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Gaucher's disease or Gaucher disease (GD) is a genetic disorder in which glucocerebroside accumulates in cells and certain organs. The disorder is characterized by bruising,fatigue,anemia,low blood platelet count and enlargement of the liver and spleen,and is caused by a hereditary deficiency of the enzyme glucocerebrosidase,which acts on glucocerebroside. When the enzyme is defective,glucocerebroside accumulates,particularly in white blood cells and especially in macrophages. Glucocerebroside can collect in the spleen,liver,kidneys,lungs,brain,and bone marrow.
Fabry disease,also known as Anderson–Fabry disease,is a rare genetic disease that can affect many parts of the body,including the kidneys,heart,brain,and skin. Fabry disease is one of a group of conditions known as lysosomal storage diseases. The genetic mutation that causes Fabry disease interferes with the function of an enzyme that processes biomolecules known as sphingolipids,leading to these substances building up in the walls of blood vessels and other organs. It is inherited in an X-linked manner.
Sphingolipids are a class of lipids containing a backbone of sphingoid bases,which are a set of aliphatic amino alcohols that includes sphingosine. They were discovered in brain extracts in the 1870s and were named after the mythological sphinx because of their enigmatic nature. These compounds play important roles in signal transduction and cell recognition. Sphingolipidoses,or disorders of sphingolipid metabolism,have particular impact on neural tissue. A sphingolipid with a terminal hydroxyl group is a ceramide. Other common groups bonded to the terminal oxygen atom include phosphocholine,yielding a sphingomyelin,and various sugar monomers or dimers,yielding cerebrosides and globosides,respectively. Cerebrosides and globosides are collectively known as glycosphingolipids.
The enzyme phospholipase A2 (EC 3.1.1.4,PLA2,systematic name phosphatidylcholine 2-acylhydrolase) catalyses the cleavage of fatty acids in position 2 of phospholipids,hydrolyzing the bond between the second fatty acid “tail”and the glycerol molecule:
Cerebrosides (monoglycosylceramides) are a group of glycosphingolipids which are important components of animal muscle and nerve cell membranes.
Enzyme replacement therapy (ERT) is a medical treatment which replaces an enzyme that is deficient or absent in the body. Usually,this is done by giving the patient an intravenous (IV) infusion of a solution containing the enzyme.
Clofazimine,sold under the brand name Lamprene,is a medication used together with rifampicin and dapsone to treat leprosy. It is specifically used for multibacillary (MB) leprosy and erythema nodosum leprosum. Evidence is insufficient to support its use in other conditions though a retrospective study found it 95% effective in the treatment of Mycobacterium avium complex (MAC) when administered with a macrolide and ethambutol,as well as the drugs amikacin and clarithromycin. However,in the United States,clofazimine is considered an orphan drug,is unavailable in pharmacies,and its use in the treatment of MAC is overseen by the Food and Drug Administration. It is taken orally.
β-Glucocerebrosidase is an enzyme with glucosylceramidase activity that cleaves by hydrolysis the β-glycosidic linkage of the chemical glucocerebroside,an intermediate in glycolipid metabolism that is abundant in cell membranes. It is localized in the lysosome,where it remains associated with the lysosomal membrane. β-Glucocerebrosidase is 497 amino acids in length and has a molecular mass of 59,700 Da.
Glucocerebroside is any of the cerebrosides in which the monosaccharide head group is glucose.
Sphingolipidoses are a class of lipid storage disorders or degenerative storage disorders caused by deficiency of an enzyme that is required for the catabolism of lipids that contain ceramide,also relating to sphingolipid metabolism. The main members of this group are Niemann–Pick disease,Fabry disease,Krabbe disease,Gaucher disease,Tay–Sachs disease and metachromatic leukodystrophy. They are generally inherited in an autosomal recessive fashion,but notably Fabry disease is X-linked recessive. Taken together,sphingolipidoses have an incidence of approximately 1 in 10,000,but substantially more in certain populations such as Ashkenazi Jews. Enzyme replacement therapy is available to treat mainly Fabry disease and Gaucher disease,and people with these types of sphingolipidoses may live well into adulthood. The other types are generally fatal by age 1 to 5 years for infantile forms,but progression may be mild for juvenile- or adult-onset forms.
Lipid signaling, broadly defined,refers to any biological cell signaling event involving a lipid messenger that binds a protein target,such as a receptor,kinase or phosphatase,which in turn mediate the effects of these lipids on specific cellular responses. Lipid signaling is thought to be qualitatively different from other classical signaling paradigms because lipids can freely diffuse through membranes. One consequence of this is that lipid messengers cannot be stored in vesicles prior to release and so are often biosynthesized "on demand" at their intended site of action. As such,many lipid signaling molecules cannot circulate freely in solution but,rather,exist bound to special carrier proteins in serum.
