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Biochemistry II > Eicosanoids > Flashcards

Eicosanoids Flashcards

1
Q

What are eicosanoids?

In what way are they similar to steroid hormones?

A

formed from 20C polyunsaturated arachidonic acid

ALSO: cannot be stored due to short half-life

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2
Q

Where is arachidonic acid derived from?

Which enzyme is involved?

Structure.

A

cell membrane phospholipids
cleaved by phospholipase A2

→ arachidonic acid

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3
Q

List the 3 subclasses of eicosanoids.

Which pathway do they use for their synthesis?

A
  • cyclooxygenase pathway → prostanoids (prostaglandins + thromboxanes)
  • lipoxygenase pathway → leukotrienes + lipoxins
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4
Q

What are desaturases?

List some common examples.

A

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
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5
Q

List the 2 essential polyunsaturated FAs.

Which substances can they form?

A

essential PUFAs = linoleic + α-linolenic acid

ω6 PUFA(s):

linoleic acid →→ arachidonic acid

ω3 PUFA:

α-linolenic acid →→ EPA →→ DHA

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6
Q

What is PLA2?

Differentiate btw its 2 types.

A

phospholipase that cleaves phospholipid at 2nd position

  • sPLA2 = secretory, not arachidonic acid specific, involved in lipid digestion
  • cPLA2 = cytosolic, arachidonic acid specific, Ca2+ dependent
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7
Q

Describe the COX pathway.

Which enzymes are involved?

A
  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)
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8
Q

Describe the structure of PGH synthase.

What is its function?

A

2 catalytic sites:

  • cyclooxygenase activity: arachidonic acid → PGG2
    O2 dependent, uses heme-proteins
  • peroxidase activity: PGG2 → PGH2
    by oxidation of glutathione
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9
Q

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

A
  • prostaglandins: PGD2, PGE2, PGF2α, PGI2
  • thromboxane: TXA2
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10
Q

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

A

also prostanoids formed, but less active inflammatory mediators

bc: the more double bounds, the less effective

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11
Q

Describe the antagonistic action of TXA2 and PGI2.

A

both act via G receptors

  • TXA2 (in platelets) → ↑[Ca2+] → platelet aggregation + vasoconstriction
  • PGI2 (in endothelial cells) → ↑[cAMP] → inhibits platelet aggregation + vasodilation
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12
Q

What is the function of PGD2?

Where are they produced?

Why is it clinically important?

A

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

⇒ associated w/ asthma

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

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13
Q

List effects of PGE2.

A
  • protection of gastric mucosa (cf. picture)
  • brain: fever, pain
  • via EP2, EP3, EP4 receptor:
    ↑[cAMP] ⇒ SM relaxation (bronchi, vessels, uterus, GI)
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14
Q

What is the effect of PGF2α?

Hence its effect is antagonistic to.. ?

A

via binding to FP receptor

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

⇒ antagonistic effect to PGE2

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15
Q

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

  • location
  • binding specificity
  • type of expression
A
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16
Q

How do steroids affect the COX pathway?

A

inhibit PLA2 + COX 2

17
Q

What are NSAIDs?

Differentiate.

A

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

18
Q

What are coxibs?

A

COX-2 inhibitors

19
Q

Explain the effect of aspirin.

A

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

20
Q

What are the functions of stable PGE analogues?

Example.

A

= obviously analogues of PGE2, e.g. misoprostol

  • induce labor
  • prevent gastric ulcer
21
Q

What are the adverse effects of NSAIDs?

A

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

22
Q

Describe the lipoxygenase pathway.

Which enzymes are involved?

A
  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)
23
Q

Which cells show 5-lipoxygenase activity?

When are they induced?

A

leukocytes, induced by inflammatory responses ↑[Ca2+]

  • neutrophils
  • macrophages
  • mast cells

⇒ lipoxygenase pathway

24
Q

What is the function of LTB4?

Which enzyme catalyzes its formation?

Where can this enzyme be found?

A

LTA4 hydrolase
LTA4 → LTB4

  • only expressed in neutrophils
  • binds to B-LT1 receptor → chemotaxis (movement of leukocytes to site of inflammation)
25
Q

Which enzyme is involved for the formation LTC4?

Where can this enzyme be found?

A

LTC4 synthase
binds glutathione to LTA4 → LTC4

  • expressed in macrophages, basophils, eosinophils
26
Q

How are LTD4 and LTE4 formed?

Which enzymes is involved?

A

extracellular gamma-glutamyl-transpeptidase

formed from LTC4

  1. ​loses Glu → LTD4
  2. loses Gly → LTE4
27
Q

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

A

bind to CysLT1 receptor

  • on airway SMC: very strong bronchoconst.
  • on vascular SMC: edema, Leu adhesion
28
Q

Why are CysLT1 receptor inhibitors clinically important?

Examples.

A
  • montelukast (singulair)
  • zafirkulast (accolate)

→ decr. effect of LTC4, LTD4, LTE4

⇒ used to treat asthma, relax bronchial SMC

29
Q

Which substance inhibits 5-LO?

A

zileuton (Zyflo)

→ no production of LTA4

30
Q

How are lipoxins produced?

What is their function?

A

formed from AA via isoforms of lipoxygenase
→ resolve inflammation

Biochemistry II (16 decks)

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