PDBsum entry 1r47

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Hydrolase PDB id
Protein chain
390 a.a. *
GAL ×2
EDO ×2
Waters ×18
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: Structure of human alpha-galactosidase
Structure: Alpha-galactosidase a. Chain: a, b. Synonym: melibiase, alpha-d-galactoside galactohydrolase, a galactosidase a, agalsidase alfa. Engineered: yes. Other_details: complex with alpha-galactose
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: gla. Expressed in: homo sapiens. Expression_system_taxid: 9606
3.45Å     R-factor:   0.285     R-free:   0.321
Authors: S.C.Garman,D.N.Garboczi
Key ref:
S.C.Garman and D.N.Garboczi (2004). The molecular defect leading to Fabry disease: structure of human alpha-galactosidase. J Mol Biol, 337, 319-335. PubMed id: 15003450 DOI: 10.1016/j.jmb.2004.01.035
03-Oct-03     Release date:   16-Mar-04    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P06280  (AGAL_HUMAN) -  Alpha-galactosidase A
429 a.a.
390 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.  - Alpha-galactosidase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Melibiose + H2O = galactose + glucose

      Cofactor: Mg(2+); NAD(+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   6 terms 
  Biological process     metabolic process   11 terms 
  Biochemical function     catalytic activity     10 terms  


DOI no: 10.1016/j.jmb.2004.01.035 J Mol Biol 337:319-335 (2004)
PubMed id: 15003450  
The molecular defect leading to Fabry disease: structure of human alpha-galactosidase.
S.C.Garman, D.N.Garboczi.
Fabry disease is an X-linked lysosomal storage disease afflicting 1 in 40,000 males with chronic pain, vascular degeneration, cardiac impairment, and other symptoms. Deficiency in the lysosomal enzyme alpha-galactosidase (alpha-GAL) causes an accumulation of its substrate, which ultimately leads to Fabry disease symptoms. Here, we present the structure of the human alpha-GAL glycoprotein determined by X-ray crystallography. The structure is a homodimer with each monomer containing a (beta/alpha)8 domain with the active site and an antiparallel beta domain. N-linked carbohydrate appears at six sites in the glycoprotein dimer, revealing the basis for lysosomal transport via the mannose-6-phosphate receptor. To understand how the enzyme cleaves galactose from glycoproteins and glycolipids, we also determined the structure of the complex of alpha-GAL with its catalytic product. The catalytic mechanism of the enzyme is revealed by the location of two aspartic acid residues (D170 and D231), which act as a nucleophile and an acid/base, respectively. As a point mutation in alpha-GAL can lead to Fabry disease, we have catalogued and plotted the locations of 245 missense and nonsense mutations in the three-dimensional structure. The structure of human alpha-GAL brings Fabry disease into the realm of molecular diseases, where insights into the structural basis of the disease phenotypes might help guide the clinical treatment of patients.
  Selected figure(s)  
Figure 1.
Figure 1. The reaction catalyzed by a-GAL. (a) The general reaction of a-GAL. A terminal galactose in the a anomeric configuration is cleaved from an oligosaccharide, glycoprotein, or glycolipid, producing a-galactose (Gala1) and an alcohol. The carbon atoms are numbered on a-galactose. (b) a-GAL and Fabry disease. The Fabry disease substrate globotriaosylceramide is cleaved by a-GAL to form lactosylceramide. In the absence of the functional enzyme, globotriaosylceramide accumulates in the tissues.
Figure 5.
Figure 5. The active site of a-GAL. (a) and (b) Electron density in human a-GAL from native and galactose-soaked crystals. The electron density is shown in stereo contoured at 1.1s from a s[A]-weighted simulated annealing composite omit map, with side-chains from active site residues colored as in Figure 3. The red density does not derive from the protein and is interpreted as an ethylene glycol molecule in (a) and the catalytic product galactose in (b). In (c) and (d), the superimposed active sites of human a-GAL (green), chicken a-NAGAL (yellow), and rice a-GAL (blue) are shown in stereo. The b5-a5 loop that differs among the three structures appears at lower right.