β-Glucosidase is an enzyme that catalyses the following reaction:
Globosides are a sub-class of the lipid class glycosphingolipid with three to nine sugar molecules as the side chain of ceramide. The sugars are usually a combination of N-acetylgalactosamine,D-glucose or D-galactose. One characteristic of globosides is that the "core" sugars consists of Glucose-Galactose-Galactose (Ceramide-βGlc4-1βGal4-1αGal),like in the case of the most basic globoside,globotriaosylceramide (Gb3),also known as pk-antigen. Another important characteristic of globosides is that they are neutral at pH 7,because they usually do not contain neuraminic acid,a sugar with an acidic carboxy-group. However,some globosides with the core structure Cer-Glc-Gal-Gal do contain neuraminic acid,e.g. the globo-series glycosphingolipid "SSEA-4-antigen".
Miglustat,sold under the brand name Zavesca among others,is a medication used to treat type I Gaucher disease and Pompe disease.
Lapaquistat (TAK-475) is a cholesterol-lowering drug candidate that was abandoned before being marketed.
In enzymology,a ceramide kinase,also abbreviated as CERK,is an enzyme that catalyzes the chemical reaction:
LYPLA3,also known as Group XV phospholipase A2, is an enzyme that in humans is encoded by the PLA2G15 gene.
The Lactosylceramides,also known as LacCer,are a class of glycosphingolipids composed of a variable hydrophobic ceramide lipid and a hydrophilic sugar moiety. Lactosylceramides are found in microdomains on the plasma layers of numerous cells. Moreover,they are a type of ceramide including lactose,which is an example of a globoside.
Substrate reduction therapy offers an approach to treatment of certain metabolic disorders,especially glycogen storage diseases and lysosomal storage disorders. In a storage disorder,a critical failure in a metabolic pathway prevents cellular breakdown and disposal of some large molecule. If residual breakdown through other pathways is insufficient to prevent harmful accumulation,the molecule accumulates in the cell and eventually interferes with normal biological processes. Examples of lysosomal storage disorders include Gaucher's disease,Tay–Sachs disease,Sandhoff disease,and Sanfilippo syndrome.
Eliglustat,sold under the brand name Cerdelga,is a medication used for the treatment of Gaucher's disease. It was discovered at the University of Michigan,developed by Genzyme Corp,and was approved by the FDA in August 2014. Commonly used as the tartrate salt,the compound is believed to work by inhibition of glucosylceramide synthase. According to an article in Journal of the American Medical Association the oral substrate reduction therapy resulted in "significant improvements in spleen volume,hemoglobin level,liver volume,and platelet count" in untreated adults with Gaucher disease Type 1.
References
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- ↑ Abe, Akira; Gregory, Susan; Lee, Lihsueh; Killen, Paul D.; Brady, Roscoe O.; Kulkarni, Ashok; Shayman, James A. (June 1, 2000). "Reduction of globotriaosylceramide in Fabry disease mice by substrate deprivation". The Journal of Clinical Investigation. 105 (11): 1563–1571. doi:10.1172/JCI9711. PMC 300859 . PMID 10841515 – via www.jci.org.
- ↑ Marshall, John; McEachern, Kerry Anne; Chuang, Wei-Lien; Hutto, Elizabeth; Siegel, Craig S.; Shayman, James A.; Grabowski, Greg A.; Scheule, Ronald K.; Copeland, Diane P.; Cheng, Seng H. (June 1, 2010). "Improved management of lysosomal glucosylceramide levels in a mouse model of type 1 Gaucher disease using enzyme and substrate reduction therapy". Journal of Inherited Metabolic Disease. 33 (3): 281–289. doi:10.1007/s10545-010-9072-z. PMC 3683842 . PMID 20336375 – via Springer Link.
- ↑ Shayman, J.A. (August 1, 2010). "ELIGLUSTAT TARTRATE: Glucosylceramide Synthase Inhibitor Treatment of Type 1 Gaucher Disease". Drugs of the Future. 35 (8): 613–620. doi:10.1358/dof.2010.35.8.1505566. PMC 3340614 . PMID 22563139.
- ↑ Shayman, James A. (October 23, 2013). "The Design and Clinical Development of Inhibitors of Glycosphingolipid Synthesis: Will Invention Be the Mother of Necessity?". Transactions of the American Clinical and Climatological Association. 124: 46–60. PMC 3715929 . PMID 23874009.
- ↑ "Cell Cycle Arrest Induced by an Inhibitor of Glucosylceramide Synthase - Journal of Biological Chemistry".
- ↑ Zador, I. Z.; Deshmukh, G. D.; Kunkel, R.; Johnson, K.; Radin, N. S.; Shayman, J. A. (March 1, 1993). "A role for glycosphingolipid accumulation in the renal hypertrophy of streptozotocin-induced diabetes mellitus". The Journal of Clinical Investigation. 91 (3): 797–803. doi:10.1172/JCI116299. PMC 288030 . PMID 8450061 – via www.jci.org.
