Eicosanoids

Question 1

What are eicosanoids?

In what way are they similar to steroid hormones?

Answer 1

formed from 20C polyunsaturated arachidonic acid

ALSO: cannot be stored due to short half-life

Question 2

Where is arachidonic acid derived from?

Which enzyme is involved?

Structure.

Answer 2

cell membrane phospholipids
cleaved by phospholipase A₂

→ arachidonic acid

Question 3

List the 3 subclasses of eicosanoids.

Which pathway do they use for their synthesis?

Answer 3

• cyclooxygenase pathway → prostanoids (prostaglandins + thromboxanes)
• lipoxygenase pathway → leukotrienes + lipoxins

Question 4

What are desaturases?

List some common examples.

Answer 4

reduce FA to insert double bond

→ use NADPH/H⁺, FA dehydrated (= H₂O leaves)

• stearyl-CoA desaturase (Δ⁹)
• Δ⁴-, Δ⁵-, Δ⁶-desaturases insert add. double bond in unsaturated FA

Question 5

List the 2 essential polyunsaturated FAs.

Which substances can they form?

Answer 5

essential PUFAs = linoleic + α-linolenic acid

ω6 PUFA(s):

linoleic acid →→ arachidonic acid

ω3 PUFA:

α-linolenic acid →→ EPA →→ DHA

Question 6

What is PLA₂?

Differentiate btw its 2 types.

Answer 6

phospholipase that cleaves phospholipid at 2^nd position

• sPLA₂ = secretory, not arachidonic acid specific, involved in lipid digestion
• cPLA₂ = cytosolic, arachidonic acid specific, Ca²⁺ dependent

Question 7

Describe the COX pathway.

Which enzymes are involved?

Answer 7

1. PLA_{<u><strong>2</strong></u>}
   cleaves arachidonic acid from cell membrane phospholipid
2. PGH snythase
   converts it via PGG₂ to prostaglandin H₂
3. tissue specific synthases
   convert PGH₂ to … (cf. own card)

Question 8

Describe the structure of PGH synthase.

What is its function?

Answer 8

2 catalytic sites:

• cyclooxygenase activity: arachidonic acid → PGG₂
  O₂ dependent, uses heme-proteins
• peroxidase activity: PGG₂ → PGH₂
  by oxidation of glutathione

Question 9

Which substances are eventually formed from PGH₂ via the COX pathway?

Answer 9

• prostaglandins: PGD₂, PGE₂, PGF_2α, PGI₂
• thromboxane: TXA₂

Question 10

What is the consequence if a ω3 PUFA is used by PGH synthase instead of arachidonic acid?

Answer 10

also prostanoids formed, but less active inflammatory mediators

bc: the more double bounds, the less effective

Question 11

Describe the antagonistic action of TXA₂ and PGI₂.

Answer 11

both act via G receptors

• TXA₂ (in platelets) → ↑[Ca²⁺] → platelet aggregation + vasoconstriction
• PGI₂ (in endothelial cells) → ↑[cAMP] → inhibits platelet aggregation + vasodilation

Question 12

What is the function of PGD₂?

Where are they produced?

Why is it clinically important?

Answer 12

produced in mast cells
→ ↑[Ca²⁺] → pulmonary vasoconstriction + bronchoconstriction

⇒ associated w/ asthma

ALSO: v​asodilation + relaxation of GI and uterus (via cAMP)

Question 13

List effects of PGE₂.

Answer 13

• protection of gastric mucosa (cf. picture)
• brain: fever, pain
• via EP2, EP3, EP4 receptor:
  ↑[cAMP] ⇒ SM relaxation (bronchi, vessels, uterus, GI)

Question 14

What is the effect of PGF_2α?

Hence its effect is antagonistic to.. ?

Answer 14

via binding to FP receptor

↑[Ca²⁺] → SM contraction (bronchi, vessel wall, uterus, GI)

⇒ antagonistic effect to PGE₂

Question 15

Compare COX 1 and COX-2 w/r/t

• location
• binding specificity
• type of expression

Answer 15

Question 16

How do steroids affect the COX pathway?

Answer 16

inhibit PLA₂ + COX 2

Question 17

What are NSAIDs?

Differentiate.

Answer 17

non-steroidal anti-inflammatory drugs,
2 groups

• aspirin: acetylation of COX 1, 2 (cf. own card)
• others: reversible competitive inhibition

⇒ COX 1 and 2 blockers

Question 18

What are coxibs?

Answer 18

COX-2 inhibitors

Question 19

Explain the effect of aspirin.

Answer 19

acetylation causing..

• ..irreversibe inhibition of COX 1 in platelets:
  no TXA₂ produced → ↓platelet aggregation
• ..switched catalytic activity of COX 2 in endothelial cells:
  no PGI₂ produced → ↑platelet aggregation
  _{NOTE: altered COX is replaced after some time in endothelial cells, hence aspirin less potent there}

⇒ overall: ↓ blood coagulation
⇒ effective prevention of art. thrombosis

Question 20

What are the functions of stable PGE analogues?

Example.

Answer 20

= obviously analogues of PGE₂, e.g. misoprostol

• induce labor
• prevent gastric ulcer

Question 21

What are the adverse effects of NSAIDs?

Answer 21

e.g. aspirin
COX 1 blocked → no production of PGE₂
→ gastric erosion + ulcer

Question 22

Describe the lipoxygenase pathway.

Which enzymes are involved?

Answer 22

1. PLA₂
   cleaves arachidonic acid from cell membrane phospholipid
2. 5-lipoxygenase
   converts it to leukotriene A₄ (also O₂ dependent)
3. either: LTA₄ hydrolase, or LTC₄ synthase
   convert to LTB₄, LTC₄ resp. (cf. own cards)

Question 23

Which cells show 5-lipoxygenase activity?

When are they induced?

Answer 23

leukocytes, induced by inflammatory responses ↑[Ca2+]

• neutrophils
• macrophages
• mast cells

⇒ lipoxygenase pathway

Question 24

What is the function of LTB₄?

Which enzyme catalyzes its formation?

Where can this enzyme be found?

Answer 24

LTA₄ hydrolase
LTA₄ → LTB₄

• only expressed in neutrophils
• binds to B-LT1 receptor → chemotaxis (movement of leukocytes to site of inflammation)

Question 25

Which enzyme is involved for the formation LTC₄? Where can this enzyme be found?

Answer 25

**_LTC₄ synthase_** binds glutathione to LTA₄ → LTC₄ * expressed in macrophages, basophils, eosinophils

Question 26

How are LTD₄ and LTE₄ formed? Which enzymes is involved?

Answer 26

**_extracellular gamma-glutamyl-transpeptidase_** formed from LTC₄ 1. ​loses Glu → **LTD₄** 2. loses Gly → **LTE₄**

Question 27

What is the common function of LTC₄, LTD₄, and LTE₄?

Answer 27

_bind to CysLT1 receptor_ * *on airway SMC:* very strong **bronchoconst.** * *on vascular SMC:* **edema, Leu adhesion**

Question 28

Why are CysLT1 receptor inhibitors clinically important? Examples.

Answer 28

* **montelukast** (singulair) * **zafirkulast** (accolate) → decr. effect of LTC₄, LTD₄, LTE₄ ⇒ used to treat asthma, relax bronchial SMC

Question 29

Which substance inhibits 5-LO?

Answer 29

**zileuton** (Zyflo) → no production of LTA₄

Question 30

How are lipoxins produced? What is their function?

Answer 30

formed from AA via isoforms of **lipoxygenase → resolve inflammation**