Lipid metabolism – IV: Eicosanoid Metabolism. Synthesis of Prostaglandins and related compounds. Role in inflammation

Question 1

What are the two most common monounsaturated fatty acids in animal tissues, and what are their precursors?

Answer 1

Palmitoleate [16:1(Δ⁹)] and oleate [18:1(Δ⁹)], derived from palmitate (16:0) and stearate (18:0), respectively.

Question 2

Which enzyme introduces a cis double bond at the Δ⁹ position in fatty acids?

Answer 2

Fatty acyl-CoA desaturase.

Question 2

Why can’t humans synthesize arachidonate de novo?

Answer 2

Humans lack enzymes to introduce double bonds beyond the Δ⁹ position. Arachidonate is instead derived from linolenate (an essential fatty acid obtained from the diet).

Question 2

What is the role of phospholipase A₂ in eicosanoid synthesis?

Answer 2

It releases arachidonate from membrane phospholipids, making it available for eicosanoid biosynthesis.

Question 2

How does aspirin inhibit prostaglandin synthesis?

Answer 2

It irreversibly acetylates a serine residue in COX-1 and COX-2, blocking their cyclooxygenase activity.

Question 2

Name the two isoforms of prostaglandin H₂ synthase (COX) and their primary functions.

Answer 2

COX-1: Maintains gastric mucin secretion. COX-2: Mediates inflammation, pain, and fever.

Question 2

What medical benefit does low-dose aspirin provide?

Answer 2

Reduces thromboxane A₂ production, lowering the risk of heart attacks and strokes by inhibiting platelet aggregation.

Question 2

Which enzyme converts PGH₂ to thromboxane A₂, and where is it found?

Answer 2

hromboxane synthase, present in blood platelets (thrombocytes).

Question 3

What distinguishes the synthesis of leukotrienes from prostaglandins/thromboxanes?

Answer 3

Leukotrienes use a linear pathway with lipoxygenases, while prostaglandins/thromboxanes use the COX-mediated cyclic pathway.

Question 3

Which eicosanoids are synthesized via lipoxygenases, and what is their primary role?

Answer 3

Leukotrienes (e.g., LTC₄, LTD₄). They mediate inflammation and bronchoconstriction and are not inhibited by NSAIDs.

Question 3

Why is linolenate considered an essential fatty acid?

Answer 3

Humans cannot synthesize it; it must be obtained from the diet to produce arachidonate and other polyunsaturated fatty acids.

Question 3

: Name three types of eicosanoids and their general effects.

Answer 3

Prostaglandins: Regulate inflammation, pain, fever.

Thromboxanes: Promote vasoconstriction and platelet aggregation.

Leukotrienes: Cause bronchoconstriction and allergic responses.

Question 3

What structural feature defines arachidonate?

Answer 3

20:4(Δ⁵,⁸,¹¹,¹⁴) – a 20-carbon chain with four cis double bonds at positions 5, 8, 11, and 14.

Question 3

Which dietary source provides precursors for omega-3 fatty acids?

Answer 3

Fish oils and plant sources (e.g., flaxseeds), which supply α-linolenic acid (18:3, Δ⁹,¹²,¹⁵).

Question 3

How do NSAIDs like ibuprofen differ from acetaminophen?

Answer 3

NSAIDs inhibit both COX-1 and COX-2, reducing prostaglandin synthesis. Acetaminophen primarily targets COX-2 in the brain (weak peripheral action).

Question 3

Which leukocyte-derived molecules are involved in asthma pathophysiology?

Answer 3

Leukotrienes (e.g., LTC₄, LTD₄), which induce bronchoconstriction and inflammation.

Question 3

Why is linolenate (18:3 Δ⁹,¹²,¹⁵) considered an essential fatty acid?

Answer 3

Humans lack Δ¹² and Δ¹⁵ desaturases; linolenate must be obtained from the diet to synthesize arachidonate (20:4) and omega-3 FAs.

Question 3

What is the role of γ-linolenate in fatty acid metabolism?

Answer 3

It is an intermediate (18:3, Δ⁶,⁹,¹²) in the pathway converting linolenate to arachidonate.

Question 3

Why are COX-2 inhibitors preferred for pain relief over COX-1 inhibitors?

Answer 3

COX-2 inhibitors reduce inflammation without disrupting COX-1-mediated gastric protection.

Question 3

What enzyme activity does prostaglandin H₂ synthase possess?

Answer 3

Cyclooxygenase (adds two oxygen molecules to arachidonate) and peroxidase (reduces hydroperoxide groups).

