L22: Lipid Metabolism III

Question 1

What are the lipid components of membranes?

Answer 1

• Phospholipids: two FAs and a phosphate head group on glycerol - Plasmalogens: one FA, one fatty alcohol and a polar head group on glycerol - Sphingolipids: one FA, one polar head group on sphingosine - Cholesterol

Question 2

What are the types of phospholipids found in a membrane?

Answer 2

• Phosphatidylcholine (PC), Phosphatidylethanolamine (PE), Phosphatidylserine (PS) - Phosphatidylinositol (PI) - Cardiolipin

Question 3

Describe how PC, PE and PS are synthesized. Include the necessary components.

Answer 3

PC synthesis: a.) CTP + phosphocholine = CDP-choline (via phosphocholine cytidyltransferase ez) b.) CDP-choline + inactivated DAG (from phosphatidic acid from TAG synthesis) = PC (via choline phosphotransferase ez) c.) OR: via PE-N-methyltransferase, which takes PE and converts to PC with addition of 3 methyl groups via SAM enzyme PE synthesis: (similar to PC synthesis) a.) CTP + phosphoethanolamine = CDP-ethanolamine (unk ez) b.) CDP-ethanolamine + inactivated DAG = PE (via ethanolamine phosphotransferase ez) PS synthesis: a.) PE + serine = PS (via phosphatidylserine synthase)

Question 4

What is the role of CTP in the synthesis of phospholipids? What is the biochemical principle seen here?

Answer 4

• CTP=cytosine triphosphate is used to activate choline, ethanolamine and serine precursors for use in down stream pathways for membrane phospholipids. - Utilizes same activating biochemical principle as seen with other activated nt diphosphate molecules – eg. UDP-X (glucose polymers-glycogen), GDP-X (activates mannose for protein synthesis) and rarely ADP-X (mostly used as energy currency) - Principle = use of energy conserved in phosphodiester bond to drive bond formation in downstream reactions

Question 5

Explain how phosphatidylinositol is synthesized.

Answer 5

• Inactivated DAG + CTP = CDP-diacylglycerol (activated DAG) – via unk ez - CDP-diacylglycerol + inositol = phosphatidylinositol (via phosphatidylinositol-synthase ez)

Question 6

What is cardiolipin?

Answer 6

• It is a phospholipid found in the inner mitochondrial membranes. It helps with folding of mitochondrial electron transport complexes and buffers electrons in membranes. Decline in this impairs oxidative phosphorylation and leads to membrane peroxidation. Insufficiency in this can lead to neurodegenerative disorders such as Alzheimer’s and PD. Dysregulated also leads to heart diseases.

Question 7

Describe important of asymmetric distribution of lipids between lipid bilayers. What is typical distribution? Implication in RBCs

Answer 7

• Outer leaflet is rich in PC and sphingomyelin (both have choline) - Inner leaflet is rich in PE and PS - Stress activates enzymes known as flippases that flips lipids between leaflets - Eg. When PS appears in outer leaflet of RBCs, RBCs are destroyed by macrophages.

Question 8

What is the function of phospholipases?

Answer 8

• Phospholipases separate FAs and head groups from phospholipids. These have functions in signal transduction (eg. PLC produces IP3 and DAG from PIP2) - Phospholipases initiate FA exchange on phospholipids.

Question 9

Types of phospholipases and their functions?

Answer 9

• Phospholipase A1: removal of FAs from C1 of phospholipid - Phospholipase A2: removal of FAs from C2 of phospholipid, usually arachidonic acid - Phospholipase C: removal of phosphate head group from C3 of PIP2 phospholipid creating DAG and IP3

Question 10

What is the function of phospholipase C/PLC? What carbon position of phospholipid does it cleave at?

Answer 10

• PIP2 cleaved to DAG and IP3. Cleaves at C3 position.

Question 11

What is the function of phospholipase A2? What carbon position of phospholipid does it cleave at?

