Block 3 Eicosanoids & Active Lipids

Question 1

What are eicosanoids? Examples? What cells produce them?

Answer 1

C20 compounds; prostaglandins, prostacyclins, thromboxanes, leukotrienes; all cells but RBCs

Question 2

What are the functions of eicosanoids?

Answer 2

Mediate inflam (RA, psoriasis, eyes), pain/fever, BP, blood clotting, repro fxns like labor induction, sleep/wake reg

Question 3

What is the structure of AA?

Answer 3

5,8,11,14-eicosatetraenoic acid; a w6 FA, synthesized from linoleic acid elong/desat

Question 4

What is found in esterified glyceroPLs on C2?

Answer 4

Arachidonic acid

Question 5

What are the three pathways to release AA from membrane?

Answer 5

1) PI + PLC -> 1,2-DAG + DAG-K -> PA + PLA2 -> lysoPA + AA
2) 1,2-DAG + DAG lipase -> MAG + AA
3) PI + PLA2 -> lysoPL + AA

Question 6

What is the cyclic pathway of AA metabolism?

Answer 6

AA + COX -> PGG2 -> thromboxanes, PGs, PC

Question 7

What is the linear pathway of AA metabolism?

Answer 7

AA + lipoxygenase -> HPETE -> LKTs, HETE, lipoxins

Question 8

What are prostaglandins?

Answer 8

Derivatives of C20 prostanoic acid (cyclopentane ring C8-12)

Question 9

Describe the steps and enzymes of the cyclic AA metab pathway.

Answer 9

PL + PLA2 -> AA + COX -> cyclic endoperoxidases -> PGI2, PGF2a, PGD2, PGE2, TXA2

Question 10

How do glucocorticoids and NSAIDS affect the cyclic AA pathway?

Answer 10

Glucocorticoids inhibit PLA2 (PL -> AA), decrease synth

NSAIDS inhibit COX-1,2 (irr aspirin, or reversible acet, ibu)

Question 11

What are functions and site of PGI2?

Answer 11

Kidney & vascular endothelium; vasodilator, hyperalgesic, stops platelet agg

Question 12

What are functions and site of PGF2a?

Answer 12

Uterus; bronchoconstrictor, myometrial contractions

Question 13

What are functions and site of PGD2?

Answer 13

Mast cells; vasodilator, inhibits platelet agg

Question 14

What are functions and site of PGE2?

Answer 14

Macrophages; vasodilator, hyperalgesic

Question 15

What are functions and site of TXA2?

Answer 15

Platelets; thrombotic vasoconstrictor

Question 16

What is COX? What are its other names?

Answer 16

First step of PG synthesis with COX and perox activity, and heme; adds 2 O2, then converts hydroperoxy fxn of PGG2 to OH
*AKA PHG2 synthase, PG endoperoxide synthase

Question 17

What are the isoforms of COX?

Answer 17

COX-1: constitutive in many cells, physiological regulation

COX-2: inducible as part of inflam response

Question 18

What is PGH2?

Answer 18

The immediate precursor to all series-2 PGs, prostacyclin, and thromboxanes

Question 19

What enzymes convert PGH2 to PGI2 prostacyclin and TXA2?

Answer 19

PGI synthase or TXA synthase

Question 20

How do COX-2 selective inhibitors work?

Answer 20

Inhibit COX-2 only to limit - effects on GI lining b/c general inhibition PG synthesis

Question 21

How does aspirin affect PG synthesis?

Answer 21

Irreversible COX inhibitor, acetylates Ser not in catalytic site to block AA access to site; inh platelet agg w/o harming vasc endo

Question 22

How do acetaminophen and ibuprofen work?

Answer 22

Reversible COX inhibitors bind in COX channel, blocking active site

Question 23

What PGs does the heart make?

Answer 23

PGI2, PGE2, PGF2a

Question 24

How are PGs like and unlike hormones?

Answer 24

Like: low concentration = big effect, many intracellular effects by cAMP
Unlike: local mediators (auto and paracrine), chemically unstable (minutes)

Question 25

How are PGs released from cells, and what kind of receptors are on target cells?

Answer 25

PG transporter (PGT); to EP, FP, IP, etc. receptors (GPCRs)

Question 26

How are PGs inactivated and excreted?

Answer 26

Inact: 15-hydroxy-PG DH

Then oxidized to be more polar and excreted

Question 27

What are the enzymes and products of the linear AA metab pathway?

Answer 27

5-, 12-, and 15-lipoxygenase (LO) to HPETES: hepoxin (from 12-LPO), lipoxins (15-LPO), leukotrienes (5-LPO)

Question 28

What are LTC4, LTD4, and LTE4?

Answer 28

LKTs, components of slow-reacting substances to anaphylaxis (SRS-A) by contracting vasculature, resp/int SM, increase mucus secretion in airway; impl in type 1 HS, inflam, MI

Question 29

How are LKTs synthesized?

Answer 29

5-HPETE unstable epoxide LTA4 -> GSH S-transferase -> LTC4 -> extracellularly LTD4 - glycine -> LTE
OR LTA4 -> LTB4 to fight infection

Question 30

What are the 4 known receptors of LKTs?

Answer 30

B-LT1 on leukos binds LTB4 with high aff
B-LT2 ubiquitous binds LTB4 low aff
CysLT on airway SMC, endo binds LTC/D4
CysLT2 in heart, adrenal, spleen binds LTD4

Question 31

What is a FLAP (5-LO activating protein)?

Answer 31

Required for 5-LO activity, binds AA and helps intx bt enzyme, substrate, membrane; inh by MK0886

Question 32

What types of drugs are used in long-term maintenance of asthma control?

Answer 32

CysLT1 receptor antagonist (Accolate/Singulair)

Question 33

What are isoprostanes?

Answer 33

PGs produced non-enzymatically by ROS, excretion in urine a measure of ox stress (PLA2 removes FA/AA damaged by lipid perox)

Question 34

What is anandamide? How might its effects be prolonged?

Answer 34

An endocannabinoid of ethanolamine amide linked to AA; inhibition FA amide hydrolase prolongs effects

Question 35

What are endocannabinoids?

Answer 35

Analgesic effects on NS, made when AA + PE in membrane, release by special PLD

Question 36

What is the major component of marine lipids? What is it the precursor for?

Answer 36

EPA (w3 FA); precursor of series 5 LKTs (lower activity than AA-derived series 4) & inhibits TxA2

Question 37

What are the effects of dietary EPA?

Answer 37

Inhibit agg of neutros, decreases chol/TG levels in hyperTG patients

Question 38

What are the pro-resolving mediators derived from EPA and DHA?

Answer 38

EPA: E-series resolvins
DHA: D-series resolvins, protectins, maresins