Question 3

Which eicosanoid is produced by endothelial cells to inhibit platelet aggregation?

Answer 3

Prostacyclin (PGI₂), synthesized from PGH₂ via prostacyclin synthase.

Question 3

What enzyme introduces the first double bond (Δ⁹) in palmitate and stearate to form palmitoleate and oleate?

Answer 3

Fatty acyl-CoA desaturase.

Question 3

How do COX-1 and COX-2 differ in function and clinical significance?

Answer 3

COX-1: Constitutively active; protects gastric mucosa and regulates platelet function.

COX-2: Induced during inflammation; mediates pain, fever, and inflammation.
Drug Note: NSAIDs inhibit both; COX-2 inhibitors spare gastric mucosa.

Question 3

Which enzyme releases arachidonate from membrane phospholipids, initiating eicosanoid synthesis?

Answer 3

Phospholipase A₂.
Clinical Link: Glucocorticoids inhibit this enzyme, reducing inflammation.

Question 4

Why does low-dose aspirin reduce cardiovascular risk?

Answer 4

Irreversibly inhibits platelet COX-1, blocking thromboxane A₂ (TXA₂) synthesis and platelet aggregation. Trick Detail: Endothelial cells regenerate COX-1, but platelets cannot.

Question 5

A patient with asthma exacerbation does not respond to NSAIDs. Why?

Answer 5

Leukotrienes (via lipoxygenase) drive bronchoconstriction, unaffected by COX inhibitors. Use leukotriene receptor antagonists (e.g., montelukast).

Question 6

Which eicosanoid promotes vasodilation and inhibits platelet aggregation, countering TXA₂?

Answer 6

Prostacyclin (PGI₂), synthesized by endothelial cells via prostacyclin synthase.

Question 7

What structural feature distinguishes arachidonate (20:4) from other fatty acids?

Answer 7

20 carbons with four cis double bonds at Δ⁵,⁸,¹¹,¹⁴. Exam Tip: Memorize "20:4 Δ5,8,11,14" for biosynthesis questions.

Question 8

Which enzyme converts PGH₂ to thromboxane A₂, and where is it found?

Answer 8

Thromboxane synthase, located in platelets. Clinical Link: Aspirin’s antiplatelet effect lasts 7–10 days (platelet lifespan).

Question 9

Why might chronic NSAID use cause peptic ulcers?

Answer 9

COX-1 inhibition reduces gastric mucin and bicarbonate secretion, increasing acid damage.

Question 10

Which eicosanoid pathway is targeted by zileuton, and for what condition?

Answer 10

Lipoxygenase pathway (leukotriene synthesis). Used in asthma to block LTB₄/LTC₄ production.

Question 11

What is the role of γ-linolenate (18:3 Δ⁶,⁹,¹²) in humans?

Answer 11

Intermediate in converting dietary linolenate to arachidonate. Trick Fact: Plants, not humans, can synthesize γ-linolenate.

Question 12

Which eicosanoids mediate fever, pain, and vasodilation?

Answer 12

Prostaglandins (e.g., PGE₂). Drug Example: Acetaminophen reduces brain COX-2, lowering fever without GI effects.

Question 13

How do leukotrienes contribute to anaphylaxis?

Answer 13

LTC₄ and LTD₄ cause bronchoconstriction, vascular leakage, and chemotaxis (e.g., in peanut allergy).

Question 14

What is the mechanism of irreversible COX inhibition by aspirin?

Answer 14

Acetylation of serine residue (Ser530 in COX-1), blocking arachidonate binding. Contrast: Ibuprofen is a reversible competitive inhibitor.

Question 15

Which dietary components are precursors for anti-inflammatory resolvins and protectins?

Answer 15

Omega-3 fatty acids (e.g., EPA/DHA from fish oil). Clinical Link: Used in managing chronic inflammation (e.g., rheumatoid arthritis).

Question 16

Why is PGF₂α clinically administered during labor?

Answer 16

Induces uterine contractions (used in obstetrics for induction/augmentation).

Question 17

Which lab finding suggests thromboxane synthase deficiency?

Answer 17

Prolonged bleeding time (reduced TXA₂ → impaired platelet aggregation).

Question 18

What distinguishes the synthesis of prostaglandins from leukotrienes?

Answer 18

Prostaglandins: Cyclic pathway via COX (cyclooxygenase). Leukotrienes: Linear pathway via lipoxygenase.

Question 19

Which eicosanoid is elevated in allergic rhinitis, and what drug class targets it?

Answer 19

Leukotriene D₄ (LTD₄); treated with leukotriene receptor antagonists (e.g., montelukast).