Eicosanoids Flashcards
Def of eicosanoids
A lipid mediator of inflammation derived from the 20-carbon atom arachidonic acid or Eicosapentaenoic acid (EPA)
Steps of omega 3 FA
Alpha-linolenic acid (ALA, C18:3) is the precursor for eicosapentaenoic acid (EPA, C20:5) and EPA can be further metabolized to docosahexaenoic acid (DHA, C22:6)
Steps of omega 6 FA
Linoleic acid (C18:2) is the precursor for arachidonic acid (AA, C20:4)
What defines an essential fatty acid?
The presence of a double bond within 6 carbons of the methyl end of the fatty acid chain defines an essential fatty acid.
This is because humans do not express a desaturase enzyme capable of introducing a double bond within 6 carbons of the methyl end of a fatty acid.
What are the 3 eicosanoid production pathways
- cyclooxygenase pathway for prostaglandin and thromboxane synthesis
- lipoxygenase pathway for leukotriene synthesis
- cytochrome P450 pathways for epoxide synthesis
first step in eicosanoid synthesis in cyclooxygenase pathway
release of arachidonic acid from glycerophospholipids in the plasma membrane
How is PLA2 involved in ecodanoid synthesis
Arachidonic acid is a fatty acid and is incorporated into glycerophospholipids. In glycerophospholipid synthesis, acyltransferases catalyze the ester linkage between the carboxylic group of a FA with the hydroxyl groups of the glycerol backbone. Typically unsaturated FAs are located at the C that is proximal to the C with the phosphate group, the site that is recognized by phospholipase A2 (PLA2). Thus, stimuli that activate PLA2 control eicosanoid synthesis by increasing free AA levels (substrate supply).
Difference between COX-1 and COX-2
COX-1 is constitutively expressed in most tissues and can be induced in the vasculature upon sheer stress.
COX-2 has a more restricted expression and is associated with inflammation.
The COX enzyme has two catalytic activities:
a cyclooxygenase (COX) activity that generates the PGG2 intermediate and a peroxidase (POX) activity that generates PGH2 (prostaglandin endoperoxide H2)
How do NSAIDs work
NSAIDs target the cyclooxygenase activity of the COX enzymes and decrease prostaglandin and thromboxane synthesis. NSAIDs are anti-pyretic (fever reducing), analgesic (pain reducing) and anti-inflammatory.
Aspirin mechanism of action
Aspirin is an irreversible inhibitor of COX-1 in platelets. Acetylsalicylate (aspirin) transacetylates COX at a serine residue within the active site of the enzyme
Ibuprofen and naproxen mechanisms
reversible competitive inhibitors of the cyclooxygenase enzymatic activity of both COX-1 and COX-2 (so are nonselective)
potential problems associated with long-term aspirin use
COX-1 responses are part of normal physiolog, so Decreased mucus and bicarbonate levels in the GI leading to gastrointestinal disorders bc PGE2 and PGI2 (peptic ulcers) , inhibition of platelet aggregation and increased bleeding, and renal disorders resulting in fluid retention
What is Celecoxib
a COX-2 specific inhibitor that is marketed as an anti-inflammatory drug for the treatment of osteoarthritis and rheumatoid arthritis
Why would CHD patients take aspirin daily
The therapeutic target in this case is to reduce thromboxane A2 (TXA2) synthesis in platelets to reduce platelet aggregation and artery plaque build up. The use of aspirin is key as this is an irreversible inhibitor of the COX-1 enzyme.
5-LOX pathway
5-LOX (5‑lipoxygenase) generates 5-HPETE which is converted to the leukotriene LTA4. LTA4 is the common precursor for the leukotrienes LTB4 and LTC4. The addition of glutathione to LTA4 generates LTC4. Modification of the glutathione moiety of LTC4 by loss of glutamate generates LTD4 and further loss of glycine produces LTE4.
12-LOX and 15-LOX pathways
HPETEs are reduced to hydroxyeicosatetraenoic acids (HETEs). 12-HETE and 15-HETE are major end products of these pathways.
Function and mechanism of glucocorticoids
Anti-inflammatory glucocorticoids inhibit PLA2 and block the release of AA from plasma membrane glycerophospholipids
Bind to glucocorticoid receptor (GR), which then targets lipocortin that controls PLA2. Lipocortin binds to PLA2 and inhibits activity. The consequence is reduced free arachidonic acid levels leading to reduced eicosanoid synthesis. Basically, decrease substrate availability.
