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Biochem 1 > Eicosanoid Metabolism & Function > Flashcards

Eicosanoid Metabolism & Function Flashcards

1
Q

What are eicosanoids?

A
  • Among the most potent regulators of cellular function in nature
  • Produced by almost every cell in the body
  • Includes prostaglandins (PG) and thromboxane (TX), leukotrienes (LT)
  • Act mainly as local hormone, affecting them cells that produce them or neighbouring cells of a different type
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2
Q

What are the functions of eicosanoids?

A
  1. Inflammatory response that occurs following infection or injury
  2. Regulation of water and sodium excretion, particularly in the intestine and uterus
  3. Increase water and sodium excretion by the kidney
  4. Regulate blood pressure
  5. Regulate bronchoconstriction and bronchodilation
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3
Q

What is the source/precursor of eicosanoids?

A

arachidonic acid

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4
Q

How do we get arachidonic acid ?

A
  • Can’t be synthesized de novo in the body
  • Our diet must contain it
  • Major precursor is the essential fatty acid linoleate (present in plant oils)
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5
Q

How is arachidonic acid released from the lipid bilayer?

A

by activation of membrane bound phospholipase A2 or C

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6
Q

How does activation of phospholipase A2 or C occur

A

When stimuli, such as histamine or cytokines, interact with a specific plasma membrane receptor on the target cell surface

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7
Q

What are the 3 pathways for eicosanoid synthesis?

A
  1. Cyclooxygenase pathway
  2. Lipoxygenase pathway
  3. Cytochrome P450 system
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8
Q

Which of the eicosanoid synthesis pathways leads to the production of prostaglandins and thromboxane?

A

The cyclooxygenase pathway

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9
Q

Which of the eicosanoid synthesis pathways leads to the production of leukotrienes, HETEs and lipoxins?

A

The lipoxygenase pathway

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10
Q

Which of the eicosanoid synthesis pathways is responsible for the synthesis of epoxides, HETEs and diHETEs?

A

The cytochrome P450 system

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11
Q

Describe the structure of prostaglandins

A
  • fatty acids containing 20 C atoms
  • an internal saturated 5C ring

If biologically active:
- OH at C15
- double bond between C13-14
various substituents on the ring

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12
Q

Describe the structure of thromboxane

Describe the structure of thromboxane A2 (TXA2)

A
  • fatty acids containing 20 C atoms
  • an internal saturated 6C ring which has an attached O atom

TXA2 has O atom attached to C9 and 11 on the carbon ring

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13
Q

Describe the biosynthesis of prostaglandins

A
  • First biochemical reaction catalyzed by a cyclooxygenase to form PGG2
  • PGG2 is reduced to form the endoperoxide-PGH2
  • After this is tissue specific/cell dependent
  • In vascular endothelium, PGH2 is converted to prostaglandin PGI2 by PGI synthase
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14
Q

Describe the biosynthesis of thromboxane

A
  • First biochemical reaction catalyzed by a cyclooxygenase to form PGG2
  • PGG2 is reduced to form the endoperoxide-PGH2
  • After this is tissue specific/cell dependent
  • In platelets, PGH2 is converted to thromboxane TXA 2 by TXA synthase
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15
Q

What is the half lives of prostaglandins and thromboxane

A

seconds to minutes

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16
Q

How are prostaglandins inactivated?

A
  1. Oxidation of the 15-OH group to a ketone
  2. Reduction of double bond at C 13
  3. b-oxidation and w-oxidation of the non-ring portions (producing dicarboxylic acids which are secreted in the urine)
17
Q

How is thromboxane A (TXA2) inactivated?

A
  1. Rapid metabolism into TXB2 via cleavage of the oxygen bridge bw C9-11 to form TXB2 in urine (it has no biological activity)
18
Q

Describe the synthesis of leukotriene

A
  1. Formation of 5-HPETEs from arachidonic acid catalyzed by 5-lipoxygenase
  2. 5-HPETEs metabolized to leukotrienes
19
Q

Describe the synthesis of leukotriene A4 (LTA4)

A

conversion of 5-HPETEs to an epoxide in leukocytes and mast cells

20
Q

How are other leukotrienes formed from the LTA4?

A

Two pathways:

  1. LTA4 is converted to LTB4
  2. reduced glutathione is added to C6 to form LTC4, catalyzed by glutathione S-transferase
    - Glutamate is removed from glutathione of LTC4 by gamma-glutamyl transpeptidase to form LTD4
    - Glycine residue from LTD4 is cleaved to form LTE4
21
Q

Describe the mechanism of action of eicosanoids (PGE, PGD PGI series)

A
  • Eicosanoid binds with a specific G linked receptor on the plasma membrane of a target cell
  • Activates adenylate cyclase –> cAMP –> protein kinase A
22
Q

Describe the mechanism of action of eicosanoids (PGF2alpha, TXA2 and leukotrienes)

A
  • Eicosanoid binds with a specific G linked receptor on the plasma membrane of a target cell
  • Activates phospholipase-C
  • Activates inositol phospholipid signaling pathway
  • Increase in level of Ca+ in the cytosol of target cells
23
Q

What type of signals do eicosanoids produce?

A

Paracrine (released from one cell type and acts on neighboring cells of a different type)
Autocrine (released and acts on the same cell type)

24
Q

What is an example of a paracrine action by eicosanoids?

A

contraction of vascular smooth muscle cells caused by TXA2 released from circulating platelets

25
Q

What is an example of a autocrine action by eicosanoids?

A

platelet aggregation by TXA2 produced by platelets

26
Q

Which of the following increases vasodilation?

Prostaglandins, thromboxane’s or leukotrienes

A

prostagalndines

27
Q

Which of the following increases vasoconstriction?

Prostaglandins, thromboxane’s or leukotrienes

A

thromboxane’s and leukotrienes

28
Q

Which NSAID irreversibly inhibits cyclooxygenase?

How?

A

aspirin

By transferring an acetyl group to the enzyme

29
Q

Which NSAID reversibly inhibits cyclooxygenase?

A

All other NSAIDS eg acetaminophen, ibuprofen

30
Q

How is low dose aspirin effective in prevention of acute myocardial infarction?

A
  • Predominant eicosanoid in platelets is TXA2
  • TXA2 is a potent stimulator of platelet aggregation
  • It initiates thrombus formation at sites of vascular injury which can cause occlusion of vascular lumen causing acute ischemic damage (myocardial infarction)
  • Aspirin covalently acetylates the active site of cyclooxygenase and blocks production of TXA2

Biochem 1 (22 decks)

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