Midterm II: Eicosanoids (Ben) Flashcards Preview

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What structural molecules are eicosanoids formed from?

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

Formed from membrane phospholipids

- cleaved by phospholipase A2

- forms Arachidonic Acid


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

And their general products?

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


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

And its final product (after several steps)

Linoleic Acid 18:2 (9,12)

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


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

What is its product (after several steps)?

α-Linolenic Acid 18:3 (9,12,15)

- makes EPA and DHA


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.)

PGH Synthase

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


Describe the structure + location of PGH synthase.


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


  • ER + nuclear membrane


What is an eicosanoid product of platelets?

What is its effect?

Thromboxane A2

- activates platelet aggregation (via calcium signal)

(and vascular smooth muscle contraction)


What is an eicosanoid product of endothelial cells?

What is its effect?

Prostaglandin I2

decreases platelet aggregation (via cAMP increase)

(and relaxes vascular smooth muscle)


What is an important effect of PGE2?

- protects gastric mucosa



What are the COX isoenzymes?

And what are important characteristics of them?

  • 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


What part of the eicosanoid production pathway do steroids inhibit?

Creation of arachidonic acid via Phospholipase A2

(inhibits this enzyme)


How do aspirin differ from other NSAIDs in its action?

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


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

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


How are selective COX II inhibitors selective?

What is an example of one?

- they are too big to fit in COX I's narrow substrate binding channel

- Coxibs such as Vioxx are selective to COX II


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

  • 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


Where are leukotrienes made?

And why?

in neutrophilsmacrophages, and mast cells

- induced by inflammatory stimuli



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

What is the precursor it makes?


- with dioxygenase + dehydrase activity

- makes Leukotriene A4 (LTA4)


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

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


What are lipoxins?

lipoxygenase products which are anti-inflammatory