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Tissues > T18 - Sphingolipids > Flashcards

T18 - Sphingolipids Flashcards

1
Q

Sphingolipids comprise what percentage of membrane lipids?

A

10% of membrane lipids

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2
Q

What are the two subclasses of sphingolipids?

A

sphingomyelins (no sugars)

glycosphingolipids (with sugars)

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3
Q

Differentiate between glycosphingolipids and sphingomyelins in terms of hydrophilicity.

A

glycosphingolipids are more hydrophilic than sphingomyelins

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4
Q

What is the core unit of all glycolipids?

A

ceramide

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5
Q

Describe the structure of ceramide.

A

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

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6
Q

What are the four primary functions of glycolipids?

A

myelination

lipid asymmetry in cell membranes/organelles

form lipid rafts

ABO blood groups

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7
Q

Describe the basis of Tay-Sachs disease.

A

GM2 gangliosides accumulate due to deficiency in hexoasaminidase A

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8
Q

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

A

accumulation of GM2 gangliosides in nerve cells → mental retardation

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

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9
Q

What are the treatment options for Tay-Sachs disease?

A

no treatment available

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10
Q

What is the basis of Gaucher’s diease?

A

mutation in lysosomal enzyme glucocerebrosidase that leads to buildup of glucocerebrosides

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11
Q

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

A

enzyme replacement (cerebrase, a recombinant glucosylceramidase 1)

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

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12
Q

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

A

mutation of lysosomal enzyme sphingomyelinase that leads to buildup of sphingomyelin

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13
Q

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

A

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

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

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14
Q

Where in the cell are glycolipids usually found?

A

on outer leaflet of cell membranes

on inner leaflet of organelle membranes

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15
Q

Draw a diagram illustrating the three major components of glycolipids.

A
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16
Q

Draw out the structure of a general sphingolipid molecule.

A
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17
Q

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

A

ceramide (-H)

sphingomyelin (-phosphocholine)

glucosylcerebroside, a neutral glycolipid (-glucose)

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

ganglioside GM2 (-complex oligosaccharide)

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18
Q

What are four subtypes of glycosphingolipids that have medical relevance?

A

galactocerebrosides (single sugar)

glucocerebrosides (single sugar)

globosides (2 or more sugars linked linearly)

gangliosides (branched sugars)

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19
Q

Where are galactocerebrosides found?

A

plasma membrane of neurons

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20
Q

Where are glucocerebrosides found?

A

plasma membrane of non-neuronal cells

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21
Q

What enzyme mediates the first step of sphingolipid synthesis?

A

serine palmitoyltransferase

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22
Q

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

A

ER

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23
Q

What is the rate limiting step in sphingolipid synthesis?

A

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

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24
Q

Write out the first reaction of sphingolipid synthesis.

A

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

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25
Q

What is the structure of serine palmitoyltransferase?

A

heterotrimer

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26
Q

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

A

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

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27
Q

Serine palmitoyltransferase is inhibited by

A

myriocin, isolated from fungi

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28
Q

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

A

hereditary sensory neuropathy type I

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29
Q

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

A

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

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30
Q

Where does the second step of sphingolipid synthesis take place?

A

ER

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31
Q

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

A

dihydrosphingosine + RCSCoA → dihydroceramide + HSCoA

[mediated by ceramide synthase]

32
Q

Where does the third reaction of sphingolipid synthesis occur?

A

ER

33
Q

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

A

fumonisin B1, produced by fungi → linked to esophageal cancer

34
Q

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

A

dihydroceramide + FAD → ceramide + FADH2

[mediated by dihydroceramide desaturase]

35
Q

Where does the fourth reaction of sphingolipid synthesis occur?

A

ER

36
Q

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

A
37
Q

What is the target of the drug Zavesca?

A

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

38
Q

What drug targets glucosylceramide synthase?

A

Zavesca

39
Q

Zavesca is used in the treatment of what disease?

A

Gaucher’s disease

40
Q

Where is the sphingomyelin synthase enzyme located?

A

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

41
Q

Where is the glucosyl/galactosylceramide synthase enzyme located?

A

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

42
Q

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

A

ceramide transport protein (CERT)

43
Q

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

A

glucocerebrosides are reacted with activated sugars to produce globosides and gangliosides

44
Q

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

A

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

45
Q

What are the most abundant sphingolipids in myelin?

A

the cerebrosides:

glucosylceramide

galactosylceramide

46
Q

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

A

outer leaflet: PC + sphingomyelin

inner leaflet: PI, PE, PS

equal cholesterol

47
Q

Describe the physical characteristics of lipid rafts. (2)

A

lower phase transition temperature

stiffer

48
Q

What is the primary composition of lipid rafts?

A

sphingolipids

cholesterol

49
Q

What is the function of lipid rafts?

A

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

50
Q

Describe the role of glycosphingolipids in blood groups.

A

glycosphingolipids on surface of RBCs form ABO blood group antigen series

51
Q

Describe how blood type A arises.

A

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

52
Q

Describe how blood type B arises.

A

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

53
Q

Describe how blood type O arises.

A

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

54
Q

What sphingolipid derivative plays a major role in signaling?

A

sphingosine-1-phosphate

55
Q

How is sphingosine-1-phosphate made?

A

derived from glycosphingolipids and sphingolipids on the surfaces of plasma cells

56
Q

Sphingosine-1-phosphate acts as a ligand for

A

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

57
Q

Describe the significance of the drug fingolimond/Gilenya.

A

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

58
Q

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

A

lipoprotein lipase

acetylcholine esterase (attenuates action of ACh at neuromuscular junctions)

59
Q

What is the deficiency in Tay-Sachs disease?

A

hexosaminidase A

60
Q

What accumulates in Tay-Sachs disease?

A

GM2 ganglioside

61
Q

What is the inheritance pattern of Tay Sachs disease?

A

autosomal recessive

[especially prevalent in Ashkenazi Jewish population]

62
Q

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

A

infantile onset = rapid and lethal neurodegeneration

adult onset = slowly progressive neuropathy with no effect on intellect + cherry red spot on macula (blindness)

63
Q

What is the deficiency in Gaucher’s Disease?

A

GBA1 (beta glucosidase)

64
Q

What accumulates in Gaucher’s disease?

A

glucosylceramide (a cerebroside)

65
Q

What is the inheritance pattern of Gaucher’s disease?

A

autosomal recessive

66
Q

What is the most common lipid storage disease?

A

Gaucher’s disease

67
Q

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

A

infantile onset = rapid and lethal neurodegeneration

adult onset = slowly progressive neuropathy, hepatosplenomegaly, bone disease

68
Q

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

A

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

69
Q

What is the normal function of the hexosaminidase enzyme?

A

catalyzes removal of GalNac from GM2 ganglioside during breakdown of glycosphingolipids

70
Q

Describe the structure/composition of the hexosaminidase enzyme.

A

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

71
Q

Is there a treatment for Niemann-Pick disease?

A

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

72
Q

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

A

deficiency = alpha-galactosidase

accumulation = globotriaosylceramide

73
Q

What is the deficiency and accumulation in metachromatic leukodystrophy?

A

deficiency = arylsulfatase A

accumulation = 3-sulfogalactosylceramide

74
Q

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

A

deficiency = beta-galactosidase

accumulation = galactosylceramide

75
Q

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

A

deficiency = ceramidase

accumulation = ceramide

Tissues (23 decks)

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