α-Galactosidase
This article may be too technical for most readers to understand.(October 2022) |
α-galactosidase | |||||||||
---|---|---|---|---|---|---|---|---|---|
ExPASy NiceZyme view | | ||||||||
KEGG | KEGG entry | ||||||||
MetaCyc | metabolic pathway | ||||||||
PRIAM | profile | ||||||||
PDB structures | RCSB PDB PDBe PDBsum | ||||||||
Gene Ontology | AmiGO / QuickGO | ||||||||
|
alpha galactosidase family | ||||||
---|---|---|---|---|---|---|
Identifiers | ||||||
Ensembl |
|
| ||||
UniProt |
| |||||
RefSeq (mRNA) |
|
| ||||
RefSeq (protein) |
|
| ||||
Location (UCSC) | n/a | n/a | ||||
PubMed search | n/a | n/a |
View/Edit Human |
α-Galactosidase ( EC 3.2.1.22, α-GAL, α-GAL A; systematic name α-D-galactoside galactohydrolase) is a glycoside hydrolase enzyme that catalyses the following reaction:[1]
- Hydrolysis of terminal, non-reducing α-D-galactose residues in α-D-galactosides, including galactose oligosaccharides, galactomannans and galactolipids
It catalyzes many catabolic processes, including cleavage of glycoproteins, glycolipids, and polysaccharides.
The enzyme is encoded by the GLA gene.
Function
This enzyme is a homodimeric glycoprotein that hydrolyses the terminal α-galactosyl moieties from glycolipids and glycoproteins. It predominantly hydrolyzes ceramide trihexoside, and it can catalyze the hydrolysis of melibiose into galactose and glucose.[citation needed]
Reaction mechanism
Disease relevance
Fabry disease
Signs and Symptoms
Defects in human α-GAL result in
Fabry disease is an X-linked disease, affecting 1 in 40,000 males. However, unlike other X-linked diseases, this condition also creates significant medical problems for females carrying only 1 copy of the defective GLA gene. These women may experience many classic symptoms of the disorder including cardiac and kidney problems. However, a small number of females carrying only one copy of the mutated GLA gene never shows any symptoms of Fabry disease.[citation needed]
Cause
Mutations to the GLA gene encoding α-GAL may result in complete loss of function of the enzyme. α-GAL is a lysosomal protein responsible for breaking down globotriaosylceramide, a fatty substance stored various types of cardiac and renal cells.[8] When globotriaosylceramide is not properly catabolized, it is accumulated in cells lining blood vessels in the skin, cells in the kidney, heart and nervous system. As a result, signs and symptoms of Fabry disease begin to manifest.[7]
Treatment
There are three treatment options for Fabry disease: recombinant enzyme replacement therapy, pharmacological chaperone therapy, and organ specific treatment.
Recombinant enzyme replacement therapy (RERT)
RERT was approved as a treatment for Fabry disease in the United States in 2003.[9][10][11]
Two recombinant enzyme replacement therapies are available to functionally compensate for α-galactosidase deficiency. Agalsidase α and β are both recombinant forms of the human α-galactosidase A enzyme and both have the same amino acid sequence as the native enzyme. Agalsidase α and β differ in the structures of their oligosaccharide side chains.[12]
In Fabry disease patients, 88% percent of patients develop
Agalsidase α
The pharmaceutical company
Agalsidase β
Clinical data | |
---|---|
Trade names | Fabrazyme |
AHFS/Drugs.com | Monograph |
License data | |
Intravenous | |
ATC code | |
Legal status | |
Legal status |
The pharmaceutical company
Pharmacological chaperone therapy
Fabry patients who display neurological symptoms cannot receive RERT because recombinant enzymes cannot normally pass the blood-brain barrier. Thus, a more suitable alternative treatment is used: pharmacological chaperone therapy.[citation needed]
It has been shown that more potent
Modifying blood type group B to group O
α-GAL, known as B-zyme in this context, has also demonstrated its ability to convert human blood group B to human blood group O, which can be transfused to patients of all blood types in the ABO blood group categorization. The current B-zyme used comes from Bacteroides fragilis.[21] The idea of maintaining a blood supply at healthcare facilities with all non-O units converted to O units is achieved using enzyme-converted to group O technology, first developed in 1982.[24]
Advantages
A blood bank with ECO blood demonstrates the following advantages:[25]
- Compatible with and transfusable to patients of all blood groups
- Reduce the demand for specific ABO blood groups A, B, AB
- Reduce cost of maintaining a blood bank inventory in hospitals
- Reduce blood transfusion reactions due to human error and ABO incompatibility
- Reduce wastage of less needed blood types
Mechanism of Action
Red blood cell (RBC) surfaces are decorated with the glycoproteins and glycolipids that have the same basic sequence with terminal sugar α1‐2‐linked fucose linked to the penultimate galactose. This galactose molecule is called the H antigen.[26][27][28] Blood type A, B, AB, and O differ only in the sugar (red molecule in the illustration) linked with the penultimate galactose. For blood type B, this linked sugar is an α-1‐3‐linked galactose. Using α-GAL, this terminal galactose molecule can be removed, converting RBC to type O.
Supplements
α-GAL derived from the mold Aspergillus niger is an active ingredient in products marketed to reduce stomach gas production after eating foods known to cause gas. It is optimally active at 55 °C, after which its half-life is 120 minutes.[29]
Commercial products with α-galactosidase include:
- Beano
- CVS BeanAid
- Enzymedica's BeanAssist
- Gasfix
- Bloateez (in India as Cogentrix)
See also
- β-galactosidase
- Migalastat, a drug targeting α-galactosidase
- Classification of α-galactosidases (according to CAZy)
References
- ISBN 978-0-07-913035-8.
