1

18:3n3

18∆9,12,15

20:3n9 20:4n6

20∆5,8,11,14

20:5n3

20:∆5,8,11,14,17

22:6n3

22:∆4,7,10,13,16,19

Structure of some common fatty acids found in human body

http://www.springerimages.com/Images/Biomedicine/1-10.1007_s13596-011-0002-x-5

2

Omega 6 and omega 3 fatty acid metabolism

(EPA)

(AA)

(DHA)

(LA) (ALA)

* ?

(DGLA)

Gamma linolenic acid, 18:3n6

20:3n6

20:4n6

3

Note the sn2 position

Phospholipase D mainly in plants

4

http://www.sivabio.50webs.com/ip3.htm

Kinase

(PIP2)

http://lipidlibrary.aocs.org/lipids/pi/index.htm

Membrane phospholipid involves in cellular signaling

Role of inositol triphosphate (IP3) and diacylglycerol (DAG) in intracellular signaling

Lippincott’s Illustrated Reviews: Biochemistry, 2011

5

J Allergy Clin Immunol 115: 1109-1117, 2005

Fatty acids in the sn-2 position or from the diet

Sources, metabolic fate and products of essential fatty acids

PG – prostaglandins; PGI – prostacyclin; TX –

thromboxane; LT – leukotriene; LX - lipoxin

Grouping summary

Substrate PG & TX LT

20:3ω6 1 3

20:4ω6 2 4

20:5ω3 3 5

6

From LTA4

12-lipoxygenase

LXA4 & A5

7

Figure 2 Biosynthetic pathways of prostaglandins and

leukotrienes from arachidonic acid and eicosapentaenoic acid.

www.john-libbey-eurotext.fr/e-docs/00/04/30/C...

20:4ω6 20:5ω3

[COX]

Leukotrienes (LTs)

Mediate allergic reactions & inflammation

20:46 “4 series” LTs

20: 53 “5 series” LTs

for activity - “4 series” >> “5 series”

“4 series” stimulate mucus production

constrict bronchial & GI smooth muscles

Therefore antagonists are useful against allergy / asthma

8

Some Functions of the Prostaglandins and Thromboxanes

PGI2, PGE1, PGD2 PGF2

increases increases

vasodilation vasoconstriction

cAMP bronchoconstriction

smooth muscle contraction

decreases

platelet aggregation TXA2

leukocyte aggregation increases

interleukin-1 and interleukin-2 vasoconstriction

T-cell proliferation platelet aggregation

lymphocyte migration lymphocyte proliferation

bronchoconstriction

http://www.adha.org/CE_courses/course15/art/jdh-sup172006-f001.jpg Anti-thrombotic effects

Pro-thrombotic effects

Platelets 血小板

Thrombus 血栓

Thrombosis 血栓塞

Summary effects of PGs and TXs

20:4n6 metabolites

TXA2 have PRO-thrombotic actions

PGI2 (prostacyclin) has ANTI-thrombotic actions

(T1/2 is around 40 seconds)

20:3n6 (evening primrose oil月見草油) metabolite

PGE1 has ANTI-thrombotic actions

20:5n3 (Eskimo diet)

PGE3 has ANTI-thrombotic actions

9

Nature 409:145-147, 2001 http://classroom.sdmesa.edu/eschmid/Chapter14-Zoo145.htm

PLA2 Steroids

Aspirin

Indomethacin

Phospholipase A2 activity determines precursor availability (inhibited by steroids)

Non-steroidal anti-inflammatory drugs (NSAIDs) suppress PG formation

10

Cyclooxygenase pathway for PGs and TXs will

be inhibited by non-steroidal anti-inflammatory

drugs such as aspirin and indomethacin. The

lipoxygenase pathway is not affected by

NSAIDs.

http://pharmacologycorner.com/antiplatelet-agents/

Aspirin inhibition of COX-1

decreases TXA2 production

BUT, also prevents synthesis

of PGI2 in endothelial cells

Figure 2.

Antithrombotic and prothrombotic platelet-vessel wall interactions. Nitric oxide (NO), also known as

endothelial-derived relaxing factor (EDRF), and prostacyclin (PGI2) are synthesized and released from

endothelial cells in response to stimulation. Prostacyclin2 is a prostaglandin derived from arachidonic acid

(AA) through an endoperoxide (EPO) intermediate. These compounds increase intracellular levels of cyclic

adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) in platelets, which inhibit

platelet activation, adhesion to the endothelium, and aggregation. Adenosine, which is synthesized from

adenosine triphosphate (ATP) and adenosine diphosphate (ADP) by endothelial cells, is rapidly taken up by

endothelial cells and erythrocytes. Circulating adenosine also increases intracellular cAMP levels in platelets.

Activated platelets synthesize and release a number of compounds, including EPO, thromboxane A2 (TXA2),

and ADP. The EPO derived from AA in platelets is converted to the prostaglandin TXA2. Both TXA2 and ADP

bind to receptors on the surfaces of other platelets, causing them to activate and promoting aggregation.

www.medscape.com/viewarticle/409696_2

11

Essential fatty acid metabolism and production of eicosanoids

Seki et al. Prostaglandinins & other Lipid Mediators 89:126-130, 2009

12

Seki et al. Prostaglandinins & other Lipid Mediators 89:126-130, 2009

In endothelial cells (aspirin & COX-2) In phagocytes

Alternatively, microbial cytochrome P450 can transform host-derived LTB5 to RvE1.

Resolvins are produced by the COX-2 pathway especially in the presence of aspirin.

DHA gives rise to RvD1, RvD2, RvD3 and RvD4.

Via another pathway, DHA also give rise to protectin D1 (brain)

Resolvins can reduce cellular inflammation by inhibiting the production and

transportation of inflammatory cells and chemicals to the sites of inflammation.

For example, RvE1 blocks ADP-stimulated and TXA2 receptor agonist stimulated

platelet aggregation BUT not collagen-induced platelet aggregation. Suggesting that

RvE1 blocks excessive aggregation but not physiologic coagulation. This may be a

mechanism underlying the antithrombotic effects of EPA.

RvE1 also inhibits airway inflammatory cell recruitment, ameliorates airway

hyperresponsiveness and decreases production of the proinflammatory cytokines

(opposite to the effects of LTB4).

Increase in EPA/DHA intake also increase precursors of resolvin E and D families via

CYP-dependent pathways. BUT resolvins were not detected (Fischer et al. J Lipid

Research 55: 1150-1164, 2014