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17 Cards in this Set
- Front
- Back
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Structure of Sphingolipids
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-Have sphingosine backbone (an amino alcohol)
-C3 OH of sphingosine is always free -C2 NH2 of sphingosine has a long-chain FA in amide linkage= ceramides -are FA derivatives of sphingosine -backbone of sphingomyelin and glycosphingolipids |
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Dihydrosphingosine synthesis
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Dihydrosphingosine: precoursor to ceramides (which is a precoursor to sphingomyelin)
-Made from Palmitoyl-CoA and Serine -uses enzyme pyrodoxal phosphate and NADPH oxidation to make Spinganine (dihydrospngosine) |
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Ceramide synthesis
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-Made from dihydrosphingosine and a long chain FA (mostly Behenyl CoA)
-reduces FAD to FADH2 to make a double bond b/t C4 and C5 -Behenyl unit added in amide bond to C2 to make ceramide |
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Sphingomyelin synthesis
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-uses ceramide and phosphatidylcholine
-products are sphingomyelin and DAG |
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Gluco and Galactocerebroside synthesis
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Glucocerebroside (glucosylceramide) made from ceramide + UDP-glucose
Galactocerebroside (Galactolipid) made from ceramide + UDP-galactose |
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sulphogalactocerbroside synthesis
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-made from galactocerebroside (ceramide + UDP-galactose) and PAPS (3' phosphoadenosine 5' phosphosulfate) by sulfotransferase
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Niemann Pick disease
-cause -type A and B characteristics |
-liver and spleen enlargement, mental retardation
-defeciency in sphingomyelinase which converts sphingomyelin to ceramide and phosphocholine leads to accumulation of sphingomyelin Type A: onset in 1st 6 months, CNS degeneration, spasticity, failure to thrive, massive hepatosplenomegaly Type B: later/variable onset, hepatoslenomegaly, cirrhosis, progressive pulmonary disease with reticular infiltratve pattern |
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Gaucher disease
-cause -symptoms -who does it affect -diagnosis -treatment |
*most common of lysosomal storage diseases
-defeciency in beta-glucocerebrosidase enzyme that converts Cer-Glu to ceramide + glucose. Accumulation of glucocerebroside (glucosylceramide) -Hepatosplenomegaly, erosion of long bones and pelvis, mental retardation in infantile form -accumulated enzyme in the marrow, spleen, liver, and liver macrophages -bone pain, bone disease in older patients, throbocytopenia, and anemia -1 of 12-15 Ashkenazi Jews are carriers Diagnosis: demonstrating decreased b-glucocerbrosidase activity in nucleated cells like leukocytes or fibloblasts -4 common mutations= 90% of cases Treatment: enzyme replacement therapy with B-glucosidase cerezyme |
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Krabbe disease
-deficiency -affects leading to disease -symptoms |
-Deficiency in beta-galactocerebrosidase which normally cleaves galactocerebroside into ceramide + galactose
-deficiency impairs growth/maintanence of myelin, which affects nerve cell signaling -multinucleated macrophages called globoid cells accumulate around blood vessels in brain -leads to Krabbe or globoid leukodystrophy -Symptoms: mental retardation, blind/deaf, absence of myelin |
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Metachromatic leucodistrophy
-deficiency -symptoms -diagnosis |
-deficiency in Arylsulfatase A
-leads to accumulation of cerebroside sulfate/sulfatide/sulphogalactocerebroside (ceramide+sulfogalactose) in brain due to lack of lysosomal sulfphatidase (Arylsulphatase A) -symptoms: mental retardation, and the nerve stains yellowish brown with cresyl violet die |
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Gangliosides
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-acid glycosphingolipids
-contain sialic acid (also called NANA) -concentrated in ganglion cells of CNS |
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Generalized Gangliosidosis
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-Deficiency in beta galactosidase which normally cleaves GM1 (removes one Gal); accumulation of GM1 ganglioside
-mental retardation, cherry red macula (part of retina), liver enlargment, skeletal deformities, death w/in a few years |
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Tay-Sachs Disease
Sandhoff Disease |
-deficiency in beta-hexosaminidase A that cleaves GM2 to GM3 (removes NAcGal); accumulation of GM2 ganglioside
-ganglion cells of cerebral cortex become swollen and lysosomes engorged with acidic lipid GM2 ganglioside -mental retardation, blindness, cherry red macula (part of retina) due to loss of ganglion cells, death b/t 2nd and 3rd year -1 out of 30 Ashkenazi Jews is a carrier Sandhoff Disease: same as Tay Sachs but more progressive -deficiency in Hexosaminidase A and B |
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Fabry Disease
-cause -symptoms -diagnosis -treatment |
-X-linked deficiency in alpha-galactosidase A that cleaves globoside ceramide trihexoside
-accumulation of ceramide trihexoside -symptoms: skin rash with angiokeratomas (dark red papulae), kidney failure, pain in lower extremities Diagnosis: look for low levels of deficient enzyme in peripheral leukocytes; DNA sequence analysis of the coding region and promoter of the alpha galactosidase gene Treatment: enzyme therapy |
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Sphingolipidoses Overview
-definition -what diseases does it include -how are they inherited? -which diseases have enzyme therapy as a treatment option? |
-activity of one enzyme in the sphingolipid catabolism pathway is reduced due to genetic error, then the substrate of that enzyme accumulates in the lysosomes of the tissue where the catabolism occurs
Includes: Niemann-Pick, Gaucher's, Krabbe disease, Metachromatic leukodystrophy, generalized gangliosidosis, Tay-Sachs, Sandhoff Disease, and Fabry Disease *All are Autosomal recessive except Fabry disease is X-linked *Enzyme therapy only available for Gaucher and Fabry disease |
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Catabolic sphingolipid pathway
-where do rxns occur? -what type of enzymes are they? what type of proteins are they made of? |
-all rxns happen in lysosomes
-all enzymes are hydrolases -acidic optima for enzymes -enzymes occur as isoenzymes -enzymes are membrane-bound glycoproteins -sequential stepwise removal of costituents -enzymes are specific for a type of linkage rather than a specific compound |
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Cholera toxin and gangliosides
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-toxin is a protein secreted by pathogen Vibrio Cholera
-stimulates Chloride secretion and water in the gut lumen with heavy diarrhea -has alpha and beta subunits -beta subunit binds to gangliosides and allows entry of alpha subunit into cell -alpha subunit acts as an ADP-ribosyltransferase= transfers ADP-ribose from NAD to a G protein -this activates Adenylate cyclase -this stimulates Cl- secretion |
