Eicosanoids: Local Signaling, Pathways, and Enzyme Functions in Inflammation

What are eicosanoids?

Potent, short-lived signaling molecules produced locally by many tissues.

What is the most common source of eicosanoids in humans?

Arachidonic acid.

What are the major groups of eicosanoids discussed in the lecture?

Prostaglandins (PG), thromboxanes (TX), and leukotrienes (LT).

What is the significance of eicosanoids being short-lived?

They exert effects locally and are rapidly metabolized to inactive products.

What is the direct pathway for the liberation of arachidonic acid?

Receptor signaling activates PLA₂, which cleaves arachidonic acid from membrane phospholipids.

What is the indirect pathway for the liberation of arachidonic acid?

Receptor signaling activates PLC, producing IP₃, which increases intracellular Ca²⁺ and stimulates PLA₂.

Which enzyme converts arachidonic acid into prostaglandins?

Cyclooxygenase (COX).

What is the role of thromboxane synthase?

It converts PGH₂ to TXA₂.

What enzyme produces HETEs and leukotrienes from arachidonic acid?

Lipoxygenase.

What is the difference between 5-, 12-, and 15-lipoxygenase?

The number indicates the carbon position at which oxygen is incorporated, and activity is tissue-dependent.

What structural feature at carbon 15 indicates biological activity in prostaglandins and thromboxanes?

A hydroxyl (-OH) group.

What happens to the 15-hydroxyl group during inactivation of prostaglandins?

It is oxidized to a ketone, which terminates activity.

What is the carbon skeleton of prostaglandins and thromboxanes?

Both have a 20-carbon fatty acid skeleton.

What does the capital letter in PGA, PGE, PGF, etc. signify?

It designates the substituents attached to the ring.

How is the series of prostaglandins determined?

By the number of double bonds in the non-ring portion of the hydrocarbon chain.

What is the general association of Series 1 prostaglandins?

More commonly anti-inflammatory.

What is the general association of Series 2 prostaglandins?

More commonly inflammatory.

What is the key distinction between aspirin, ibuprofen, and acetaminophen regarding COX inhibition?

Aspirin is irreversible, ibuprofen is competitive/reversible, and acetaminophen is competitive but not an NSAID.

What is the mechanism of action of NSAIDs?

They inhibit cyclooxygenase (COX), decreasing prostaglandin formation.

What is the significance of the hydroxyl group at carbon 15 in eicosanoids?

It indicates that the molecule is active; oxidation to a ketone inactivates it.

What is the role of phospholipase A₂ (PLA₂) in eicosanoid synthesis?

It releases arachidonic acid from membrane phospholipids.

What is the function of phospholipase C (PLC) in the indirect pathway?

It produces IP₃, which leads to an increase in intracellular Ca²⁺ and activates PLA₂.

What are the breakdown products of eicosanoids?

They are excreted in urine.

What is the half-life of eicosanoids?

Seconds to minutes.

What does the numerical subscript in TXA₂ indicate?

The number of double bonds in the linear/non-ring portion of the hydrocarbon chain.

What is the key recognition rule for identifying the indirect pathway of arachidonic acid liberation?

If IP₃ and increased cytosolic Ca²⁺ are present before PLA₂ activation, it is the indirect pathway.

What is the role of DAG lipase in the eicosanoid pathway?

It can liberate arachidonic acid associated with DAG.

What is the significance of the 5-membered ring in prostaglandins?

It is a distinguishing structural feature of prostaglandins.

What is the significance of the 6-membered ring in thromboxanes?

It is a distinguishing structural feature of thromboxanes.