its application in removal of flatulence-causing factors from soymilk". Journal of Microbiology and Biotechnology. 20 (11): 1546–54. PMID 21124061. doi:10.4014/jmb.0912.12012.
- Naumov DG (2004). "[Phylogenetic analysis of alpha-galactosidases of the GH27 family]". Molekuliarnaia Biologiia (in Russian). 38 (3): 463–76. PMID 15285616. Republished as: Naumoff, D. G. (2004). "Phylogenetic Analysis of α-Galactosidases of the GH27 Family". Molecular Biology. 38 (3): 388–400. doi:10.1023/B:MBIL.0000032210.97006.de.
- Eng CM, Desnick RJ (1994). "Molecular basis of Fabry disease: mutations and polymorphisms in the human alpha-galactosidase A gene". Human Mutation. 3 (2): 103–11. PMID 7911050. doi:10.1002/humu.1380030204.
- Caillaud C, Poenaru L (2002). "Maladies de Gaucher et de Fabry: aspects biochimiques et génétiques" [Gaucher's and Fabry's diseases: biochemical and genetic aspects]. Journal De La SociéTé De Biologie (in French). 196 (2): 135–40. PMID 12360742. Template:INIST.
- Germain DP (2002). "Maladie de Fabry (déficit en alpha-galactosidase A): Physiopathologie, signes cliniques et aspects génétiques" [Fabry's disease (alpha-galactosidase-A deficiency): physiopathology, clinical signs, and genetic aspects]. Journal De La SociéTé De Biologie (in French). 196 (2): 161–73. PMID 12360745. Template:INIST.
- Schaefer E, Mehta A, Gal A (2005). "Genotype and phenotype in Fabry disease: analysis of the Fabry Outcome Survey". Acta Paediatrica. 94 (447): 87–92; discussion 79. PMID 15895718. doi:10.1080/08035320510031045.
- Levin M (2006). "Fabry disease". Drugs of Today. 42 (1): 65–70. PMID 16511611. doi:10.1358/dot.2006.42.1.957357.
- Lidove O, Joly D, Barbey F, Bekri S, Alexandra JF, Peigne V, Jaussaud R, Papo T (2007). "Clinical results of enzyme replacement therapy in Fabry disease: a comprehensive review of literature". International Journal of Clinical Practice. 61 (2): 293–302. PMID 17263716. doi:10.1111/j.1742-1241.2006.01237.x.
- Dean KJ, Sweeley CC (1979). "Studies on human liver alpha-galactosidases. I. Purification of alpha-galactosidase A and its enzymatic properties with glycolipid and oligosaccharide substrates". The Journal of Biological Chemistry. 254 (20): 9994–10000. PMID 39940.
- Ishii S, Sakuraba H, Suzuki Y (1992). "Point mutations in the upstream region of the alpha-galactosidase A gene exon 6 in an atypical variant of Fabry disease". Human Genetics. 89 (1): 29–32. PMID 1315715. doi:10.1007/BF00207037.
- Ioannou YA, Bishop DF, Desnick RJ (1992). "Overexpression of human alpha-galactosidase A results in its intracellular aggregation, crystallization in lysosomes, and selective secretion". The Journal of Cell Biology. 119 (5): 1137–50. PMC . PMID 1332979. doi:10.1083/jcb.119.5.1137.
- von Scheidt W, Eng CM, Fitzmaurice TF, Erdmann E, Hübner G, Olsen EG, Christomanou H, Kandolf R, Bishop DF, Desnick RJ (1991). "An atypical variant of Fabry's disease with manifestations confined to the myocardium". The New England Journal of Medicine. 324 (6): 395–9. PMID 1846223. doi:10.1056/NEJM199102073240607.
- Koide T, Ishiura M, Iwai K, Inoue M, Kaneda Y, Okada Y, Uchida T (1990). "A case of Fabry's disease in a patient with no alpha-galactosidase A activity caused by a single amino acid substitution of Pro-40 by Ser". FEBS Letters. 259 (2): 353–6. PMID 2152885. doi:10.1016/0014-5793(90)80046-L.
- Kornreich R, Bishop DF, Desnick RJ (1990). "Alpha-galactosidase A gene rearrangements causing Fabry disease. Identification of short direct repeats at breakpoints in an Alu-rich gene". The Journal of Biological Chemistry. 265 (16): 9319–26. PMID 2160973.
- Sakuraba H, Oshima A, Fukuhara Y, Shimmoto M, Nagao Y, Bishop DF, Desnick RJ, Suzuki Y (1990). "Identification of point mutations in the alpha-galactosidase A gene in classical and atypical hemizygotes with Fabry disease". American Journal of Human Genetics. 47 (5): 784–9. PMC . PMID 2171331.
- Bernstein HS, Bishop DF, Astrin KH, Kornreich R, Eng CM, Sakuraba H, Desnick RJ (1989). "Fabry disease: six gene rearrangements and an exonic point mutation in the alpha-galactosidase gene". The Journal of Clinical Investigation. 83 (4): 1390–9. PMC . PMID 2539398. doi:10.1172/JCI114027.
- Kornreich R, Desnick RJ, Bishop DF (1989). "Nucleotide sequence of the human alpha-galactosidase A gene". Nucleic Acids Research. 17 (8): 3301–2. PMC . PMID 2542896. doi:10.1093/nar/17.8.3301.
- Bishop DF, Kornreich R, Desnick RJ (1988). "Structural organization of the human alpha-galactosidase A gene: further evidence for the absence of a 3' untranslated region". Proceedings of the National Academy of Sciences of the United States of America. 85 (11): 3903–7. Bibcode:1988PNAS...85.3903B. PMC . PMID 2836863. doi:10.1073/pnas.85.11.3903.
- Quinn M, Hantzopoulos P, Fidanza V, Calhoun DH (1987). "A genomic clone containing the promoter for the gene encoding the human lysosomal enzyme, alpha-galactosidase A". Gene. 58 (2–3): 177–88. PMID 2892762. doi:10.1016/0378-1119(87)90374-X.
- Bishop DF, Calhoun DH, Bernstein HS, Hantzopoulos P, Quinn M, Desnick RJ (1986). "Human alpha-galactosidase A: nucleotide sequence of a cDNA clone encoding the mature enzyme". Proceedings of the National Academy of Sciences of the United States of America. 83 (13): 4859–63. Bibcode:1986PNAS...83.4859B. PMC . PMID 3014515. doi:10.1073/pnas.83.13.4859.
- Lemansky P, Bishop DF, Desnick RJ, Hasilik A, von Figura K (1987). "Synthesis and processing of alpha-galactosidase A in human fibroblasts. Evidence for different mutations in Fabry disease". The Journal of Biological Chemistry. 262 (5): 2062–5. PMID 3029062.
- Tsuji S, Martin BM, Kaslow DC, Migeon BR, Choudary PV, Stubbleflied BK, Mayor JA, Murray GJ, Barranger JA, Ginns EI (1987). "Signal sequence and DNA-mediated expression of human lysosomal alpha-galactosidase A". European Journal of Biochemistry. 165 (2): 275–80. PMID 3036505. doi:10.1111/j.1432-1033.1987.tb11438.x.