Eicosanoids Lippincot Chapter 17 - PowerPoint Presentation

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Eicosanoids

Lippincot Chapter 17

Eicosanoids

Several Classes of Signal Molecules:

Prostaglandins, Thromboxanes, LeukotrienesProduced In Almost all TissuesWide Range of ResponsesLocal HormonesVery PotentShort Half Life secondssNot Stored When needed they synthesized and released

The name eicosanoids was derived from eicosa which means 20 because the structure of all those molecules contains 20 carbons

The first class discovered was named prostaglandin because it was isolated from prostate, . Later it was found in other tissues as well. The other classes were shown to share some properties with PG

They are not transported in blood as in hormones, but act locally. Affecting the cells in the neighborhood of the secreting cells

Prostaglandin

Leucotriene

Thromboxane

What is this

?

Arachidonic Acid

Charactarized by 5 membered ring and two side chains attached to it.

(7 and 8 carbons) 1-3 double bonds in the chains.

Linear (no ring) charatarized by having 3 conjugated (alternating single-double) double bonds

All three classes are contain carboxyl group

Functional Groups on the Cyclopentane Ring Determine PG Class

Just have a look at the functional groups

. You are not expected to recognize each class

E

2

F

2

I2A2A4

The number in the name is the number of double bonds in the linear portion of the molecule.

Some Functions of the Prostaglandins and Thromboxanes

PGI

2

, PGE2, PGD2Increase - Vasodilation, cAMPDecrease - Platelet Agregation - Leucocyte Aggregation - Lymphocyte Migration

PGF2α Increses - Vasoconstriction - Bronchoconstriction - Smooth Muscle ContractionThromboxane Increases - Vasocostriction - Platelet Agregation - Lymphocyte Proliferation - Bronchoconstriction

Diversity of functions. Mostly affecting smooth muscles, leucocytes and platelets. You are not expected to memorize the functions.

You are not expected to memorize the functions. Just be familiar wit them. Notice that some have opposite effects

Overview of Eicosanoid Synthesis

Dietary Linoleic Arachidonic Acid

Membrane Phospholipids Arachidonic Acid PGH2 Prostaglandins Thromboxanes

Phospholipase A

2

Leukotrienes

HETE

The second fatty acid in the phospholipid is usually unsaturated. The second fatty acid is hydrolyzed by phospholipase A2.

This the rate limiting step in eicosanoids synthesis

Prostaglandin G (PGH) is the first product. Contains this peroxide

The peroxide is rapidly reduced to hydroxyl group to produce PGH which is the parent compound for other prostaglandins and thromboxane

C

yclo

ox

ygenase Complex (

COX) 1- Cyclooxygenase 2- Peroxidase

PGH is the Parent Compound for other Prostaglandins, Thromboxanes and Prostacyclin

Cycloxygenase that catalyzes the first step contains two activities. Cycoloxgease and peroxidase

Eicosanoids Can be Synthesized from other Polyunsaturated Fatty Acids

Arachidonic Acid (Eicosatetraenoic acid)

 PG

2

Arachidonic acid has 4 double bonds. It produces PG2. ( 2 double bonds in the side chains)

Eicosapentaenoic Acid

E

icosa

p

entanenoic

acid (EPA)has 5 double bonds. It produces PG3. (3 double bonds in the side chains)

Some of the 3 series have opposite effect .than 2 series Thromboxane B3 produced from EPA inhibit platelets aggregation. May protect from myocardial infarction

Eicosatrienoic Acid

Eicosatrienoic acid has 5 double bonds. It produces PG1. ( 1 double bonds in the side chains)

Inhibition of Prostaglandin Synthesis

Steroidal Anti Inflamatory

Phospholipase A2Nonsteroidal Anti Inflamatory Aspirin; Acetylation of Cyclooxygenase or Irreversible Binding to the Enzyme

Aspirin transfers acetyl group to the active site of cycloxygenase inhibiting it

This the basis for using low dose aspirin to prevent thrombosis by inhibiting thromboxane synthesis.

C

yclo

ox

ygenase exists in two FormsCox 1ConstitutiveGastric Mucosa, Kidney, PlateletesCox 2 - Inducible; in Response to inflamation signals - Monocytes, Macrophages, Smooth Muscle

Inactivation of Prostaglandins

Rapid

Oxidation of Hydroxyl group at C15

Reduction of Douple bond at C13

L

euko

t

rienes and (LT) Hydroxyeicosatetraenoic acid(HETE)Signal MoleculesProduced from Arachidonic AcidLinear Molecules; No RingLT Contain 3 Conjugated Double Bonds

Lipooxygenase Catalyzes the First Step

Arachidonic Acid

Lipooxygenase

H

ydro

P

eroxy

e

icosa

t

etra

e

noic Acid