Block 3 Eicosanoids & Active Lipids Flashcards
What are eicosanoids? Examples? What cells produce them?
C20 compounds; prostaglandins, prostacyclins, thromboxanes, leukotrienes; all cells but RBCs
What are the functions of eicosanoids?
Mediate inflam (RA, psoriasis, eyes), pain/fever, BP, blood clotting, repro fxns like labor induction, sleep/wake reg
What is the structure of AA?
5,8,11,14-eicosatetraenoic acid; a w6 FA, synthesized from linoleic acid elong/desat
What is found in esterified glyceroPLs on C2?
Arachidonic acid
What are the three pathways to release AA from membrane?
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
What is the cyclic pathway of AA metabolism?
AA + COX -> PGG2 -> thromboxanes, PGs, PC
What is the linear pathway of AA metabolism?
AA + lipoxygenase -> HPETE -> LKTs, HETE, lipoxins
What are prostaglandins?
Derivatives of C20 prostanoic acid (cyclopentane ring C8-12)
Describe the steps and enzymes of the cyclic AA metab pathway.
PL + PLA2 -> AA + COX -> cyclic endoperoxidases -> PGI2, PGF2a, PGD2, PGE2, TXA2
How do glucocorticoids and NSAIDS affect the cyclic AA pathway?
Glucocorticoids inhibit PLA2 (PL -> AA), decrease synth
NSAIDS inhibit COX-1,2 (irr aspirin, or reversible acet, ibu)
What are functions and site of PGI2?
Kidney & vascular endothelium; vasodilator, hyperalgesic, stops platelet agg
What are functions and site of PGF2a?
Uterus; bronchoconstrictor, myometrial contractions
What are functions and site of PGD2?
Mast cells; vasodilator, inhibits platelet agg
What are functions and site of PGE2?
Macrophages; vasodilator, hyperalgesic
What are functions and site of TXA2?
Platelets; thrombotic vasoconstrictor
What is COX? What are its other names?
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
What are the isoforms of COX?
COX-1: constitutive in many cells, physiological regulation
COX-2: inducible as part of inflam response
What is PGH2?
The immediate precursor to all series-2 PGs, prostacyclin, and thromboxanes
What enzymes convert PGH2 to PGI2 prostacyclin and TXA2?
PGI synthase or TXA synthase
How do COX-2 selective inhibitors work?
Inhibit COX-2 only to limit - effects on GI lining b/c general inhibition PG synthesis
How does aspirin affect PG synthesis?
Irreversible COX inhibitor, acetylates Ser not in catalytic site to block AA access to site; inh platelet agg w/o harming vasc endo
How do acetaminophen and ibuprofen work?
Reversible COX inhibitors bind in COX channel, blocking active site
What PGs does the heart make?
PGI2, PGE2, PGF2a
How are PGs like and unlike hormones?
Like: low concentration = big effect, many intracellular effects by cAMP
Unlike: local mediators (auto and paracrine), chemically unstable (minutes)
How are PGs released from cells, and what kind of receptors are on target cells?
PG transporter (PGT); to EP, FP, IP, etc. receptors (GPCRs)
How are PGs inactivated and excreted?
Inact: 15-hydroxy-PG DH
Then oxidized to be more polar and excreted
What are the enzymes and products of the linear AA metab pathway?
5-, 12-, and 15-lipoxygenase (LO) to HPETES: hepoxin (from 12-LPO), lipoxins (15-LPO), leukotrienes (5-LPO)
What are LTC4, LTD4, and LTE4?
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
How are LKTs synthesized?
5-HPETE unstable epoxide LTA4 -> GSH S-transferase -> LTC4 -> extracellularly LTD4 - glycine -> LTE
OR LTA4 -> LTB4 to fight infection
What are the 4 known receptors of LKTs?
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
What is a FLAP (5-LO activating protein)?
Required for 5-LO activity, binds AA and helps intx bt enzyme, substrate, membrane; inh by MK0886
What types of drugs are used in long-term maintenance of asthma control?
CysLT1 receptor antagonist (Accolate/Singulair)
What are isoprostanes?
PGs produced non-enzymatically by ROS, excretion in urine a measure of ox stress (PLA2 removes FA/AA damaged by lipid perox)
What is anandamide? How might its effects be prolonged?
An endocannabinoid of ethanolamine amide linked to AA; inhibition FA amide hydrolase prolongs effects
What are endocannabinoids?
Analgesic effects on NS, made when AA + PE in membrane, release by special PLD
What is the major component of marine lipids? What is it the precursor for?
EPA (w3 FA); precursor of series 5 LKTs (lower activity than AA-derived series 4) & inhibits TxA2
What are the effects of dietary EPA?
Inhibit agg of neutros, decreases chol/TG levels in hyperTG patients
What are the pro-resolving mediators derived from EPA and DHA?
EPA: E-series resolvins
DHA: D-series resolvins, protectins, maresins