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2004, 337, 319-335) copyright 2004.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21229318 A.Gal, D.A.Hughes, and B.Winchester (2011).
Toward a consensus in the laboratory diagnostics of Fabry disease - recommendations of a European expert group.
  J Inherit Metab Dis, 34, 509-514.  
20131008 M.Yoshimitsu, K.Higuchi, X.Fan, S.Takao, J.A.Medin, C.Tei, and T.Takenaka (2011).
Sequencing and characterization of the porcine α-galactosidase A gene: towards the generation of a porcine model for Fabry disease.
  Mol Biol Rep, 38, 3145-3152.  
21353612 T.Tsukimura, Y.Chiba, K.Ohno, S.Saito, Y.Tajima, and H.Sakuraba (2011).
Molecular mechanism for stabilization of a mutant α-galactosidase A involving M51I amino acid substitution by imino sugars.
  Mol Genet Metab, 103, 26-32.  
19940122 A.I.Guce, N.E.Clark, E.N.Salgado, D.R.Ivanen, A.A.Kulminskaya, H.Brumer, and S.C.Garman (2010).
Catalytic mechanism of human alpha-galactosidase.
  J Biol Chem, 285, 3625-3632.
PDB codes: 3hg2 3hg3 3hg4 3hg5
20660166 A.Mehta, M.Beck, F.Eyskens, C.Feliciani, I.Kantola, U.Ramaswami, A.Rolfs, A.Rivera, S.Waldek, and D.P.Germain (2010).
Fabry disease: a review of current management strategies.
  QJM, 103, 641-659.  
20505683 B.H.Lee, S.H.Heo, G.H.Kim, J.Y.Park, W.S.Kim, D.H.Kang, K.H.Choe, W.H.Kim, S.H.Yang, and H.W.Yoo (2010).
Mutations of the GLA gene in Korean patients with Fabry disease and frequency of the E66Q allele as a functional variant in Korean newborns.
  J Hum Genet, 55, 512-517.  
19941952 C.Filoni, A.Caciotti, L.Carraresi, C.Cavicchi, R.Parini, D.Antuzzi, A.Zampetti, S.Feriozzi, P.Poisetti, S.C.Garman, R.Guerrini, E.Zammarchi, M.A.Donati, and A.Morrone (2010).
Functional studies of new GLA gene mutations leading to conformational Fabry disease.
  Biochim Biophys Acta, 1802, 247-252.  
21092187 D.P.Germain (2010).
Fabry disease.
  Orphanet J Rare Dis, 5, 30.  
21138548 G.Andreotti, M.R.Guarracino, M.Cammisa, A.Correra, and M.V.Cubellis (2010).
Prediction of the responsiveness to pharmacological chaperones: lysosomal human alpha-galactosidase, a case of study.
  Orphanet J Rare Dis, 5, 36.  
20714719 J.Zhou, P.Shi, H.Huang, Y.Cao, K.Meng, P.Yang, R.Zhang, X.Chen, and B.Yao (2010).
A new α-galactosidase from symbiotic Flavobacterium sp. TN17 reveals four residues essential for α-galactosidase activity of gastrointestinal bacteria.
  Appl Microbiol Biotechnol, 88, 1297-1309.  
20601723 N.Kulik, L.Weignerová, T.Filipi, P.Pompach, P.Novák, H.Mrázek, K.Slámová, K.Bezouska, V.Kren, and R.Ettrich (2010).
The α-galactosidase type A gene aglA from Aspergillus niger encodes a fully functional α-N-acetylgalactosaminidase.
  Glycobiology, 20, 1410-1419.  
19958207 R.Krüger, K.Bruns, S.Grünhage, H.Rossmann, J.Reinke, M.Beck, and K.J.Lackner (2010).
Determination of globotriaosylceramide in plasma and urine by mass spectrometry.
  Clin Chem Lab Med, 48, 189-198.  
20629180 R.Kuipers, T.van den Bergh, H.J.Joosten, R.H.Lekanne dit Deprez, M.M.Mannens, and P.J.Schaap (2010).
Novel tools for extraction and validation of disease-related mutations applied to Fabry disease.
  Hum Mutat, 31, 1026-1032.  
