Midterm II: Eicosanoids (Ben)

Question 1

What structural molecules are eicosanoids formed from?

What is the first step (enzyme) in this process and its product?

Answer 1

Formed from membrane phospholipids

• cleaved by phospholipase A2
• forms Arachidonic Acid

Question 2

What are the two pathways that arachidonic acid can take to form eicosanoids?

And their general products?

Answer 2

1. COX Pathway - forms prostanoids (prostaglandins + thromboxanes)
2. Lipoxygenase Pathway - forms leukotrienes + lipoxins

Question 3

What is the important omega-6 PUFA in the creation of eicosanoids?

And its final product (after several steps)

Answer 3

Linoleic Acid 18:2 (9,12)

makes Arachidonic Acid 20:4 (5,8,11,14)

Question 4

What is the important omega-3 PUFA in the creation of eicosanoids?

What is its product (after several steps)?

Answer 4

α-Linolenic Acid 18:3 (9,12,15)

• makes EPA and DHA

Question 5

What are the two steps of the COX pathway that convert arachidonic acid to the common precursor for all other COX pathway products?

(One enzyme system with 2 activities.)

Answer 5

PGH Synthase

1. Cyclooxygenase - makes PGG₂ from AA
2. Peroxidase - makes PGH₂ from PGG₂

Question 6

Describe the structure + location of PGH synthase.

Answer 6

Structure:

• heme-protein homodimer
• 2 catalytic sites/activities: COX + peroxidase
• tetrahelical membrane-binding domains

Location:

• ER + nuclear membrane

Question 7

What is an eicosanoid product of platelets?

What is its effect?

Answer 7

Thromboxane A2

• activates platelet aggregation (via calcium signal)

(and vascular smooth muscle contraction)

Question 8

What is an eicosanoid product of endothelial cells?

What is its effect?

Answer 8

Prostaglandin I2

• decreases platelet aggregation (via cAMP increase)

(and relaxes vascular smooth muscle)

Question 9

What is an important effect of PGE₂?

Answer 9

• protects gastric mucosa

Question 10

What are the COX isoenzymes?

And what are important characteristics of them?

Answer 10

• COX I
  
  • ​Constitutively expressed in many tissues
  • cytosolic
  • narrow substrate-binding site
  • secretes PG products
• COX II
  
  • ​Induced in inflammation + physio imbalance (via IL-1, TNFα, NFkB, cAMP)
  • in nuclear membrane
  • wider binding site
  • PG products go to nucleus

Question 11

What part of the eicosanoid production pathway do steroids inhibit?

Answer 11

Creation of arachidonic acid via Phospholipase A2

(inhibits this enzyme)

Question 12

How do aspirin differ from other NSAIDs in its action?

Answer 12

• Aspirin - irreversible acetylation of Serine residue
• Others - reversible competitive COX inhibition

Question 13

How does aspirin’s effect on COX I and COX II differ?

Answer 13

• COX I - inactivated via serine acetylation
• COX II - changed activity to creation of lipoxins (anti-inflammatory eicosanoids)

Question 14

How are selective COX II inhibitors selective?

What is an example of one?

Answer 14

• they are too big to fit in COX I’s narrow substrate binding channel
• Coxibs such as Vioxx are selective to COX II

Question 15

How do selective COX-II inhibitors negatively effect vascular health?

Answer 15

• In platelets…
  
  • only COX-I makes thromboxane A2 so platelet aggregation is not inhibited
• In endothelial cels…
  
  • both COX-I and II make PGI-2, so its anti-aggregation effect is partially inhibited

Question 16

Where are leukotrienes made?

And why?

Answer 16

in neutrophils, macrophages, and mast cells

• induced by inflammatory stimuli

Question 17

What is the common pathway for the synthesis of the main leukotriene precursor from arachidonic acid?

What is the precursor it makes?

Answer 17

5-Lipoxygenase

• with dioxygenase + dehydrase activity
• makes Leukotriene A4 (LTA4)

Question 18

What 4 leukotrienes can be made from leukotriene A4 and how?

Answer 18

1. LTB4 - directly
2. LTC4 - conjugation with glutathione
3. LTD4 - LTC4 loses glutamine
4. LTE4 - LTD4 loses glycine

Question 19

What are lipoxins?

Answer 19

lipoxygenase products which are anti-inflammatory