phospholipids -Brar

Question 1

What is the structure of a phospholipid?

Answer 1

2 classes:

1. glycerophospholipids: glycerol backbone with FA chains on C1 and C2 and a phosphate group on C3
   - -> when nothing is attached to the phosphate=”phosphatidic acid”=precursor for others
   - other phospholipids can be formed from phosphatidic acid and an alcohol –> serene, etanolamine, choline, inositol
2. sphingosine backbone–> “spingolipids”

Question 2

What is the structure of cardiolipin and what is its role in the cell?

Answer 2

2 molecules of phosphatidic acid esterfies through their phosphate group to an additional glycerol
–> it is antigenic

found in the inner mitochondrial membrane–> crucial in mitochondrial activity

abnormal cardiolipins associated with alzheimers and parkinsons
also barth syndrome–> infantile cardiomyopathy linked to an X chromosome defect in cardiolipin processing gene

Question 3

What is the structure and function of platelet activating factor?

Answer 3

ether glycerophospholipid with a saturated alkyl group with a link to carbon 1 (usually 16-18 carbons long)
Carbon 2 has an acetyl group instead of a fatty acid group
PAF is produced by many different type of cells by the action of phospholipase A2 on phosphatidylcholine
Some functions include
Activating inflammatory cells
Mediates hypersensitivity, acute inflammatory and anaphylactic reactions
Also causes platelets to aggregate and degranulate
Promotes the generation of superoxide radicals from neutrophils and alveolar macrophages
PAF is considered to be one of the most potent bioactive compounds
Can elicit a biological response at concentrations as low as 10-12 mol/l

Question 4

Describe the process of phospholipid synthesis

Answer 4

synthesized in the smooth ER and transported to the Golgi and then to membranes of organelles or to the plasma membrane

requires either:

1. donation of phosphatidic acid from CDP-diacylglycerol or (CTP + phosphatidic acid–> CDP-diacylglycerol)
2. donation of phosphomonoester of the alcohol from CDP-alcohol to 1,2, diacylglycerol

phosphatidic acid=precursor for other phospholipids –> precursor for TAGs
-made in all cells except mature RBCs

Question 4

Describe the process of phospholipid synthesis

Answer 4

synthesized in the smooth ER and transported to the Golgi and then to membranes of organelles or to the plasma membrane

requires either:

1. donation of phosphatidic acid from CDP-diacylglycerol or (CTP + phosphatidic acid–> CDP-diacylglycerol)
2. donation of phosphomonoester of the alcohol from CDP-alcohol to 1,2, diacylglycerol

phosphatidic acid=precursor for other phospholipids –> precursor for TAGs
-made in all cells except mature RBCs

Question 5

What is the major component of lung surfactant?

Answer 5

DPPC ==> dipalmitoylphosphatidylcholine

palmitate at C1 andC2 of glycerol backbone

Question 5

What is the major component of lung surfactant?

Answer 5

DPPC ==> dipalmitoylphosphatidylcholine

palmitate at C1 andC2 of glycerol backbone

Question 6

What is the structure and function of phosphatidylinositol (PI)?

Answer 6

stearic acid at C1 and arachidonic acid at C2
–> reservoir of arachidonic acid –> used for prostaglandin synthesis
* important in signal transduciton
hormone binds to Gq –> GTP binds to alpha subunit and activates it–> PLC activated —> cleaves PIP2 into IP3 and diacylglycerol –> IP3 travels to the ER and binds to a receptor opening a Ca2+ channel–> Ca2+ and diacylglycerol activate PKC to phosphorylate proteins

Question 6

What is the structure and function of phosphatidylinositol (PI)?

Answer 6

stearic acid at C1 and arachidonic acid at C2
–> reservoir of arachidonic acid –> used for prostaglandin synthesis
* important in signal transduciton
hormone binds to Gq –> GTP binds to alpha subunit and activates it–> PLC activated —> cleaves PIP2 into IP3 and diacylglycerol –> IP3 travels to the ER and binds to a receptor opening a Ca2+ channel–> Ca2+ and diacylglycerol activate PKC to phosphorylate proteins

Question 7

Phospholipase activity and their site of action

Answer 7

phospholipases are found in all tissues==> hydrolyze the phosphodiester bonds of phosphoglycerides sat specific sites.
–> can degrade and remodel phospholipids

Phospholipase A1: cleaves the ester bond of C1 of a phospholipid. present in many tissues

A2: cleave the ester bond of C2–> in many tissues and in pancreatic juice
acts on phosphatidylinositol releasing arachidonic acid
-trypsin activates the pancreatic release of A2 and glucocorticoids inhibit its release

C: cleave just before the P on the C3. found in liver and lysosomes and in the alpha-toxin of clostridia

D: cleaved just beyond the P of C3 group (before the O-R===> found mostly in plants

Question 8

What is the structure of a sphingolipid ?