- ↑ Natoli, Thomas A.; Smith, Laurie A.; Rogers, Kelly A.; Wang, Bing; Komarnitsky, Svetlana; Budman, Yeva; Belenky, Alexei; Bukanov, Nikolay O.; Dackowski, William R.; Husson, Hervé; Russo, Ryan J.; Shayman, James A.; Ledbetter, Steven R.; Leonard, John P.; Ibraghimov-Beskrovnaya, Oxana (July 23, 2010). "Inhibition of glucosylceramide accumulation results in effective blockade of polycystic kidney disease in mouse models". Nature Medicine. 16 (7): 788–792. doi:10.1038/nm.2171. PMC 3660226 . PMID 20562878.
- ↑ Wilson, Michael W.; Shu, Liming; Hinkovska-Galcheva, Vania; Jin, Yafei; Rajeswaran, Walajapet; Abe, Akira; Zhao, Ting; Luo, Ruijuan; Wang, Lu; Wen, Bo; Liou, Benjamin; Fannin, Venette; Sun, Duxin; Sun, Ying; Shayman, James A.; Larsen, Scott D. (October 21, 2020). "Optimization of Eliglustat-Based Glucosylceramide Synthase Inhibitors as Substrate Reduction Therapy for Gaucher Disease Type 3". ACS Chemical Neuroscience. 11 (20): 3464–3473. doi:10.1021/acschemneuro.0c00558. PMC 7919060 . PMID 33035424.
- ↑ Arthur, Julian R.; Wilson, Michael W.; Larsen, Scott D.; Rockwell, Hannah E.; Shayman, James A.; Seyfried, Thomas N. (April 1, 2013). "Ethylenedioxy-PIP2 Oxalate Reduces Ganglioside Storage in Juvenile Sandhoff Disease Mice". Neurochemical Research. 38 (4): 866–875. doi:10.1007/s11064-013-0992-5. PMC 6554746 . PMID 23417430 – via Springer Link.
- ↑ "Property-based design of a glucosylceramide synthase inhibitor that reduces glucosylceramide in the brain - Journal of Lipid Research".
- ↑ Kang, Justin J.; Kaissarian, Nayiri M.; Desch, Karl C.; Kelly, Robert J.; Shu, Liming; Bodary, Peter F.; Shayman, James A. (January 1, 2019). "α-galactosidase A deficiency promotes von Willebrand factor secretion in models of Fabry disease". Kidney International. 95 (1): 149–159. doi:10.1016/j.kint.2018.08.033. PMC 6320285 . PMID 30470436.
- ↑ Shu, Liming; Park, James L.; Byun, Jaeman; Pennathur, Subramaniam; Kollmeyer, Jessica; Shayman, James A. (September 23, 2009). "Decreased Nitric Oxide Bioavailability in a Mouse Model of Fabry Disease". Journal of the American Society of Nephrology. 20 (9): 1975–1985. doi:10.1681/ASN.2008111190. PMC 2736776 . PMID 19628671.
- ↑ Shu, Liming; Vivekanandan-Giri, Anuradha; Pennathur, Subramaniam; Smid, Bouwien E.; Aerts, Johannes M. F. G.; Hollak, Carla E. M.; Shayman, James A. (July 1, 2014). "Establishing 3-nitrotyrosine as a biomarker for the vasculopathy of Fabry disease". Kidney International. 86 (1): 58–66. doi:10.1038/ki.2013.520. PMC 4077934 . PMID 24402087.
- ↑ Kang, Justin J.; Shu, Liming; Park, James L.; Shayman, James A.; Bodary, Peter F. (January 15, 2014). "Endothelial nitric oxide synthase uncoupling and microvascular dysfunction in the mesentery of mice deficient in α-galactosidase A". American Journal of Physiology. Gastrointestinal and Liver Physiology. 306 (2): G140–G146. doi:10.1152/ajpgi.00185.2013. PMC 3920075 . PMID 24232002.
- ↑ Hiraoka, Miki; Abe, Akira; Lu, Ye; Yang, Kui; Han, Xianlin; Gross, Richard W.; Shayman, James A. (August 1, 2006). "Lysosomal Phospholipase A2 and Phospholipidosis". Molecular and Cellular Biology. 26 (16): 6139–6148. doi:10.1128/MCB.00627-06. PMC 1592808 . PMID 16880524.
- ↑ "Preferential hydrolysis of truncated oxidized glycerophospholipids by lysosomal phospholipase A2 - Journal of Lipid Research".
- ↑ Hinkovska-Galcheva, Vania; Treadwell, Taylour; Shillingford, Jonathan M.; Lee, Angela; Abe, Akira; Tesmer, John J.G.; Shayman, James A. (June 1, 2021). "Inhibition of lysosomal phospholipase A2 predicts drug-induced phospholipidosis". Journal of Lipid Research. 62: 100089. doi: 10.1016/j.jlr.2021.100089 . PMC 8243516 . PMID 34087196.
- ↑ "Shayman named 2016 Distinguished University Innovator | The University Record". record.umich.edu.
- ↑ https://medicine.umich.edu/sites/default/files/content/downloads/UM%20Shayman%20Professorship%20Inaugural%20booklet%207.2019%20FINAL.pdf
- ↑ https://www.findagrave.com/memorial/17678886/david-aaron-shayman