Biochem Exam 4: Eicosanoids And Platelet Aggregation

Front 1

How many carbons are in eicosanoids?

Back 1

20 (“eicosa” Greek for 20)

Front 2

What are eicosanoids primarily produced from?

Back 2

Arachidonic acid

Front 3

T/F

Eicosanoids are local mediators (lipids) that act where synthesized or in adjacent cells.

Back 3

True!

autocrines & paracrines

Front 4

T/F

Eicosanoids are transported in the blood.

Back 4

False!

Unlike hormones, they are not transported in the blood

Front 5

What are the 4 major classes of eicosanoids?

Back 5

Prostaglandins, leukotrienes, thromboxanes, and lipoxins.

Front 6

T/F

Eicosanoids exert control over only a few physiological processes.

Back 6

False!

They exert control over a wide range of physiological processes.

Front 7

Many of the effects of eicosanoids are mediated by what (2 answers)?

Back 7

Cyclic AMP or calcium second messengers

Front 8

Name the 20-carbon ω-6 FA precursor of eicosanoids.

Back 8

Arachidonic acid (AA)

Front 9

Most arachidonic acid (AA) in the human body is synthesized from what?

Back 9

Dietary linoleic acid (essential FA, 18:3 ω-6)

Front 10

What enzyme frees arachidonic acid from phospholipid molecule?

Back 10

Phospholipase A2

Front 11

alpha-Linolenic acid (ALA) is a omega-____ fatty acid.

Back 11

3

Front 12

Which is more stable: alpha-linolenic acid (ALA) or linoleic acid?

Back 12

Linoleic acid (omega-6 more stable than omega-3)

Front 13

Which FA is converted in the body to EPA (eicosapentaenoic acid) then to DHA (docosahexaenoic acid)?

Back 13

alpha-Linolenic acid (ALA)

Front 14

Which metabolites are more inflammatory: metabolites of omega-6 FAs or omega-3 FAs?

Back 14

Metabolites of omega-6 FAs

Front 15

* What is the range for the healthy ratios of omega6/omega3?

What types of oil have a healthy ratio in this this range?

Back 15

From 1:1 to 4:1
*if too much omega 6, too much prostaglandins & overreaction to stress will occur

Canola and sometimes olive oil.

Front 16

What factors can activate phospholipase A2 (PLA2)?

Back 16

Mechanical trauma (stress), histamine, cytokines, and growth factors.

Front 17

What factors can inhibit PLA2?

Back 17

Anti-inflammatories, glucocorticoids, and cortisone.

*glucocorticoids (cortisol) through the release of annexins (lipocortins)

Front 18

T/F

Glucocorticoids' effect on phospholipase A2 will cause release of arachidonic acid from membrane lipids.

Back 18

False!

This would actually inhibit phospholipase A2, thereby inhibiting release of AA from lipids.

Front 19

What are the enzymes in the 3 pathways that free arachidonic acid is converted to eicosanoids?

Back 19

Cyclooxygenases/COX isozymes (constitutive COX-1 and inducible COX-2)
*by most cells

Lipoxygenases/LOX enzymes (5-LO, 12-LO, 15-LO)
*predominantly be inflammatory cells, eisinophils, monocytes, & epithelia cells

Cytochrome P450/P-450 epoxygenase

Front 20

a) Which enzyme(s) catalyze(s) the formation of PGH2?

b) Then, cell-specific PG synthases convert PGH2 to what compounds?

Back 20

a) COX isozymes (constitutive COX-1 and inducible COX-2)

b) Prostaglandins, prostacyclin and thromboxanes.

Front 21

Which enzyme(s) catalyze(s) the formation of:
a) LTs
b) 12-HETEs
c) Lipoxins (LXs)

Back 21

LOX enzymes
a) 5-LO
b) 12-LO
c) 15-LO

Front 22

Which enzyme(s) catalyze(s) the formation of hydroxyeicosatetraenoic acids (HETEs) and epoxides?

Back 22

P-450 epoxygenase

Front 23

Prostaglandins can be produced from ___(how many?)____ different precursors, but the major pathway uses what as a precursor?