Answer 8

a sphingosine backbone formed from a serine and a fatty acid

don’t have a phosphate group but have an amino group

Question 9

Ceramide

Answer 9

a sphingosine with a single acyl group attached via an amide linkage is a ceramide

can be further altered by the addition of groups to the terminal OH

ex: sphingomyelin=important in neurons

Question 10

cerebrosides:

Answer 10

have a glucose or galactose connected to the terminal OH group by a glycosidic bond

important in cerebral/nervous tissue

Question 11

What are eicosanoids?

Answer 11

prostaglandins, thromboxanes and leukotrienes
originate from 20 C long PUFAs
Potent compounds
Produced in very small amounts in almost all tissues (rather than specialized glands)
Act locally (instead of being transported by blood to distant sites)
Are not stored
Extremely short half life (rapidly metabolized to inactive products)
Plasma and nuclear membranes mediate the action of eicosanoids

Question 12

Which FA is the precursor for PGs?

Answer 12

linoleic acid

it is elongated and desaturated to arachidonic acid

• occurs in the ER
• requires 2 NADH and 2 O2

Question 13

What are eicosanoids?

Answer 13

prostaglandins, thromboxanes and leukotrienes
originate from 20 C long PUFAs
Potent compounds
Produced in very small amounts in almost all tissues (rather than specialized glands)
Act locally (instead of being transported by blood to distant sites)
Are not stored
Extremely short half life (rapidly metabolized to inactive products)
Plasma and nuclear membranes mediate the action of eicosanoids

Question 14

Which FA is the precursor for PGs?

Answer 14

linoleic acid

it is elongated and desaturated to arachidonic acid

• occurs in the ER
• requires 2 NADH and 2 O2

Question 15

What are the 2 isozymes of PG endoperoxide synthase and their differences?

Answer 15

PG endoperoxide synthase is the enzyme responsible for the conversion of free arachidonic acid to form PGH2
it has 2 catalytic activities: COX (requires 2O2) and peroxidase (dependent on reduced glutathione

COX-1
Is made constitutively in most tissues
Is required for normal gastric tissue, platelet aggregation and renal homeostasis
COX-2
Is inducible in response to products of immune and inflammatory cells
PG’s produced mediate the pain, heat, redness, and swelling of inflammation and fever of infection
COX 2 levels may be increases in inflammatory diseases (ex. arthritis) or in some cancer cells.
over expression of COX2 leads to the increased expression of VEGF (vascular endothelial growth factor)

Question 16

What can lead to inhibition of PG synthesis?

Answer 16

Cortisol–> through inhibiting phospholipase A2==> makes less arachidonic acid available==> less PG produced.
-inhibits COX2 (NOT COX 1)

ASA inhibit COX 1 and COX 2 –> inhibiting the synthesis of PGH2
*inhibiting COX 1 can also lead to damage of stomach cells and renal cells –> ASA toxicity

Question 17

What is celecoxib/rofecoxib? and what are their risks?

Answer 17

COX 2 inhibitors (celecoxib) are designed to maintain the function of COX 1 while reducing inflammation

A tendency to develop blood clots when taking some of these drugs has been attributed to:
decreased production of an anti-thrombotic (clot blocking) prostaglandin (PGI2) by endothelial cells lining small blood vessels
lack of inhibition of COX-1-mediated formation of pro-thrombotic thromboxanes in platelets

Question 18

how are leukotrienes produced? and what is their function?

Answer 18

Produced from arachidonic acid by the action of several lipoxygenases
Lipoxygenases are not affected by NSAID’s
LT’s are involved in allergic responses and inflammation
Used in treating asthma in the form of 5-lipoxygenase inhibitors and leukotriene receptor antagonists

Question 19

How does low dose ASA lower the risk for MIs and strokes?

Answer 19

Inhibits TXA2 synthesis in platelets by irreversible acetylation (of a serine residue) and inhibition of COX-1 by preventing binding of arachidonic acid
This irreversible inhibition can only be overcome by producing new enzyme
TXA2 is produced by activated platelets and promotes formation of blood clots by
Promoting adherence and aggregation of circulating platelets
Promoting vascular smooth muscle contraction

Platelets are anucleate so cannot produce new enzyme
Endothelial cells have a nucleus and so can produce more COX-1
This is essentially the basis for low dose ASA therapy used to lower the risk for MI and strokes

Question 23

What is sphingolipidosis?

Answer 23

caused by deficiency in lysosomal exoglycosidases which degrade sphingolipids in lysosomes (lysosomal storage diseases)

Sphingolipids are degraded in lysosomes
Requires lysosomal exoglycosidases to remove sugars from end of oligosaccharide chain
Deficiency of these enzymes leads to accumulation of certain sphingolipids in the lysosome
Enzyme deficiency is expressed in all tissues
Complete deficiency leads to severe disease
Nervous tissue most affected because of its high sphingolipid content and turnover
Diagnosis requires measuring enzyme activity in cultured leukocytes, skin fibroblasts or amniotic cells (for prenatal diagnosis)
Inheritance is autosomal recessive except for Fabry disease (which is X linked recessive)

ex: tay-sachs, Gaucher disease, metachromatic leukodystrophy, krabbe disease, Gm1 gangliosidosis, sandhog disease, fairy disease, niemann-pick disease, farmer disease