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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.
Lysosomal storage diseases are a group of over 70 rare inherited metabolic disorders that result from defects in lysosomal function. Lysosomes are sacs of enzymes within cells that digest large molecules and pass the fragments on to other parts of the cell for recycling. This process requires several critical enzymes. If one of these enzymes is defective due to a mutation,the large molecules accumulate within the cell,eventually killing it.
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) catalyse the cleavage of fatty acids in position 2 of phospholipids,hydrolyzing the bond between the second fatty acid “tail”and the glycerol molecule:
Ceramides are a family of waxy lipid molecules. A ceramide is composed of sphingosine and a fatty acid joined by an amide bond. Ceramides are found in high concentrations within the cell membrane of eukaryotic cells,since they are component lipids that make up sphingomyelin,one of the major lipids in the lipid bilayer. Contrary to previous assumptions that ceramides and other sphingolipids found in cell membrane were purely supporting structural elements,ceramide can participate in a variety of cellular signaling:examples include regulating differentiation,proliferation,and programmed cell death (PCD) of cells.
Cerebrosides is the common name for a group of glycosphingolipids called monoglycosylceramides which are important components in 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.
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.
α-Galactosidase is a glycoside hydrolase enzyme that catalyses the following reaction:
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.
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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- ↑ 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 – via CrossRef.
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