Eicosanoids Flashcards
What are the FOUR subfamilies of Eicosanoids?
- Prostaglandins
- Prostacyclin
- Thromboxanes
- Leukotrienes
What is the structure of Eicosanoids?
20-carbon fatty acid derivative
What are Eicosanoids synthesised from?
- Polyunsaturated fatty acids
- Particularly Arachidonic Acid
What is the structure of Arachidonic Acid?
20 C:4 unsaturated bond structure
Are Eicosanoids soluble in water?
No.
Poorly soluble in water
What are the functions of Eicosanoids?
Act as autocrine or paracrine local mediators
Where do Eicosanoids bind to receptors?
Cell surface
What receptors do Eicosanoids bind and how does signalling occur?
7-TM receptors and signalling occurs via heterotrimeric G-proteins (GCPRs)
What biological functions are Eicosanoids involved in?
- Inflammation
- Pain sensation
- Platelet aggregation
- Asthma
Are Eicosanoids stored or produced on demand?
Produced on demand
When are Eicosanoids synthesised?
When a cell is activated by mechanical trauma, growth factors, cytokines, or other stimuli
How is the rate of release of Eicosanoids determined?
Mainly by rate of synthesis, which is dependent on availability of precursor (arachidonic acid)
What type of fatty acid is Arachidonic Acid?
- Essential fatty acid
- Cannot be synthesised from scratch
Where is Arachidonic Acid normally present?
In cells that are esterified at the 2-position in phospholipids
How is Arachidonic Acid released from phospholipids?
By the action of phospholipase A2 (PLA2) enzymes
What is the mechanism of action in the production of Eicosanoids from Arachidonic Acid?
- Arachidonic Acid released at ER and nuclear membranes by PLA2 and presented to prostaglandin H synthase (PGHS / COX)
- PGHS / COX converts arachidonic acid to prostaglandin H2 (PGH2)
- Enzymatically catalysed reduction or isomerisation of PGH2 generates eicosanoids
How is PLA2 regulated?
Phosphorylation and an influx of Ca2+ which triggers PLA2 activation and translocation to the nuclear membrane
Which amino acid does phosphorylation of PLA2 occur on?
Serine-505
What causes the phosphorylation of PLA2?
Result of ligand binding to receptors such as the interferon receptors, mGLUR1, etc
What inhibits PLA2 and reduces inflammation?
Glucocorticoids stimulate the release of lipoprotein
How is Arachidonic Acid generated?
- By the action of Phospholipase C (PLC) on phospholipids to form DAG
- Cleaved by DAG lipase to form Arachidonic Acid and monoacylglycerol
What are the TWO isoforms of Prostaglandin H synthase?
- COX-1
- COX-2
What is the function of COX-1?
Responsible for basal prostaglandin synthesis
What is the function of COX-2?
Important for induced prostaglandin synthesis (inflammatory response)
What major group of anti-inflammatory drugs target Eicosanoid biosynthesis?
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
What do NSAIDs target in Eiscosanoid biosynthesis?
COX-1 and COX-2
Which isoform of Prostaglandin H synthase is the target preference for NSAIDs in Eicosanoid biosynthesis?
COX-2
Which classical NSAIDs inhibit COX-1 and COX-2?
Aspirin and Ibuprofen
What causes the anti-coagulant properties of Aspirin?
Inhibits the formation of Thromboxane A2
* released by platelets and causes aggregation
TRUE OR FALSE:
Eicosanoids often act in agonist pairs
False.
Act in ANTAGONIST pairs
How are Leukotrienes synthesised?
By Lipo-Oxygenases
How are Leukotrienes modified?
Conjugation to more polar molecules such as Glutathione (Leukotriene C4) or Cysteinylglycine (Leukotriene D4)
How do Leukotrienes affect airway smooth muscle?
Cause contraction
(LTD4)
What are TWO examples of lipophilic hormones that bind cell surface receptors?
- Platelet Activating Factor (PAF)
- Lysophosphatidic Acid (LPA)
What effect does Lysophosphatidic Acid (LPA) have on target cells?
- Stimulation of growth
- Cell division
- Transformation
- Alteration of cell morphology