20501459 R.Torra, J.P.Oliveira, and A.Ortiz (2010).
UGA hopping: a sport for nephrologists too?
  Nephrol Dial Transplant, 25, 2391-2395.  
19387866 E.R.Benjamin, J.J.Flanagan, A.Schilling, H.H.Chang, L.Agarwal, E.Katz, X.Wu, C.Pine, B.Wustman, R.J.Desnick, D.J.Lockhart, and K.J.Valenzano (2009).
The pharmacological chaperone 1-deoxygalactonojirimycin increases alpha-galactosidase A levels in Fabry patient cell lines.
  J Inherit Metab Dis, 32, 424-440.  
19287194 J.Y.Park, G.H.Kim, S.S.Kim, J.M.Ko, J.J.Lee, and H.W.Yoo (2009).
Effects of a chemical chaperone on genetic mutations in alpha-galactosidase A in Korean patients with Fabry disease.
  Exp Mol Med, 41, 1-7.  
19683538 N.E.Clark, and S.C.Garman (2009).
The 1.9 a structure of human alpha-N-acetylgalactosaminidase: The molecular basis of Schindler and Kanzaki diseases.
  J Mol Biol, 393, 435-447.
PDB codes: 3h53 3h54 3h55 3igu
19859978 P.A.Rozenfeld (2009).
Fabry Disease: Treatment and diagnosis.
  IUBMB Life, 61, 1043-1050.  
19374450 R.L.Lieberman, J.A.D'aquino, D.Ringe, and G.A.Petsko (2009).
Effects of pH and iminosugar pharmacological chaperones on lysosomal glycosidase structure and stability.
  Biochemistry, 48, 4816-4827.
PDB codes: 3gxd 3gxf 3gxi 3gxm 3gxn 3gxp 3gxt
19318041 R.Schiffmann (2009).
Fabry disease.
  Pharmacol Ther, 122, 65-77.  
19005653 T.Goulas, A.Goulas, G.Tzortzis, and G.R.Gibson (2009).
A novel alpha-galactosidase from Bifidobacterium bifidum with transgalactosylating properties: gene molecular cloning and heterologous expression.
  Appl Microbiol Biotechnol, 82, 471-477.  
19790257 T.S.Kang, and R.C.Stevens (2009).
Structural aspects of therapeutic enzymes to treat metabolic disorders.
  Hum Mutat, 30, 1591-1610.  
19288093 Y.Cao, Y.Wang, K.Meng, Y.Bai, P.Shi, H.Luo, P.Yang, Z.Zhou, Z.Zhang, and B.Yao (2009).
A novel protease-resistant alpha-galactosidase with high hydrolytic activity from Gibberella sp. F75: gene cloning, expression, and enzymatic characterization.
  Appl Microbiol Biotechnol, 83, 875-884.  
19853240 Y.Tajima, I.Kawashima, T.Tsukimura, K.Sugawara, M.Kuroda, T.Suzuki, T.Togawa, Y.Chiba, Y.Jigami, K.Ohno, T.Fukushige, T.Kanekura, K.Itoh, T.Ohashi, and H.Sakuraba (2009).
Use of a modified alpha-N-acetylgalactosaminidase in the development of enzyme replacement therapy for Fabry disease.
  Am J Hum Genet, 85, 569-580.  
19809163 Z.Fujimoto, S.Kaneko, W.D.Kim, G.G.Park, M.Momma, and H.Kobayashi (2009).
The tetramer structure of the glycoside hydrolase family 27 alpha-galactosidase I from Umbelopsis vinacea.
  Biosci Biotechnol Biochem, 73, 2360-2364.
PDB code: 3a5v
18633574 K.Sugawara, K.Ohno, S.Saito, and H.Sakuraba (2008).
Structural characterization of mutant alpha-galactosidases causing Fabry disease.
  J Hum Genet, 53, 812-824.  
18698230 S.H.Shin, S.Kluepfel-Stahl, A.M.Cooney, C.R.Kaneski, J.M.Quirk, R.Schiffmann, R.O.Brady, and G.J.Murray (2008).
Prediction of response of mutated alpha-galactosidase A to a pharmacological chaperone.
