T18 - Sphingolipids Flashcards
Sphingolipids comprise what percentage of membrane lipids?
10% of membrane lipids
What are the two subclasses of sphingolipids?
sphingomyelins (no sugars)
glycosphingolipids (with sugars)
Differentiate between glycosphingolipids and sphingomyelins in terms of hydrophilicity.
glycosphingolipids are more hydrophilic than sphingomyelins
What is the core unit of all glycolipids?
ceramide
Describe the structure of ceramide.
long-chain fatty acid attahched in amide linkage to serine, which in turn is liked via C-C to sphingosine
What are the four primary functions of glycolipids?
myelination
lipid asymmetry in cell membranes/organelles
form lipid rafts
ABO blood groups
Describe the basis of Tay-Sachs disease.
GM2 gangliosides accumulate due to deficiency in hexoasaminidase A
What are the two primary effects of Tay-Sachs disease?
accumulation of GM2 gangliosides in nerve cells → mental retardation
accumulation of GM2 gangliosides in eye → “cherry red spot”
What are the treatment options for Tay-Sachs disease?
no treatment available
What is the basis of Gaucher’s diease?
mutation in lysosomal enzyme glucocerebrosidase that leads to buildup of glucocerebrosides
What are the treatment options for Gaucher’s disease? (2)
enzyme replacement (cerebrase, a recombinant glucosylceramidase 1)
substrate-reduction therapy (Zavesca, which inhibits glucosylceramide synthase)
What is the basis of Neimann-Pick disease, types A and B?
mutation of lysosomal enzyme sphingomyelinase that leads to buildup of sphingomyelin
Differentiate between Neimann-Pick types A and B in terms of their respective effects.
Type A: rapidly progressive, ataxia, hepatosplenomegaly, cherry red spot
Type B: more protracted course, hepatosplenomegaly, CNS rarely affected
Where in the cell are glycolipids usually found?
on outer leaflet of cell membranes
on inner leaflet of organelle membranes
Draw a diagram illustrating the three major components of glycolipids.
Draw out the structure of a general sphingolipid molecule.
Sphingolipids have a variable group attached to C1 via an ether linkage. What are the five most common variable groups?
ceramide (-H)
sphingomyelin (-phosphocholine)
glucosylcerebroside, a neutral glycolipid (-glucose)
lactosylceramide, a globoside (-di/tri/tetrasaccharide)
ganglioside GM2 (-complex oligosaccharide)
What are four subtypes of glycosphingolipids that have medical relevance?
galactocerebrosides (single sugar)
glucocerebrosides (single sugar)
globosides (2 or more sugars linked linearly)
gangliosides (branched sugars)
Where are galactocerebrosides found?
plasma membrane of neurons
Where are glucocerebrosides found?
plasma membrane of non-neuronal cells
What enzyme mediates the first step of sphingolipid synthesis?
serine palmitoyltransferase
Where in the cell does the first step of sphingolipid synthesis occur?
ER
What is the rate limiting step in sphingolipid synthesis?
the first reaction — palmitoyl-CoA + serine = 3-ketosphinganine, mediated by serine palmitoyltransferase
Write out the first reaction of sphingolipid synthesis.
palmotyl-CoA + serine → 3-ketosphinganine + CO2 + CoASH [mediated by serine palmitoyltransferase]
What is the structure of serine palmitoyltransferase?
heterotrimer
In the first step of sphingolipid synthesis, how does serine palmitoyltransferase accomplish decarboxylation?
uses pyridoxal 5’-phosphate as cofactor to assist with decarboxylation
Serine palmitoyltransferase is inhibited by
myriocin, isolated from fungi
Mutations in the gene that encodes for serine palmitoyltransferase can lead to
hereditary sensory neuropathy type I
What happens in the second step of sphingolipid synthesis? Write out the reaction.
3-ketosphinganine + NADPH → dihydrosphingosine (a.k.a. sphinganine) + NADP+ [mediated by 3-ketosphinganine reductase]
Where does the second step of sphingolipid synthesis take place?
ER
Write out the equation for the third reaction of sphingolipid synthesis.
dihydrosphingosine + RCSCoA → dihydroceramide + HSCoA
[mediated by ceramide synthase]
Where does the third reaction of sphingolipid synthesis occur?
ER
Ceramide synthase, the enzyme that catalyzes the third reaction of sphingolipid synthesis, is inhibited by
fumonisin B1, produced by fungi → linked to esophageal cancer
Write out the equation for the fourth step of sphingolipid synthesis.
dihydroceramide + FAD → ceramide + FADH2
[mediated by dihydroceramide desaturase]
Where does the fourth reaction of sphingolipid synthesis occur?
ER
Once ceramide forms, what are the two possible pathways it can take?
