T18 - Sphingolipids

Question 1

Sphingolipids comprise what percentage of membrane lipids?

Answer 1

10% of membrane lipids

Question 2

What are the two subclasses of sphingolipids?

Answer 2

sphingomyelins (no sugars)

glycosphingolipids (with sugars)

Question 3

Differentiate between glycosphingolipids and sphingomyelins in terms of hydrophilicity.

Answer 3

glycosphingolipids are more hydrophilic than sphingomyelins

Question 4

What is the core unit of all glycolipids?

Answer 4

ceramide

Question 5

Describe the structure of ceramide.

Answer 5

long-chain fatty acid attahched in amide linkage to serine, which in turn is liked via C-C to sphingosine

Question 6

What are the four primary functions of glycolipids?

Answer 6

myelination

lipid asymmetry in cell membranes/organelles

form lipid rafts

ABO blood groups

Question 7

Describe the basis of Tay-Sachs disease.

Answer 7

GM2 gangliosides accumulate due to deficiency in hexoasaminidase A

Question 8

What are the two primary effects of Tay-Sachs disease?

Answer 8

accumulation of GM2 gangliosides in nerve cells → mental retardation

accumulation of GM2 gangliosides in eye → “cherry red spot”

Question 9

What are the treatment options for Tay-Sachs disease?

Answer 9

no treatment available

Question 10

What is the basis of Gaucher’s diease?

Answer 10

mutation in lysosomal enzyme glucocerebrosidase that leads to buildup of glucocerebrosides

Question 11

What are the treatment options for Gaucher’s disease? (2)

Answer 11

enzyme replacement (cerebrase, a recombinant glucosylceramidase 1)

substrate-reduction therapy (Zavesca, which inhibits glucosylceramide synthase)

Question 12

What is the basis of Neimann-Pick disease, types A and B?

Answer 12

mutation of lysosomal enzyme sphingomyelinase that leads to buildup of sphingomyelin

Question 13

Differentiate between Neimann-Pick types A and B in terms of their respective effects.

Answer 13

Type A: rapidly progressive, ataxia, hepatosplenomegaly, cherry red spot

Type B: more protracted course, hepatosplenomegaly, CNS rarely affected

Question 14

Where in the cell are glycolipids usually found?

Answer 14

on outer leaflet of cell membranes

on inner leaflet of organelle membranes

Question 15

Draw a diagram illustrating the three major components of glycolipids.

Answer 15

Question 16

Draw out the structure of a general sphingolipid molecule.

Answer 16

Question 17

Sphingolipids have a variable group attached to C1 via an ether linkage. What are the five most common variable groups?

Answer 17

ceramide (-H)

sphingomyelin (-phosphocholine)

glucosylcerebroside, a neutral glycolipid (-glucose)

lactosylceramide, a globoside (-di/tri/tetrasaccharide)

ganglioside GM2 (-complex oligosaccharide)

Question 18

What are four subtypes of glycosphingolipids that have medical relevance?

Answer 18

galactocerebrosides (single sugar)

glucocerebrosides (single sugar)

globosides (2 or more sugars linked linearly)

gangliosides (branched sugars)

Question 19

Where are galactocerebrosides found?

Answer 19

plasma membrane of neurons

Question 20

Where are glucocerebrosides found?

Answer 20

plasma membrane of non-neuronal cells

Question 21

What enzyme mediates the first step of sphingolipid synthesis?

Answer 21

serine palmitoyltransferase

Question 22

Where in the cell does the first step of sphingolipid synthesis occur?

Answer 22

ER

Question 23

What is the rate limiting step in sphingolipid synthesis?

Answer 23

the first reaction — palmitoyl-CoA + serine = 3-ketosphinganine, mediated by serine palmitoyltransferase

Question 24

Write out the first reaction of sphingolipid synthesis.