Back 23

3

Arachidonic acid

Front 24

a) In the synthesis of prostoglandins and thromboxanes from arachidonic acid, what enzyme is the inital step (AA --> PGG2) catalyzed by?

b) What change is occuring at this step? (think organic chem)

c) The next step is ______-specific.

Back 24

a) Cyclo-oxygenase

b) Hydroperoxy group is reduced to hydroxyl group

c) Tissue

Front 25

NSAIDs inhibit what enzymes?

Back 25

Cyclooxygenases

Front 26

Aspirin is a(n) (reversible/irreversible) inhibitor of COX-1 and COX-2.

Back 26

Irreversible

Front 27

T/F

Platelets are able to produce cyclooxygenases de novo.

Back 27

False!

Platelets cannot produce cyclooxygenases de novo.

Front 28

____________ of the active site of COX-2 changes its catalytic activity.

Back 28

Acetylation

Front 29

When COX-2 is modified by acetylation, it converts arachidonic acid(AA) to what?

If EPA or DHA are used instead of AA, what will the modified COX2 produce?

Back 29

15R-HETE


resolvins

Front 30

What enzyme converts 15R-HETE to lipoxins?

Back 30

Leukocyte 5-LO

Front 31

Aspirin inhibits the production of (pro/anti)-inflammatory eicosanoids, but stimulates synthesis of (pro/anti)-inflammatory eicosanoids.

Back 31

inhibits proinflammatory

stimulates antiinflammatory

Front 32

Acetaminophen and ibuprofen are (reversible/irreversible) inhibitors of COX-1 and COX-2.

Back 32

Reversible

Front 33

Salicylate is the same thing as:

Back 33

Aspirin
(Excedrin, Alka-Seltzer)

Front 34

Para-aminophenol is the same thing as:

Back 34

Acetaminophen
(Tylenol)

Front 35

Aryl-proprionic acid is the same thing as:

Propanoic acid is the same thing as:

Back 35

Ibuprofen (Advil, Motrin)

Naproxen (Aleve)

Front 36

What effect does aspirin have on COX-1 & COX-2?


What is a side effect due to COX-1 inhibition?

Back 36

COX-1: Reduces platelet aggregation (TxA2).
COX-2: reduces inflammation

Stomach irritation
Because the prostaglandins produced in COX-1 pathway are important in production of gastric acid and gastric mucosa (overproduction of gastric acid, higher acidity, irritation)

Front 37

What are a couple examples of specific COX-2 inhibitors?

Back 37

Celebrex/Vioxx

Front 38

What is the benefit to celebrex/vioxx over aspirin?

Back 38

They target the inflammatory response, but there is no COX-1 inhibition to produce aspirin-induced side effects (stomach irritation).

Front 39

What are the effects of PGI2, PGE2, and PGD2?(

Back 39

Increase:
vasodilation and cAMP
Decrease:
platelet aggregation, leukocyte aggregation, IL-1 and IL-2, T-cell proliferation, and lymphocyte migration

**antagonist to PGF2

Front 40

What are the effects of PGF2?


What are the effects of Thromboxane A2 (TXA2)?

Back 40

(PGF2) Increases:
vasoconstriction, bronchoconstriction, & smooth muscle contraction

(TXA2) Increases:
vasoconstriction, platelet aggregation, lymphocyte proliferation, bronchoconstriction

Front 41

Prostaglandins and thromboxanes are inactivated (slowly/rapidly).

Back 41

Rapidly

Half-lives range from seconds to minutes.

Front 42

a) What are prostaglandins inactivated by (2 things)?

b) What gets excreted in the urine?

c) Enzymes necessary for prostaglandin synthesis are located where?

Back 42

a) Oxidation of 15-hydroxyl group to a ketone
Reduction of double bond at carbon 13

b) Subsequent beta- and omega-oxidation of nonring portion results in dicarboxylic acid
excreted in urine

c) in specific cell types based on the particular prostaglandin

Front 43

TxA2 is metabolized to what by cleavage of the oxygen bridge between carbons 9 and 11?

Back 43

TxB2

TxB2 does not have any biological activity.