Answer 11

• Cleaves at C2 of phosphatidylcholine to yield arachidonic acid and lysophophatidylcholine

Question 12

Describe how arachidonic acid is synthesized and inserted into phospholipids.

Answer 12

Question 13

What essential FA is needed for arachidonic acid synthesis?

Answer 13

• Linoleic acid = omega 6 FA

Question 14

What is arachidonic acid a precursor for?

Answer 14

• prostaglandins - thromboxanes - leukotrienes

Question 15

Describe synthesis of prostaglandins, thromboxanes and leukotrienes.

Answer 15

1.) Prostaglandins - AA to PGG2 via COX1/2 - PGG2 to PGH2 via PGH synthase - PGH2 is precursor to other prostaglandins via PGD/PGE/PGF synthase enzymes 2.) Thromboxanes - PGH2 to TXA2 via thromboxane synthase - TXA2 to TXB2 via hydrolysis in blood 3.) Leukotrienes - AA to leukotrienes via lipoxygenase and other enzymes

Question 16

What are the functions of prostaglandins/thromboxanes?

Answer 16

• inflammatory mediators (vasodilation) - stimulation of contraction of uterus - platelet aggregation

Question 17

What are the function of leukotrienes?

Answer 17

• promotion of SM contraction - anaphylaxis

Question 18

What is the function of lipoxygenase inhibitors? What downstream molecule is being targeted with these inhibitors? What disorder/illness can these alleviate? How?

Answer 18

• These target synthesis of leukotrienes from AA via inhibition of the lipoxygenase enzyme. - Alleviates asthma by reducing smooth muscle contraction.

Question 19

How can prostaglandin synthesis be inhibited? Explain

Answer 19

• NSAIDs and glucocorticosteroids(aka glucocorticoids) inhibit COX1/2 and prostaglandin synthase (PGH synthase)

Question 20

Contrast synthesis of plasmalogens and phospholipids.

Answer 20

• Phospholipids contain two FAs and a phosphate head group on glycerol (has ester linkages) - Plasmalogens contain one FA, one fatty alcohol and a polar head group on glycerol (has ester and ether linkage) - Plasmalogens are synthesized in peroxisomes, where fatty acid from DHAP is exchanged with fatty alcohol - CDP-choline, a precursor in phosphatidylcholine synthetic pathway, is used in pathway of plasmalogen synthesis

Question 21

Where are plasmalogens mostly found?

Answer 21

• they are abundant in brain, CNS and heart tissue

Question 22

How are sphingolipids different to phospholipids and plasmalogens? Where are they found?

Answer 22

• The core structure is not glycerol, but rather sphingosine. - They are lipid components of membranes. Most of them contain glycosylated head groups (glycolipids), which are found on the outside of the cell and are distributed differently based on the tissue type implicated.

Question 23

Describe the synthesis of sphingosine and ceramide

Answer 23

Question 24

What are the types of sphingolipids? What are the head groups on each?

Answer 24

• Sphingomyelin: phosphocholine - Cerebrosides: glucose, ceramide, galactose - Sulfatide: galactose-sulfate - Globoside: glucose-galactose-galactose-galnac - Ganglioside: a.) GM2: glucose-galactose(nana)-galnac b.) GM1: glucose-galactose(nana)-galnac-galactose

Question 25

What is the role of phospholipids in prevention of respiratory distress syndrome in premature infants?

Answer 25

• Surface of lung epithelium is covered with secretion that prevents alveolar membranes from sticking together (surfactant) - This surfactant is rich in phospholipids, particularly dipalmitoyl phosphatidylcholine (sometimes called dipalmitoyl lecithin). - This surfactant is produced at about 31 weeks gestation. - Infants born prematurely have a lecithin/sphingomyelin ratio below 2, indicating they have insufficient amounts of surfactant, which puts them at risk for respiratory distress syndrome (RDS). - Artificial surfactant mixtures treat premature infants. - Also they are given corticosteroid growth hormones to stimulate lung maturation.