9fad
Gcase in complex with small molecule inhibitor 1
Structural highlights
DiseaseGBA1_HUMAN Gaucher disease type 3;Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome;Gaucher disease type 1;Hereditary late-onset Parkinson disease;Gaucher disease type 2;Fetal Gaucher disease;NON RARE IN EUROPE: Dementia with Lewy body;NON RARE IN EUROPE: Parkinson disease. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. Perinatal lethal Gaucher disease is associated with non-immune hydrops fetalis, a generalized edema of the fetus with fluid accumulation in the body cavities due to non-immune causes. Non-immune hydrops fetalis is not a diagnosis in itself but a symptom, a feature of many genetic disorders, and the end-stage of a wide variety of disorders.[1] Disease susceptibility may be associated with variants affecting the gene represented in this entry. FunctionGBA1_HUMAN Glucosylceramidase that catalyzes, within the lysosomal compartment, the hydrolysis of glucosylceramides/GlcCers (such as beta-D-glucosyl-(1<->1')-N-acylsphing-4-enine) into free ceramides (such as N-acylsphing-4-enine) and glucose (PubMed:15916907, PubMed:24211208, PubMed:32144204, PubMed:9201993). Plays a central role in the degradation of complex lipids and the turnover of cellular membranes (PubMed:27378698). Through the production of ceramides, participates in the PKC-activated salvage pathway of ceramide formation (PubMed:19279011). Catalyzes the glucosylation of cholesterol, through a transglucosylation reaction where glucose is transferred from GlcCer to cholesterol (PubMed:24211208, PubMed:26724485, PubMed:32144204). GlcCer containing mono-unsaturated fatty acids (such as beta-D-glucosyl-N-(9Z-octadecenoyl)-sphing-4-enine) are preferred as glucose donors for cholesterol glucosylation when compared with GlcCer containing same chain length of saturated fatty acids (such as beta-D-glucosyl-N-octadecanoyl-sphing-4-enine) (PubMed:24211208). Under specific conditions, may alternatively catalyze the reverse reaction, transferring glucose from cholesteryl 3-beta-D-glucoside to ceramide (Probable) (PubMed:26724485). Can also hydrolyze cholesteryl 3-beta-D-glucoside producing glucose and cholesterol (PubMed:24211208, PubMed:26724485). Catalyzes the hydrolysis of galactosylceramides/GalCers (such as beta-D-galactosyl-(1<->1')-N-acylsphing-4-enine), as well as the transfer of galactose between GalCers and cholesterol in vitro, but with lower activity than with GlcCers (PubMed:32144204). Contrary to GlcCer and GalCer, xylosylceramide/XylCer (such as beta-D-xyosyl-(1<->1')-N-acylsphing-4-enine) is not a good substrate for hydrolysis, however it is a good xylose donor for transxylosylation activity to form cholesteryl 3-beta-D-xyloside (PubMed:33361282).[2] [3] [4] [5] [6] [7] [8] [9] [10] Publication Abstract from PubMedbeta-Glucocerebrosidase (GBA/GCase) mutations leading to misfolded protein cause Gaucher's disease and are a major genetic risk factor for Parkinson's disease and dementia with Lewy bodies. The identification of small molecule pharmacological chaperones that can stabilize the misfolded protein and increase delivery of degradation-prone mutant GCase to the lysosome is a strategy under active investigation. Here, we describe the first use of fragment-based drug discovery (FBDD) to identify pharmacological chaperones of GCase. The fragment hits were identified by using X-ray crystallography and biophysical techniques. This work led to the discovery of a series of compounds that bind GCase with nM potency and positively modulate GCase activity in cells. Fragment-Based Discovery of a Series of Allosteric-Binding Site Modulators of beta-Glucocerebrosidase.,Palmer N, Agnew C, Benn C, Buffham WJ, Castro JN, Chessari G, Clark M, Cons BD, Coyle JE, Dawson LA, Hamlett CCF, Hodson C, Holding F, Johnson CN, Liebeschuetz JW, Mahajan P, McCarthy JM, Murray CW, O'Reilly M, Peakman T, Price A, Rapti M, Reeks J, Schopf P, St-Denis JD, Valenzano C, Wallis NG, Walser R, Weir H, Wilsher NE, Woodhead A, Bento CF, Tisi D J Med Chem. 2024 Jun 27. doi: 10.1021/acs.jmedchem.4c00702. PMID:38932616[11] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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