- PMID 2997789.
- S2CID 86709302.
- PMID 10085226.
- PMID 18558099.
- ^ "Entrez Gene: GLA galactosidase, alpha".
- ^ a b Reference. "Fabry disease". Genetics Home Reference. Retrieved 2019-03-09.
- S2CID 86482134.
- PMID 11386930.
- PMID 11439963.
- S2CID 11492320.
- PMID 19707461.
- PMID 20444686.
- PMID 22946754.
- ^ "Shire Submits Biologics License Application (BLA) for REPLAGAL with the U.S. Food and Drug Administration (FDA)". FierceBiotech. 22 December 2009.
- ^ a b "With A Life-Saving Medicine In Short Supply, Patients Want Patent Broken". NPR.org. 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.
- ^ "Genetic disorders". Health Canada. 9 May 2018. Retrieved 13 April 2024.
- ^ "Fabrazyme- agalsidase beta injection, powder, lyophilized, for solution". DailyMed. 23 February 2024. Retrieved 24 March 2024.
- PMID 11439944.
- ^ S2CID 29804004.
- PMID 10866822.
- S2CID 13193351.
- PMID 6274021.
- S2CID 10668327.
- PMID 6156588.
- PMID 2433836.
- PMID 2464874.
- S2CID 24801055.
Further reading
- Naumov DG (2004). "[Phylogenetic analysis of alpha-galactosidases of the GH27 family]". Molekuliarnaia Biologiia (in Russian). 38 (3): 463–76. S2CID 20212300.
- Eng CM, Desnick RJ (1994). "Molecular basis of Fabry disease: mutations and polymorphisms in the human α-galactosidase A gene". Human Mutation. 3 (2): 103–11. S2CID 83651922.
- Caillaud C, Poenaru L (2002). "[Gaucher's and Fabry's diseases: biochemical and genetic aspects]" [Gaucher's and Fabry's diseases: biochemical and genetic aspects]. Journal de la Société de Biologie (in French). 196 (2): 135–40. .
- Germain DP (2002). "[Fabry's disease (alpha-galactosidase-A deficiency): physiopathology, clinical signs, and genetic aspects]" [Fabry's disease (α-galactosidase-A deficiency): physiopathology, clinical signs, and genetic aspects]. Journal de la Société de Biologie (in French). 196 (2): 161–73. .
- Schaefer E, Mehta A, Gal A (March 2005). "Genotype and phenotype in Fabry disease: analysis of the Fabry Outcome Survey". Acta Paediatrica. 94 (447): 87–92, discussion 79. S2CID 43208075.
- Levin M (January 2006). "Fabry disease". Drugs of Today. 42 (1): 65–70. PMID 16511611.
- Lidove O, Joly D, Barbey F, Bekri S, Alexandra JF, Peigne V, Jaussaud R, Papo T (February 2007). "Clinical results of enzyme replacement therapy in Fabry disease: a comprehensive review of literature". International Journal of Clinical Practice. 61 (2): 293–302. S2CID 40469533.
- Dean KJ, Sweeley CC (October 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 (April 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. S2CID 23048998.
- Ioannou YA, Bishop DF, Desnick RJ (December 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. PMID 1332979.
- von Scheidt W, Eng CM, Fitzmaurice TF, Erdmann E, Hübner G, Olsen EG, Christomanou H, Kandolf R, Bishop DF, Desnick RJ (February 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.
- Koide T, Ishiura M, Iwai K, Inoue M, Kaneda Y, Okada Y, Uchida T (January 1990). "A case of Fabry's disease in a patient with no α-galactosidase A activity caused by a single amino acid substitution of Pro-40 by Ser". FEBS Letters. 259 (2): 353–6. S2CID 23578317.
- Kornreich R, Bishop DF, Desnick RJ (June 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 (November 1990). "Identification of point mutations in the α-galactosidase A gene in classical and atypical hemizygotes with Fabry disease". American Journal of Human Genetics. 47 (5): 784–9. PMID 2171331.
- Bernstein HS, Bishop DF, Astrin KH, Kornreich R, Eng CM, Sakuraba H, Desnick RJ (April 1989). "Fabry disease: six gene rearrangements and an exonic point mutation in the α-galactosidase gene". The Journal of Clinical Investigation. 83 (4): 1390–9. PMID 2539398.
- Kornreich R, Desnick RJ, Bishop DF (April 1989). "Nucleotide sequence of the human α-galactosidase A gene". Nucleic Acids Research. 17 (8): 3301–2. PMID 2542896.
- Bishop DF, Kornreich R, Desnick RJ (June 1988). "Structural organization of the human α-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. PMID 2836863.
- Quinn M, Hantzopoulos P, Fidanza V, Calhoun DH (1987). "A genomic clone containing the promoter for the gene encoding the human lysosomal enzyme, α-galactosidase A". Gene. 58 (2–3): 177–88. PMID 2892762.
- Bishop DF, Calhoun DH, Bernstein HS, Hantzopoulos P, Quinn M, Desnick RJ (July 1986). "Human α-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. PMID 3014515.
- Lemansky P, Bishop DF, Desnick RJ, Hasilik A, von Figura K (February 1987). "Synthesis and processing of α-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 (June 1987). "Signal sequence and DNA-mediated expression of human lysosomal α-galactosidase A". European Journal of Biochemistry. 165 (2): 275–80. PMID 3036505.
External links
- alpha-Galactosidase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Human GLA genome location and GLA gene details page in the UCSC Genome Browser.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.