Sphingolipids Biochemistry

Question 1

What is the difference between phospholipids, glycolipids and TAGs form a structural basis

Answer 1

TAGs
- glycerol backbone with 3 different R groups attached to it

Phospholipids

• glycerol backbone with 2 different R groups attached to it.
• 1 polar R group is attached

Glycolipids

• glycerol backbone with 2 different R groups attached to it
• 1 sugar compound is attached

Question 2

Physical properties of a sphingolipid

Answer 2

Possess a sphingosine back bone (amino alcohol groups attached to a large carbon chain)

Then attached to an FA and either

• a choline molecule (sphingomyelin)
• a carbohydrate (glycosphingolipid)

Question 3

What is the composition different types of neuronal tissues with respect to protein and lipids

Answer 3

Myelin sheaths

• 70% lipids
• 30% proteins

White matter

• 55% lipids
• 39% proteins
• 6 % cells

Gray matter

• 33% lipids
• 55% proteins
• 12% cells
• more phospholipids are found in gray matter > white matter > myelin*

Question 4

What are the different subtypes of glycosphingolipds based on?

Answer 4

What carbohydrate is attached to the sphingolipid

Question 5

What is the functions of all sphingolipid combined?

Answer 5

Structural components of cellular membranes and lipoproteins

Second messengers or precursors of bioactive messengers

Question 6

What functions are specific to glycosphingolipids

Answer 6

Regulation of cellular interactions

Growth and development

Tumorigenic properties
- target for tumor growth

Antigenic properties
- targets for cholera/toxin/viruses and microbes

Question 7

How are sphingolipid produced

Answer 7

Starts in the smooth endoplasmic reticulum
- 1) enzyme SPT catalyses (L-serine + palmitoyl-CoA -> ceramide) reactions

Ceramide then moves to the Golgi apparatus
- 2) ceramide then is transformed into sphingomyelin via the enzyme SMS1

Sphingomyelin is then transfers to cellular plasma membrane to work

Question 8

What co-enzyme is required to help SPT do its function?

Answer 8

PLP, which is synthesized from vitamin B6

- hence why vitamin B6 deficiencies affects myelinating functions and conduction pathways in the nervous system.

Question 9

What are the two ways that ceramide is transferred from smooth ER -> golgi?

Answer 9

Vesicle transport

Attachment to ceramide specific proteins

Question 10

What is the pathway of degradation of sphingolipids

Answer 10

Lysosomes take up sphingolipid from cell membrane

• 1) use ASMase to transform sphingomyelin -> ceramide
• 2) use CDase to transform ceramide -> sphingosine

Then, the sphingosine is either transferred back to Golgi apparatus or degraded even further.

• 3) sphingosine is phosphorylated into S1P via SK 1/2 enzymes
• 4) polar molecule S1P is then degraded via hydrolysis

Question 11

What’s are the bioactive properties and functions of each intermediates for sphingolipids?

Answer 11

Ceramide
- known to be second messenger for signaling apoptosis/senescence/Autophagy and differentiation

Sphingosine
- known for being a second messenger for signaling apoptosis

S1P
- known for being a second messenger for signaling cell survival/proliferation/growth/angiogenesis and inflammation.

Question 12

What’s is the role of sphingolipids in cancers?

Answer 12

Inducing intracellular increases of ceramide is used to initiate cell deaths

Also inhibiting S1P production/ signaling cascade can both decrease cancer growth and induce apoptosis secondarily

Question 13

Fingolimod (FTY720)

Answer 13

Trade name = gilenya

Is a drug that works as an antagonist of S1P
- binds to S1PR1 and internalizes the receptor as well as sequestering lymphocytes in lymph nodes

This helps prevent autoimmune reactions and is FDA-approved for relapsing MS treatment

Question 14

Sphingolipid storage diseases

Answer 14

these disorders are progressive and affect nervous tissue

Most are autosomal recessive
- except for fabry disease (X-linked)

Some are not comparable with life

All work in some fashion to prevent completel metabolization of SL’s leading to an over abundance of non metabolized products

• this leads to defective fusion of autophagosome with lysosome
• ultimately leads to accumulation of toxic proteins, generation fo free radicals and nervous cell death

Question 15

Gaucher disease

Answer 15

Deficiency in B-glucosidase which leads to over abundance of glucosylceramide

Has 3 types

1) non-neuropathic form
- 99% of all cases and leads to shortened life span
- still possess enzyme activity, just low amounts

2) acute neuronopathic form
- 0.5% of cases and leads to incapatabilty of life
- no enzyme activity detected

3) somewhere between 1 and 2
- intermediate type that is highly variable