Front 44

*a) Which prostaglandin or thromboxane causes platelet aggregation (Thrombus) and vasoconstriction?

b) It is converted from PGH2 in the _________ via ___________.

Back 44

a) TXA2 (Thrombus)

b) Platelets, thromboxane synthase

Front 45

*a) Which prostaglandin or thromboxane is involved with sleep?

b) It is converted from PGH2 in the ___________ via _________.

Back 45

a) PGD2 (Drowsy)

b) CNS, mast and fat cells; isomerase

Front 46

*a) Which prostaglandin or thromboxane is involved with wakefulness, pain, fever, inflammation, and renal arteriolar dilation?

b) It is converted from PGH2 in _________ via __________.

Back 46

a) PGE2 (Eye opener)

b) Many cells, isomerase

Front 47

*a) Which prostaglandin or thromboxane is involved with platelet disaggregation, vasodilation, and decreased stomach acid secretion?

b) It is converted from PGH2 in ____________ via _________.

Back 47

a) PGI2 (Inhibits aggregation)

b) Endothelial cells, prostacyclin synthase

Front 48

*a) Which prostaglandin or thromboxane is involved with labor induction?

b) It is converted from _______ via __________.

Back 48

a) PGF2a (Fetus)

b) PGE2, reductase

Front 49

*Which prostaglandin that we learned is the only one that isn't converted directly from PGH2?

Back 49

PGF2a

Front 50

*Which prostaglandin or thromboxane is the central intermediate?

Back 50

PGH2 (Head of pathway)

Front 51

What are the fatty compounds that simulate the proinflammatory response in asthma?

What are they produced from?

Back 51

Leukotrienes


Leukocytes (also mast cells, eosinophils, & other immunocompetent cells)

Front 52

Leukotrienes contain what typical structure?

What do they act through?

Back 52

Triene structure - three double bonds in series
(*not cyclic like rest)

GPCR

Front 53

a) What are formed by the incorporation of an O2 molecule onto a carbon of a double bond of arachidonic acid?

b) This results in formation of a ______________ group and rearrangement of the ______________.

Back 53

a) HPETEs and HETEs

b) Hydroperoxy, double bond

Front 54

Lipoxygenases can act on which carbons of arachidonic acid (AA)?

Lipoxygenases convert AA to HPETE's in what molecules?

Back 54

5, 12, or 15


luekocytes or platelets

Front 55

What is occuring (think o chem) in the conversion of HPETE to HETE?

Back 55

The unstable hydroperoxy group is being converted to a more stable hydroxyl group.

Front 56

Which enzyme produces the major leukotrienes?

Back 56

5-lipoxygenase

Front 57

Which leukotrienes is 5-HPETE converted to? And where?

Back 57

To LTA4
(which can then be converted to LTC4 or LTB4. LTC4 is then converted to LTD4 & LTE4)

In leukocytes and mast cells

Front 58

What does zyflo inhibit?

Back 58

5-lipoxygenase, and therefore leukotriene synthesis

Front 59

Which leukotriene(s) increase(s) vascular permeability, T-cell proliferation, lymphocyte aggregation, INF-y, IL-1 and IL-2?

Back 59

LTB4

Front 60

Which leukotriene(s) increase(s) bronchoconstriction, vascular permeability, and INF-y (contributing to asthma & edema)?

What does Singular do?

Back 60

LTC4 and LTD4
*LTC4, LTD4 & LTE4 = cysteinyl luekotriens (all contain Cys)

Singular blocks LTD4 receptors, prevents smooth muscle contstriction in airways, treats asthma

Front 61

Name the series of anti-inflammatory mediators that are short-lived nonclassic eicosanoids.

Back 61

Lipoxins

Front 62

Which 2 enzymes help form lipoxins?

Back 62

15-LOX and 5-LOX

Front 63

Which lipoxin acts to oppose some leukocyte responses to leukotrienes?

Back 63

LXA4

Front 64

a) Which action(s) of LTB4 does LXA4 inhibit?

b) Which action(s) of LTD4 does LXA4 inhibit?

Back 64

a) Chemotaxis and degranulation of polymorphonuclear leukocytes.

b) Vasoconstriction

Front 65

How is 15-epi-LXA4 (ATL) produced?



