Structural highlights
Disease
[GALC_MOUSE] Defects in Galc are the cause of the 'twitcher' phenotype; an autosomal recessive leukodystrophy similar to the human disease (Krabbe disease). This deficiency results in the insufficient catabolism of several galactolipids that are important in the production of normal myelin.
Function
[GALC_MOUSE] Hydrolyzes the galactose ester bonds of galactosylceramide, galactosylsphingosine, lactosylceramide, and monogalactosyldiglyceride. Enzyme with very low activity responsible for the lysosomal catabolism of galactosylceramide, a major lipid in myelin, kidney and epithelial cells of small intestine and colon.[1]
Publication Abstract from PubMed
Glycosphingolipids are ubiquitous components of mammalian cell membranes, and defects in their catabolism by lysosomal enzymes cause a diverse array of diseases. Deficiencies in the enzyme beta-galactocerebrosidase (GALC) cause Krabbe disease, a devastating genetic disorder characterized by widespread demyelination and rapid, fatal neurodegeneration. Here, we present a series of high-resolution crystal structures that illustrate key steps in the catalytic cycle of GALC. We have captured a snapshot of the short-lived enzyme-substrate complex illustrating how wild-type GALC binds a bona fide substrate. We have extensively characterized the enzyme kinetics of GALC with this substrate and shown that the enzyme is active in crystallo by determining the structure of the enzyme-product complex following extended soaking of the crystals with this same substrate. We have also determined the structure of a covalent intermediate that, together with the enzyme-substrate and enzyme-product complexes, reveals conformational changes accompanying the catalytic steps and provides key mechanistic insights, laying the foundation for future design of pharmacological chaperones.
Structural snapshots illustrate the catalytic cycle of beta-galactocerebrosidase, the defective enzyme in Krabbe disease.,Hill CH, Graham SC, Read RJ, Deane JE Proc Natl Acad Sci U S A. 2013 Dec 2. PMID:24297913[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Sakai N, Inui K, Tatsumi N, Fukushima H, Nishigaki T, Taniike M, Nishimoto J, Tsukamoto H, Yanagihara I, Ozono K, Okada S. Molecular cloning and expression of cDNA for murine galactocerebrosidase and mutation analysis of the twitcher mouse, a model of Krabbe's disease. J Neurochem. 1996 Mar;66(3):1118-24. PMID:8769874
- ↑ Hill CH, Graham SC, Read RJ, Deane JE. Structural snapshots illustrate the catalytic cycle of beta-galactocerebrosidase, the defective enzyme in Krabbe disease. Proc Natl Acad Sci U S A. 2013 Dec 2. PMID:24297913 doi:http://dx.doi.org/10.1073/pnas.1311990110