Answer 24

palmotyl-CoA + serine → 3-ketosphinganine + CO₂ + CoASH [mediated by serine palmitoyltransferase]

Question 25

What is the structure of serine palmitoyltransferase?

Answer 25

heterotrimer

Question 26

In the first step of sphingolipid synthesis, how does serine palmitoyltransferase accomplish decarboxylation?

Answer 26

uses pyridoxal 5'-phosphate as cofactor to assist with decarboxylation

Question 27

Serine palmitoyltransferase is inhibited by

Answer 27

myriocin, isolated from fungi

Question 28

Mutations in the gene that encodes for serine palmitoyltransferase can lead to

Answer 28

hereditary sensory neuropathy type I

Question 29

What happens in the second step of sphingolipid synthesis? Write out the reaction.

Answer 29

3-ketosphinganine + NADPH → dihydrosphingosine (a.k.a. sphinganine) + NADP⁺ [mediated by 3-ketosphinganine reductase]

Question 30

Where does the second step of sphingolipid synthesis take place?

Answer 30

ER

Question 31

Write out the equation for the third reaction of sphingolipid synthesis.

Answer 31

dihydrosphingosine + RCSCoA → dihydroceramide + HSCoA [mediated by ceramide synthase]

Question 32

Where does the third reaction of sphingolipid synthesis occur?

Answer 32

ER

Question 33

Ceramide synthase, the enzyme that catalyzes the third reaction of sphingolipid synthesis, is inhibited by

Answer 33

fumonisin B₁, produced by fungi → linked to esophageal cancer

Question 34

Write out the equation for the fourth step of sphingolipid synthesis.

Answer 34

dihydroceramide + FAD → ceramide + FADH₂ [mediated by dihydroceramide desaturase]

Question 35

Where does the fourth reaction of sphingolipid synthesis occur?

Answer 35

ER

Question 36

Once ceramide forms, what are the two possible pathways it can take?

Answer 36

Question 37

What is the target of the drug Zavesca?

Answer 37

glucosylceramide synthase — therefore, the drug prevents conversion of ceramide to glucosylceramide

Question 38

What drug targets glucosylceramide synthase?

Answer 38

Zavesca

Question 39

Zavesca is used in the treatment of what disease?

Answer 39

Gaucher's disease

Question 40

Where is the sphingomyelin synthase enzyme located?

Answer 40

Golgi — therefore, ceramide must be transported from ER to Golgi first

Question 41

Where is the glucosyl/galactosylceramide synthase enzyme located?

Answer 41

Golgi — therefore, ceramide must be transported from ER to Golgi first

Question 42

What protein mediates movement of ceramide from the ER to the Golgi to produce sphingomyelin and cerebrosides?

Answer 42

ceramide transport protein (CERT)

Question 43

In the context of the sphingolipid synthesis pathway, how are globosides and gangliosides produced?

Answer 43

glucocerebrosides are reacted with activated sugars to produce globosides and gangliosides

Question 44

Why is it important that negatively charged sphingolipids make up myelin sheaths?

Answer 44

negatively charged sphingolipids mean they repel negative ions and _attract positive ions such as Na⁺_ which are needed to conduct the axon potential

Question 45

What are the most abundant sphingolipids in myelin?

Answer 45

_the cerebrosides:_ glucosylceramide galactosylceramide

Question 46

Describe the composition of plasma membranes in the context of lipid asymmetry. (3)

Answer 46

outer leaflet: PC + sphingomyelin inner leaflet: PI, PE, PS equal cholesterol

Question 47

Describe the physical characteristics of lipid rafts. (2)

Answer 47

lower phase transition temperature stiffer

Question 48

What is the primary composition of lipid rafts?

Answer 48

sphingolipids cholesterol

Question 49

What is the function of lipid rafts?

Answer 49

serve as organization centers for membrane proteins that exist both on cell surface and inner leaflet

Question 50

Describe the role of glycosphingolipids in blood groups.