  Pharmacogenet Genomics, 18, 773-780.  
17004069 A.Limberger, M.Beck, S.Delgado-Sanchez, and A.Keilmann (2007).
[Hearing loss in patients with Fabry disease]
  HNO, 55, 185-189.  
17279083 A.T.Møller, and T.S.Jensen (2007).
Neurological manifestations in Fabry's disease.
  Nat Clin Pract Neurol, 3, 95.  
17573884 C.H.Orteu, T.Jansen, O.Lidove, R.Jaussaud, D.A.Hughes, G.Pintos-Morell, U.Ramaswami, R.Parini, G.Sunder-Plassman, M.Beck, and A.B.Mehta (2007).
Fabry disease and the skin: data from FOS, the Fabry outcome survey.
  Br J Dermatol, 157, 331-337.  
17545117 E.Rákóczi, S.Görögh, J.Grubits, M.Erdos, F.Garzuly, K.Hahn, K.Bencsik, L.Vécsei, C.Trinn, E.Kristóf, G.Mogyorósy, B.Tóth, and L.Maródi (2007).
[Molecular pathology and clinical manifestations of Fabry disease].
  Orv Hetil, 148, 1087-1094.  
17894781 J.Q.Fan, and S.Ishii (2007).
Active-site-specific chaperone therapy for Fabry disease. Yin and Yang of enzyme inhibitors.
  FEBS J, 274, 4962-4971.  
17437606 L.S.Ro, C.M.Chen, H.S.Chang, R.K.Lyu, Y.R.Wu, W.C.Hsu, and G.J.Lee-Chen (2007).
Contribution of clinical screening to carrier detection in a large Chinese family with Fabry disease due to a novel alpha-galactosidase A gene deletion.
  Eur J Neurol, 14, 493-497.  
17652792 M.N.Heneghan, A.M.Costa, M.P.Challen, P.R.Mills, A.Bailey, and G.D.Foster (2007).
A comparison of methods for successful triggering of gene silencing in Coprinus cinereus.
  Mol Biotechnol, 35, 283-296.  
16929352 M.Yoshimitsu, K.Higuchi, S.Ramsubir, T.Nonaka, V.I.Rasaiah, C.Siatskas, S.B.Liang, G.J.Murray, R.O.Brady, and J.A.Medin (2007).
Efficient correction of Fabry mice and patient cells mediated by lentiviral transduction of hematopoietic stem/progenitor cells.
  Gene Ther, 14, 256-265.  
  17391432 S.C.Garman (2007).
Structure-function relationships in alpha-galactosidase A.
  Acta Paediatr Suppl, 96, 6.  
16914407 A.Fellgiebel, M.J.Müller, and L.Ginsberg (2006).
CNS manifestations of Fabry's disease.
  Lancet Neurol, 5, 791-795.  
16980809 C.M.Eng, D.P.Germain, M.Banikazemi, D.G.Warnock, C.Wanner, R.J.Hopkin, J.Bultas, P.Lee, K.Sims, S.E.Brodie, G.M.Pastores, J.M.Strotmann, and W.R.Wilcox (2006).
Fabry disease: guidelines for the evaluation and management of multi-organ system involvement.
  Genet Med, 8, 539-548.  
16580615 D.G.Warnock, and M.L.West (2006).
Diagnosis and management of kidney involvement in Fabry disease.
  Adv Chronic Kidney Dis, 13, 138-147.  
  16511274 M.Foucault, H.Watzlawick, R.Mattes, R.Haser, and P.Gouet (2006).
Crystallization and preliminary X-ray diffraction studies of two thermostable alpha-galactosidases from glycoside hydrolase family 36.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 62, 100-103.  
16842369 M.S.Centeno, C.I.Guerreiro, F.M.Dias, C.Morland, L.E.Tailford, A.Goyal, J.A.Prates, L.M.Ferreira, R.M.Caldeira, E.F.Mongodin, K.E.Nelson, H.J.Gilbert, and C.M.Fontes (2006).
Galactomannan hydrolysis and mannose metabolism in Cellvibrio mixtus.
