Biochem3.prostaglandins.mcv/vcu

Front 1

BIOLOGICALLY ACTIVE LIPIDS

Back 1

-Steroid hormones
-Androgens, estrogens
-Mineralocorticoids, glucocorticoids
-Glycerolipids
-Sphingolipids
-Prostaglandins
-Retinoic acid
-Vitamin D

Front 2

Phospholipase Substrate Specificities

Back 2

-A1

-A2

-C

-D

Front 3

The Role of Phospholipase C in Production of Biologically Active Molecules (second messengers)

Back 3

-activates protein kinase C

-activates Ca2+ release from ER stores

1. 1-palmitoyl-2-linoleoylphosphatidylinositol-bis-phosphate
2. 1-palmitoyl-2-linoleoylglycerol (diacylglycerol)
3. inositol-tris-phosphate

Front 4

The Role of Phospholipase A2 in Production of Biologically Active Molecules

Back 4

1. 1-palmitoyl-2-arachidonoylphosphatidylcholine

phospholipase A2

2. 1-palmitoyl-2-lysophosphatidylcholine


3. arachidonate
4. prostaglandins, thromboxanes, and leukotrienes

Front 5

BIOLOGICAL ACTIVITIES OF PROSTAGLANDINS

Back 5

Physiological
-Inflammation
-Pain
-Platelet activity (+/-)
-Smooth muscle contraction (+/-)
-Cytoprotective (+/-)

-Pathological (concentration dependent)
-Pharmacological (dose dependent)

Front 6

PROSTAGLANDINNOMENCLATURE

Back 6

PGXN

X = (type) letter (A,B,C…I)
N = number of double bonds(1,2,3)

Front 7

Thromboxanes have similar structures and nomenclature but different biological activities.

Back 7

-Thromboxane B2, a potent platelet activator

-differ in the presence of an oxane ring instead of a cyclopentane ring

Front 8

Leukotrienes are secreted by leukocytes and mediate inflammatory responses, tumorigenesis, plaque destabilization, etc.

How are they similar/dissimilar to prostaglandins?

Back 8

Have no ring but are similarly substituted with oxygen in their side chain

Front 9

Resolvins: Active metabolites of 22-carbon polyunsaturated fatty acids.

Back 9

-Including arachidonic, eicosapentaenoic and docosahexaenoic acids

-potent anti-inflammatory molecules (EPA, DHA)

-may be able to treat inflammatory and degenerate diseases

Front 10

THE REACTIONS CATALYZED BY PROSTAGLANDIN SYNTHASE (aka cyclooxygenase)

Back 10

1. endoperoxidase
-arachidonic acid to PGG2

2. hydroperoxidase
-PGG2 to PGH2

Front 11

CLASSES OF CYCLOOXYGENASES

Back 11

1. COX-1
-Constitutive enzyme
-Pathway produces cytoprotective prostaglandins PGE2 and PGI2
2. COX-2
-Induced response to growth factors and cytokines at inflammation and tumor sites
-Pathway produces inflammatory prostaglandins
-Targeted by COX-2 inhibitors (celecoxib)

Front 12

Aspirin and other non-steroidal antiinflammatory drugs inhibit prostaglandin synthesis by binding to the active site of COX.

1. How?
2. new COX-2?

Back 12

1. Aspirin acetylates the active site and irreversibly inhibits all classes.

2. A new class of COX-2 inhibitors is specific for COX-2, specifically inhibiting production of inflammatory/pain producing prostaglandins/thromboxane while permitting synthesis of beneficial species in stomach mucosa. Recent studies suggest increased risk of heart attack/stroke.

Front 13

FA precursors

Back 13

Different fatty acids give rise to different prostaglandins with different biological activities

Front 14

Pharmacologic Inhibitors of Prostaglandin Production

Back 14

-Nonsteroidal antiinflammatory drugs (NSAIDS) inhibit cyclooxygenases.

-Steroid antiinflammatory drugs inhibit phospholipase A2 and release of the fatty acid precursors to all biologically active eicosenoids (leukotrienes, prostaglandins, thromboxanes).

Front 15

Recent Developments

Back 15

-Leukotriene receptor antagonists have antiinflammatory and antitumor activities.

-One Cox-2 inhibitor also inhibits 5-lipoxygenase.

-Another Cox-2 inhibitor is also a thromboxane receptor antagonist.

Front 16

What are eicosenoids?

Back 16

-prostaglandins, thromboxanes, leukotrienes and other inflammatory hydroxy acids

-regulated by membrane phospholipase A2 activity

Front 17

Muddy Waters

Back 17

-Unexpectedly, some Cox-2 inhibitors elevate the risk of myocardial infarction and stroke.

-Dose is critical.

Front 18

The Role of Platelets in Etiology and Progression of Atherosclerosis and Coronary Heart Disease

Back 18

-Active platelets secrete prostaglandins and cytokines that increase permeability of arterial endothelium (early).

-Active platelets become sticky and form clots (late).

Front 19

How Aspirin Reduces Risk of Atherosclerosis and MI

Back 19

Aspirin irreversibly inhibits the cyclooxygenases in both cell types (platelets and endothelial cells) but the anuclear platelets are unable to produce new cyclooxygenase.

Front 20

How Eicosapentaenoic Acid Reduces Risk of Atherosclerosis and MI

Back 20

TXA3 produced by platelets from EPA does not activate platelets. PGI3 produced by endothelial cells from EPA does inhibit platelets.