Answer 50

glycosphingolipids on surface of RBCs form ABO blood group antigen series

Question 51

Describe how blood type A arises.

Answer 51

type A patients express enzyme that transfers N-acetylgalactosamine residue to form ganglioside

Question 52

Describe how blood type B arises.

Answer 52

type B patients express enzyme similar to that of type A that transfers galactose residue to form ganglioside

Question 53

Describe how blood type O arises.

Answer 53

type O patients have mutation that inactivates transferase enzyme, meaning they lack the terminal sugar found in type A or B

Question 54

What sphingolipid derivative plays a major role in signaling?

Answer 54

sphingosine-1-phosphate

Question 55

How is sphingosine-1-phosphate made?

Answer 55

derived from glycosphingolipids and sphingolipids on the surfaces of plasma cells

Question 56

Sphingosine-1-phosphate acts as a ligand for

Answer 56

five different GPCRs: S1P1, S1P2, S1P3, S1P4, S1P5

Question 57

Describe the significance of the drug fingolimond/Gilenya.

Answer 57

sphingosine-1-phosphate derivative used to treat MS that activates S1P receptors on lymphocytes to kill them and reduce symptoms of autoimmune disease

Question 58

What are two enzymes that are primarily found on lipid rafts?

Answer 58

lipoprotein lipase acetylcholine esterase (attenuates action of ACh at neuromuscular junctions)

Question 59

What is the deficiency in Tay-Sachs disease?

Answer 59

hexosaminidase A

Question 60

What accumulates in Tay-Sachs disease?

Answer 60

GM2 ganglioside

Question 61

What is the inheritance pattern of Tay Sachs disease?

Answer 61

autosomal recessive [especially prevalent in Ashkenazi Jewish population]

Question 62

Describe the effects of Tay Sachs disease (in both infantile and adult onset).

Answer 62

infantile onset = rapid and lethal neurodegeneration adult onset = slowly progressive neuropathy with no effect on intellect + cherry red spot on macula (blindness)

Question 63

What is the deficiency in Gaucher's Disease?

Answer 63

GBA1 (beta glucosidase)

Question 64

What accumulates in Gaucher's disease?

Answer 64

glucosylceramide (a cerebroside)

Question 65

What is the inheritance pattern of Gaucher's disease?

Answer 65

autosomal recessive

Question 66

What is the most common lipid storage disease?

Answer 66

Gaucher's disease

Question 67

Describe the effects of Gaucher's disease (in both infantile and adult onset).

Answer 67

infantile onset = rapid and lethal neurodegeneration adult onset = slowly progressive neuropathy, hepatosplenomegaly, bone disease

Question 68

What is the basis of hepatosplenomegaly in adult Gaucher's disease patients?

Answer 68

build up of Kupfer cells of liver + build up of migratory macrophages in spleen

Question 69

What is the normal function of the hexosaminidase enzyme?

Answer 69

catalyzes removal of GalNac from GM2 ganglioside during breakdown of glycosphingolipids

Question 70

Describe the structure/composition of the hexosaminidase enzyme.

Answer 70

heterodimer (alpha + beta subunit) that requires a third protein named GM2 activator for full activity

Question 71

Is there a treatment for Niemann-Pick disease?

Answer 71

no treatment for Type A, but enzyme replacement therapy is a possibility for Type B

Question 72

What is the deficiency and accumulation in Fabry's disease?

Answer 72

deficiency = alpha-galactosidase accumulation = globotriaosylceramide

Question 73

What is the deficiency and accumulation in metachromatic leukodystrophy?

Answer 73

deficiency = arylsulfatase A accumulation = 3-sulfogalactosylceramide

Question 74

What is the deficiency and accumulation in Krabbe's disease?

Answer 74

deficiency = beta-galactosidase accumulation = galactosylceramide

Question 75

What is the deficiency and accumulation in Farber's disease?

Answer 75

deficiency = ceramidase accumulation = ceramide