  FEMS Microbiol Lett, 261, 123-132.  
16773563 M.Spada, S.Pagliardini, M.Yasuda, T.Tukel, G.Thiagarajan, H.Sakuraba, A.Ponzone, and R.J.Desnick (2006).
High incidence of later-onset fabry disease revealed by newborn screening.
  Am J Hum Genet, 79, 31-40.  
16630168 P.A.Rozenfeld, A.Tarabuso, R.Ebner, G.Ramallo, and C.A.Fossati (2006).
A successful approach for the detection of Fabry patients in Argentina.
  Clin Genet, 69, 344-348.  
16970764 P.A.Rozenfeld, O.Croxatto, R.Ebner, and C.A.Fossati (2006).
Immunofluorescence detection of globotriaosylceramide deposits in conjunctival biopsies of Fabry disease patients.
  Clin Experiment Ophthalmol, 34, 689-694.  
16547025 S.J.Brouns, N.Smits, H.Wu, A.P.Snijders, P.C.Wright, Vos, and J.van der Oost (2006).
Identification of a novel alpha-galactosidase from the hyperthermophilic archaeon Sulfolobus solfataricus.
  J Bacteriol, 188, 2392-2399.  
16807686 S.S.Razvi, and I.Bone (2006).
Single gene disorders causing ischaemic stroke.
  J Neurol, 253, 685-700.  
16320365 S.W.Hinz, C.H.Doeswijk-Voragen, R.Schipperus, L.A.van den Broek, J.P.Vincken, and A.G.Voragen (2006).
Increasing the transglycosylation activity of alpha-galactosidase from Bifidobacterium adolescentis DSM 20083 by site-directed mutagenesis.
  Biotechnol Bioeng, 93, 122-131.  
16131397 D.G.Naumoff (2005).
GH97 is a new family of glycoside hydrolases, which is related to the alpha-galactosidase superfamily.
  BMC Genomics, 6, 112.  
15687833 D.G.Warnock (2005).
Fabry disease: diagnosis and management, with emphasis on the renal manifestations.
  Curr Opin Nephrol Hypertens, 14, 87-95.  
15924232 F.Matsuzawa, S.Aikawa, H.Doi, T.Okumiya, and H.Sakuraba (2005).
Fabry disease: correlation between structural changes in alpha-galactosidase, and clinical and biochemical phenotypes.
  Hum Genet, 117, 317-328.  
15676072 J.Hujová, J.Sikora, R.Dobrovolný, H.Poupetová, J.Ledvinová, M.Kostrouchová, and M.Hrebícek (2005).
Characterization of gana-1, a Caenorhabditis elegans gene encoding a single ortholog of vertebrate alpha-galactosidase and alpha-N-acetylgalactosaminidase.
  BMC Cell Biol, 6, 5.  
15806320 R.Dobrovolny, L.Dvorakova, J.Ledvinova, S.Magage, J.Bultas, J.C.Lubanda, M.Elleder, D.Karetova, M.Pavlikova, and M.Hrebicek (2005).
Relationship between X-inactivation and clinical involvement in Fabry heterozygotes. Eleven novel mutations in the alpha-galactosidase A gene in the Czech and Slovak population.
  J Mol Med, 83, 647-654.  
16415520 S.Inagaki, M.Migita, M.Hayakawa, A.Fujita, J.Yoshida, M.Ishizaki, M.Kotani, H.Sakuraba, T.Shimada, M.Murakami, and Y.Fukunaga (2005).
An asymptomatic heterozygous female with fabry disease: implications for enzyme replacement therapy.
  J Nippon Med Sch, 72, 387-390.  
14975192 A.Untergasser, and U.Protzer (2004).
Hepatitis B virus-based vectors allow the elimination of viral gene expression and the insertion of foreign promoters.
  Hum Gene Ther, 15, 203-210.  
15492942 D.Rosenthal, Y.H.Lien, D.Lager, L.W.Lai, S.Shang, N.Leung, and F.C.Fervenza (2004).
A novel alpha-galactosidase a mutant (M42L) identified in a renal variant of Fabry disease.
  Am J Kidney Dis, 44, e85-e89.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.