Galactosylceramidase

From Proteopedia

Revision as of 04:49, 4 June 2014

spinqualitylabelsall models PDB ID 3zr5 Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image Galactosylceramidase (GALC) (also known as galactocerebrosidase) is a hydrolase [1] that removes galactose from galactosylceramide and other sphingolipids[2]. Galactosylceramidase in humans is encoded by the gene GALC, and mutations in this gene are associated with Krabbe disease, or globoid cell leukodystrophy[3]. EC number 3.2.1.46 CAS number 158021-47-7 BRENDA BRENDA PDB 3ZR5 theoretical extinction coefficient 195,860 1/(M cm) theoretical molecular weight 77.3 kDa theoretical pI 6.27 Contents 1 Structure 2 Function 3 Disease 4 Relevance Structure X-ray diffraction data () from mouse models indicates that GALC is an estimated 77 kDa protein consisting of 656 residues, which form a secondary structure containing 12 α-helices and 41 β-strands. Each β-strand contains three to eleven residues. Use this link to by group, and this link to view a of the protein. Function The molecular function of galactosylceramidase is hydrolysis of a O-glycosyl bond to remove galactose from ceramide and other sphingolipids. The cellular function is the maintenance of a functional hematopoietic stem/progenitor cell niche by contributing to the control of the intracellular content of key sphingolipids[4]. Reaction of galactosylceramide and water catalyzed by galactosylceramidase Disease Defects in this enzyme cause a lysosomal storage disorder known in humans as Krabbe disease (or globoid cell leukodystrophy). Krabbe disease is a neurodegenerative disorder characterized by widespread demyelination caused by reduced or mutated function of GALC[3]. The deficiency of GALC leads to the accumulation of the neurotoxic metabolite 1-β-d-galactosylsphingosine (psychosine) in the central nervous system. Psychosine causes the destruction of epithelial actin structures and is toxic to oligodendrocytes[5][6]. GALC deficiency also causes the accumulation of lipids in "globoid" macrophages, where the medical name for the disease originated[6]. A common authentic model for this disease is the twitcher mouse model[5]. The only treatment currently available is an experiemental hematopoietic stem cell transplant, and gene therapies and enzyme replacements are still being researched[6]. Relevance

Ligands

• calcium ion
• N-acetyl-D-glucosamine

NAG-galactosylceramidase ligand-enzyme interaction

Inhibitors

Inhibitory molecules in humans include:

• 6-hexadecanoylamino-4-methylbelliferyl-beta-D-galactopyranoside, competitive inhibition
• D-galactose
• galactonyl hydrazide
• lactose
• N-(6-aminohexyl)-D-galactoside
• taurocholate (at high concentrations above 0.3% w/v)^[7]

References

1. ↑ RCSB Protein Data Bank - RCSB PDB - 3ZR5 Structure Summary. (n.d.). RCSB Protein Data Bank - RCSB PDB - 3ZR5 Structure Summary. Retrieved June 3, 2014, from www.rcsb.org DOI:10.2210/pdb3zr5/pdb
2. ↑ Zizioli D, Guarienti M, Tobia C, Gariano G, Borsani G, Bresciani R, Ronca R, Giacopuzzi E, Preti A, Gaudenzi G, Belleri M, Di Salle E, Fabrias G, Casas J, Ribatti D, Monti E, Presta M. Molecular cloning and knockdown of galactocerebrosidase in zebrafish: new insights into the pathogenesis of Krabbe's disease. Biochim Biophys Acta. 2014 Apr;1842(4):665-75. doi: 10.1016/j.bbadis.2014.01.008., Epub 2014 Jan 24. PMID:24463171 doi:http://dx.doi.org/10.1016/j.bbadis.2014.01.008
3. ↑ ^{3.0 3.1} Deane JE, Graham SC, Kim NN, Stein PE, McNair R, Cachon-Gonzalez MB, Cox TM, Read RJ. Insights into Krabbe disease from structures of galactocerebrosidase. Proc Natl Acad Sci U S A. 2011 Sep 13;108(37):15169-73. Epub 2011 Aug 29. PMID:21876145 doi:10.1073/pnas.1105639108
4. ↑ Visigalli I, Ungari S, Martino S, Park H, Cesani M, Gentner B, Sergi Sergi L, Orlacchio A, Naldini L, Biffi A. The galactocerebrosidase enzyme contributes to the maintenance of a functional hematopoietic stem cell niche. Blood. 2010 Sep 16;116(11):1857-66. doi: 10.1182/blood-2009-12-256461. Epub 2010 , May 28. PMID:20511539 doi:http://dx.doi.org/10.1182/blood-2009-12-256461
5. ↑ ^{5.0 5.1} Belleri M, Ronca R, Coltrini D, Nico B, Ribatti D, Poliani PL, Giacomini A, Alessi P, Marchesini S, Santos MB, Bongarzone ER, Presta M. Inhibition of angiogenesis by beta-galactosylceramidase deficiency in globoid cell leukodystrophy. Brain. 2013 Sep;136(Pt 9):2859-75. doi: 10.1093/brain/awt215. PMID:23983033 doi:http://dx.doi.org/10.1093/brain/awt215
6. ↑ ^{6.0 6.1 6.2} Kohlschutter A. Lysosomal leukodystrophies: Krabbe disease and metachromatic leukodystrophy. Handb Clin Neurol. 2013;113:1611-8. doi: 10.1016/B978-0-444-59565-2.00029-0. PMID:23622382 doi:http://dx.doi.org/10.1016/B978-0-444-59565-2.00029-0
7. ↑ EC 3.2.1.46 - galactosylceramidase. (n.d.). Information on. Retrieved June 3, 2014, from www.brenda-enzymes.org