Galactosylceramidase

From Proteopedia

(Difference between revisions)

Revision as of 20:26, 3 June 2014

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

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.

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Function

Galactosylceramidase hydrolyzes a O-glycosyl bond. It is involved in the maintenance of a functional hematopoietic stem/progenitor cell niche by contributing to the control of the intracellular content of key sphingolipids^[4].

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

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

↑ 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
↑ 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
↑ ^3.0 ^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
↑ 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
↑ ^5.0 ^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
↑ ^6.0 ^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
↑ EC 3.2.1.46 - galactosylceramidase. (n.d.). Information on. Retrieved June 3, 2014, from www.brenda-enzymes.org

Proteopedia Page Contributors and Editors (what is this?)

Alison Stivers, Michal Harel, Dillon Shapiro, Angel Herraez, Joel L. Sussman

Retrieved from "http://52.214.119.220/wiki/index.php/Galactosylceramidase"

@@ Line 46: / Line 46: @@
 *lactose
 *N-(6-aminohexyl)-D-galactoside
-*taurocholate (at high concentrations above 0.3% w/v)<ref name=BRENDA>EC 3.2.1.46 - galactosylceramidase. (n.d.). Information on. Retrieved June 3, 2014, from http://www.brenda-enzymes.org/php/result_flat.php4?ecno=3.2.1.46</ref>
+*taurocholate (at high concentrations above 0.3% w/v)<ref name=BRENDA>EC 3.2.1.46 - galactosylceramidase. (n.d.). Information on. Retrieved June 3, 2014, from www.brenda-enzymes.org</ref>
 == References ==
 <references/>

Galactosylceramidase

From Proteopedia

Revision as of 20:26, 3 June 2014

Contents

Structure

Function

Disease

Relevance

Inhibitors

References

Proteopedia Page Contributors and Editors (what is this?)

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