14_lcpufa eicosanoids (2014)
DESCRIPTION
HKU science lecture notesTRANSCRIPT
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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
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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
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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
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From LTA4
12-lipoxygenase
LXA4 & A5
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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
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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
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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
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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
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Essential fatty acid metabolism and production of eicosanoids
Seki et al. Prostaglandinins & other Lipid Mediators 89:126-130, 2009
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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