What is the effect of ATL?

Back 65

ATL (aspirin triggered lipoxin) is formed when aspirin modifies COX-2 & redirects catalytic activity
(^this can be prevented via NSAIDS)

ATL has an inhibitory effect on inflammation & carcinogenesis

Front 66

Anandamine is produced from:

Back 66

Phosphatidylethanolamine

(which is originally AA, AA is transferred to amino group of ethanolamine)

Front 67

What enzyme releases anandamine?

Back 67

Phospholipase D

Front 68

Anandamine promotes what type of an effect?

Back 68

Analgesic effect

via Cannabinoid receptors

Front 69

What enzyme degrades anandamine?

Back 69

Hydrolase

Front 70

Which eicosanoids are increased in chronic inflammatory conditions?

Back 70

PGs and LTs

Front 71

Granulocytes, macrophages, neutrophils, platelets, mast cells and endothelial cells are involved in eicosanoid production during what?

Back 71

Inflammation

Front 72

What 5 things do eicosanoids act as during inflammation? (also, for each one, what is the eicosanoid(s) performing the action)

Back 72

Proinflammatory molecules (PGH2)
Chemoatractants (LTB4)
Platelet aggregating factors (TXA2)
Contractors of smooth muscle (CysLTs)
Modifiers of vascular permeability (LTs)

Front 73

Which eicosanoids can act as both proinflammatory and anti-inflammatory mediators depending on the array of EP (E-prostanoid) receptors with different signal transduction pathways?

Back 73

PGs

Front 74

In (white/gray) matter, there is a higher proportion of omega-6 than omega-3 PUFAs.

Back 74

White

Front 75

T/F

Normal endothelium supports platelet adhesion or blood coagulation.

Back 75

False!

Normal endothelium does NOT support platelet adhesion or blood coagulation. It has antithrombotic properties.

Front 76

Normal endothelium produces what to inhibit thrombosis?

Back 76

Prostacyclin or prostaglandin I2 (PGI2)
Nitric oxide, also known as endothelium derived relaxing factor (EDRF)
Heparin sulfate and thrombomodulin

Front 77

What is the action of prostacyclin or prostaglandin I2 (PGI2)?

What is the action of EDRF?

Back 77

Prevents platelets aggregation


stimulates smooth muscle relaxation

Front 78

What is the action of heparin sulfate and thrombomodulin?

Back 78

Both inhibit thrombin action

Front 79

Hemostasis is the process of blood clotting & subsequent clot dissolution. What are the 4 major events

Back 79

1. Vascular phase
2. Platelet phase
3. Coagulation phase
4. Fibrinolytic phase

Front 80

What leads to the activation of PLA2 and activation of platelets?

Back 80

Binding of platelets to exposed collagen + Ca2+

Front 81

Activation of PLA2 → release of _________________ → production of ___________________.

Back 81

Arachidonic acid and thromboxane A2 (TXA2)

Front 82

Contents of granules are secreted in response to what?

Back 82

Platelet activation

Front 83

What do granules contain which promotes platelet aggregation, degranulation, and vasoconstriction?

Back 83

TXA2

Front 84

What does prostacyclin (PGI2) cause in endothelial cells? and platelets?

Back 84

Endothelial cells - increased cAMP/vessel smooth
muscle relaxes.

Platelets - increase in cAMP and decreased aggregation

Front 85

What does TxA2 cause in endothelial cells? in platelets?

Back 85

Endothelial cells - increased Ca2+/vessel smooth muscle constricts

Platelets - increase in Ca2+ and increased aggregation

Front 86

Platelet aggregation is controlled by what 3 things?

Back 86

By the balance in production of TXA2 and PGI2
By drugs NSAIDs (aspirin)
By dietary intervention

Front 87

How can platelet aggregation be controlled by NSAIDs (aspirin)?

Back 87

Platelets lack nucleus; cannot replace COX – production of TXA2 is preferentially inhibited.

Front 88

How can platelet aggregation be controlled by dietary intervention?

Back 88

Supplementation of omega-3 reduces production of proinflammatory eicosanoids.