Eicosanoid Metabolism I

Question 1

Where is omega-6 fatty acid found?

What is the most common omega-6 fatty acid? What can this be converted to?

Answer 1

vegetable oils, nuts and seeds

linoleic acid, which can be converted to arachidonic acid

Question 2

How many carbons compose eicosanoids?

Which fatty acids are required for their synthesis?

What is special about these fatty acids?

Answer 2

20

omega-3 (18:3 9/12/15) and omega-6 (18:2 9/12) fatty acids are required for their synthesis

they must be consumed from the diet (cannot be synthesized)

Question 3

Synthesis of arachidonic acid

Answer 3

• linoleoyl CoA is de-saturated at carbon 6
• elongated 2 carbons by malonyl CoA
• desaturated at carbon 5 = aracidonyl CoA

Question 4

What is the function of eicosanoids?

Answer 4

most potent regulators of cellular function

act at “local” hormones

Question 5

the activation of which phospholipase is responsible for the release of arachidonic acid from phospholipid membranes?

Answer 5

A2

Question 6

How would the body inhibit inflamation during and immune response?

Answer 6

glucocorticoids inhibit phospholipase A2

Question 7

What is the enzyme responsible for producing prostaglandins from arachidonic acid?

Which molecule inhibits this enzyme?

Answer 7

cyclo-oxygenase

inhibited by aspirin and other NSAID

Question 8

Which type of tissues primarily synthesize prostaglandins?

Which type of tissues priamrily sunthesize thrombaxane A2?

Answer 8

vascular endothelial

platelets

Question 9

active prostoglandins contain how many carbons?

how many internal rings?

Hydroxy groups?

Double bonds?

Answer 9

20 carbons

5 internal rigns

Hydroxyl at carbon 15

double bond between 13 and 14

Question 10

What do the number subscript identify in prostaglandin classification?

What do the greek subscript describe?

Answer 10

the number indicates the number of double bonds

the greek subscript indicates the position of the hydroxyl group on carbon 9 found on PGF

Question 11

How does the structure of thromboxane differ from that of prostaglandins?

What is the most common thromboxane? How is its structure different?

Answer 11

thromboxanes contain a 6 member ring that includes an oxygen

TAX2–Additional O atom attached to C9 and C11 of the ring

Question 12

Synthesis of prostaglandins and thromboxanes from arachidoic acid.

Answer 12

• The 5 membered ring is formed and 4 oxygen are added (2 at C15, and two between C9 and C11)
  
  • this produces PGG2, a very unstable intermediate
• Peroxidase reduces the hydroperoxy at C15 to an alcohol
  
  • producing PGH2
• various enzymes acti on PGH2 to produce specific thromboxanes or prostaglandins

Question 13

Which biocompounds

• increase:
  
  • vasodilation
  • cAMP
• decrease
  
  • platelet aggregaion
  • leukocyte aggregation
  • IL-1 and IL-2
  • T-cell proliferation
  • Lymphocyte migration

Answer 13

PGI2, PGE2, PGD2

Question 14

Which biocompound

• vasoconstriction
• bronchoconstriction
• smooth muscle contraction

Answer 14

PGF2alpha

Question 15

Which biocompound

• increases
  
  • vasoconstriction
  • platelet aggregation
  • lymphocyte proliferation
  • bronchoconstriction

Answer 15

Thromboxane A2

Question 16

What is the difference betwen COX-1 and COX-2?

Answer 16

• COX-1
  
  • constitutive (low level)
  • Housekeeping functions
    
    • platelet regulation (blood clotting)
    • kidney function
    • regulation of stomach/mucous production
• COX-2
  
  • inducible (acute high level)
  • inflammation
    
    • heat
    • swelling
    • pain

Question 17

Which class of drugs block cyclooxygenase? What is an example of this drug?

How does it work?

Answer 17

NSAID

aspirin (irreversible) ibuprofen (reversible)

transfers an acetyl group to COX (irreversibly inhibiting it)

Question 18

What is a complication of NSAID drugs?

Answer 18

they inhibit both COX-1 and COX-2, blocking housekeeping functions

gastrointestinal and platelets effects

Question 19

What are negative impact of long-term COX-2 inhibitor use?

Answer 19

• negative effects on cardiovascular function
• alters balance of prostacyclin and thromboxane b/c platelets (major source thromboxane) do not have COX-2 receptors, so thromboxane synthesis is not decreased

Question 20

How are thromboxanes and prostaglandins inactivated?

What is their approximate length of half life?

Answer 20

• prostaglandin
  
  • inactivated by oxidation of C15 hydroxyl, reducing the double cond at C13, bet and omega oxidation –> increases in the urine
• Thromboxane
  
  • cleavage of the oxygen bridge between C9 and C11 –> TXB2 (no biologic activity)

t 1/2 = seconds to minutes

Question 21

What are the 2 types of receptors that eicosanoids can bind to?

Answer 21

stimulatory or inhibitory

Question 22

Provide a paracrine and autocrine example for TXA2 function

Answer 22

• paracrine
  
  • contraction of vascular smooth muscle caused by TXA2 released from platelets
• autocrine
  
  • platelet aggregation induced by TX2A produced by the platelets themselves