What is the target of the drug Zavesca?
glucosylceramide synthase — therefore, the drug prevents conversion of ceramide to glucosylceramide
What drug targets glucosylceramide synthase?
Zavesca
Zavesca is used in the treatment of what disease?
Gaucher’s disease
Where is the sphingomyelin synthase enzyme located?
Golgi — therefore, ceramide must be transported from ER to Golgi first
Where is the glucosyl/galactosylceramide synthase enzyme located?
Golgi — therefore, ceramide must be transported from ER to Golgi first
What protein mediates movement of ceramide from the ER to the Golgi to produce sphingomyelin and cerebrosides?
ceramide transport protein (CERT)
In the context of the sphingolipid synthesis pathway, how are globosides and gangliosides produced?
glucocerebrosides are reacted with activated sugars to produce globosides and gangliosides
Why is it important that negatively charged sphingolipids make up myelin sheaths?
negatively charged sphingolipids mean they repel negative ions and attract positive ions such as Na+ which are needed to conduct the axon potential
What are the most abundant sphingolipids in myelin?
the cerebrosides:
glucosylceramide
galactosylceramide
Describe the composition of plasma membranes in the context of lipid asymmetry. (3)
outer leaflet: PC + sphingomyelin
inner leaflet: PI, PE, PS
equal cholesterol
Describe the physical characteristics of lipid rafts. (2)
lower phase transition temperature
stiffer
What is the primary composition of lipid rafts?
sphingolipids
cholesterol
What is the function of lipid rafts?
serve as organization centers for membrane proteins that exist both on cell surface and inner leaflet
Describe the role of glycosphingolipids in blood groups.
glycosphingolipids on surface of RBCs form ABO blood group antigen series
Describe how blood type A arises.
type A patients express enzyme that transfers N-acetylgalactosamine residue to form ganglioside
Describe how blood type B arises.
type B patients express enzyme similar to that of type A that transfers galactose residue to form ganglioside
Describe how blood type O arises.
type O patients have mutation that inactivates transferase enzyme, meaning they lack the terminal sugar found in type A or B
What sphingolipid derivative plays a major role in signaling?
sphingosine-1-phosphate
How is sphingosine-1-phosphate made?
derived from glycosphingolipids and sphingolipids on the surfaces of plasma cells
Sphingosine-1-phosphate acts as a ligand for
five different GPCRs: S1P1, S1P2, S1P3, S1P4, S1P5
Describe the significance of the drug fingolimond/Gilenya.
sphingosine-1-phosphate derivative used to treat MS that activates S1P receptors on lymphocytes to kill them and reduce symptoms of autoimmune disease
What are two enzymes that are primarily found on lipid rafts?
lipoprotein lipase
acetylcholine esterase (attenuates action of ACh at neuromuscular junctions)
What is the deficiency in Tay-Sachs disease?
hexosaminidase A
What accumulates in Tay-Sachs disease?
GM2 ganglioside
What is the inheritance pattern of Tay Sachs disease?
autosomal recessive
[especially prevalent in Ashkenazi Jewish population]
Describe the effects of Tay Sachs disease (in both infantile and adult onset).
infantile onset = rapid and lethal neurodegeneration
adult onset = slowly progressive neuropathy with no effect on intellect + cherry red spot on macula (blindness)
What is the deficiency in Gaucher’s Disease?
GBA1 (beta glucosidase)
What accumulates in Gaucher’s disease?
glucosylceramide (a cerebroside)
What is the inheritance pattern of Gaucher’s disease?
autosomal recessive
What is the most common lipid storage disease?
Gaucher’s disease
Describe the effects of Gaucher’s disease (in both infantile and adult onset).
infantile onset = rapid and lethal neurodegeneration
adult onset = slowly progressive neuropathy, hepatosplenomegaly, bone disease
What is the basis of hepatosplenomegaly in adult Gaucher’s disease patients?
build up of Kupfer cells of liver + build up of migratory macrophages in spleen
What is the normal function of the hexosaminidase enzyme?
catalyzes removal of GalNac from GM2 ganglioside during breakdown of glycosphingolipids
Describe the structure/composition of the hexosaminidase enzyme.
heterodimer (alpha + beta subunit) that requires a third protein named GM2 activator for full activity
Is there a treatment for Niemann-Pick disease?
no treatment for Type A, but enzyme replacement therapy is a possibility for Type B
What is the deficiency and accumulation in Fabry’s disease?
deficiency = alpha-galactosidase
accumulation = globotriaosylceramide
What is the deficiency and accumulation in metachromatic leukodystrophy?
deficiency = arylsulfatase A
accumulation = 3-sulfogalactosylceramide
What is the deficiency and accumulation in Krabbe’s disease?
deficiency = beta-galactosidase
accumulation = galactosylceramide
What is the deficiency and accumulation in Farber’s disease?
deficiency = ceramidase
accumulation = ceramide
