Eicosanoid Biochemistry Flashcards
Eicosanoids
. Signaling molecules formed through enzymatic oxygenation and intramolecular cycle action of long-chain polyunsaturated fatty acids released from membrane phospholipids
Major classes of eicosanoids
. Prostaglandins (PG)
. Thrombocytes (TX)
. Luekotrienes (LT)
1 series eicosanoids
. PGs and TXs
. Derived from dihomo-gamma-linolenic acid (20:3(8,11,14))
2 series eicosanoids
. Derived from arachidonic acid (20:4(5,8,11,14))
3 series eicosanoids
Derived from eicosapentaenoic acid (20:4(5,8,11,14,17))
Most common precursor of eicosanoids
Arachidonic acid
Synthesis of eicosanoids
. Release arachidonic acid from phospholipids in membrane to cytosol via phospholipase A2
. Metabolized by 1 of 3 pathways to form PG, TX, to LT
. Pathway depends on cell type and type of stimulus initiating biosynthesis
Cycle-oxygenase pathway for PG and TX
. Oxygenation of arachidonic acid at 20:4 to form unstable PGG2 via COX 1 and 2
. Reduction of OOH on C15 to OH forming unstable PGH2 by peroxidase activity of PGH synthase that glutathione dependent
. Conversion to prostacyclin PGI2 via PGI synthase or thromboxane TXA2 via TXA synthase
Regulation of PGH synthase
. Pos: COX-1
. Neg: COX-2
. Peroxidase activity GSH-dependent
Lipoxygenase pathway
. Incorporating molecule of oxygen to form unstable 5-HPETE, 12-HPETE, or 15-HPETE (tissue specific) via either 5, 12, or 15-lipoxygenase
. HPETEs converted to HETEs, lipoxins, or LT
. For LT synthesis HPETE converts to corresponding epoxied LTA4
. Further metabolism to LTB4 or LTC4/LTE4 is glutathione-dependent
Cytochrome P450 epoxygenase pathway
. Cytochrome P450-dependent oxygenation of 20:4
. Needs NADPH and oxygen
. Uses epoxygenases and hydrolases to make EETs, DHETs, and HETES
. DHETs can be seen in cardiovascular disease, DM, and kidney disease
Non-enzymatic formation of oxygenation of arachidonic acid
. Makes isoprostanes (prostaglandin-like compounds)
. Formed via non-enzymatic oxidation of membrane-esterified arachidonic acid by ROS
. Phospholipase A2 releases isometric forms of prostaglandins into circulation
. Serve as markers of lipid oxidant damage, some have bioactivity
Eicosanoid mechanism of action
. Efflux of eicosanoids via ABC-type transporters
. Bind to prostanoid receptors (G-proteins)
. OR bind to nuclear receptors (PPAR) and affect gene expression
. Short distance signaling molecules via auto rinse and paracrine secretions
How is signaling molecule PAF formed?
. Lyso-PC produced during release of 20:4 from phospholipids
. Converted to PAF
ABC-type transports
. ATP-binding cell transporter
. Multi drug resistance assoc. proteins
. Example: MDR
organs and tissues effected by eicosanoids
. Smooth muscle (GI, vascular, airways) . Platelets . Kidney . Reproduction . nervous system (fever, sleep, neurotransmission) . Inflammation and immunity . Bone metabolism . Eyes . Cancer
Corticosteroid function
. Dec. inflammation by phospholipase A2 inhibition causes all eicosanoid synthesis
When is COX-2 upregulated?
Inflammatory conditions
NSAIDS
. Inhibit both COX-1 and 2, causes undesirable long-term effects
. Celebrex is selective COX-2 inhibitor good for patients w/ chronic inflammation
. Vioxx and bextra COX-2 inhibitors but withdrawn from market from adverse side effects
Why is dietary consumption of omega-3 fatty acids important?
. Crates altered eicosanoids
. Good for mediating inflammation and disease develope
. Research controversial on whether or not omega-3s prevent cardiovascular disease
Prostacyclin
. Produced by vascular endothelial cells
. Inhibits platelet aggregation
. Causes vasodilation
Thromboxane
. Produced by platelets
. Stimulate platelet aggregation
. Causes vasoconstriction
What organ do LTs have an important role?
Lung function
Transporters for PGE2 inside kidney and action caused
. EP1-4 G protein receptors . EP1: inc. intracellular Ca . EP2: . EP3: dec. cAMP . EP2 and 4: inc. cAMP
Prostaglandin functions in kidney
. Renal hemodynamics
. Renin release
. Body water balance
. Na balance
OGE2 synthetases
. 3 isozymes
. Constitutive: mPGES-2 and cPGES
. Inducible: mPGES-1
Induction of renal COX-2 seen in what diseases?
. Obstructive nephropathy . Acute kidney injury . Renal transplant . Chronic kidney disease . Hypertension . DM . Lithium nephrotoxicity . Renal artery stenosis . Glomerular diseases . Nephrotic disease . CHF
NSAID side effects
. Gastric bleeding
. Na retention
. Hypertension
. Prolonged bleeding
COX-2 inhibitor side effects
. MI
. Stroke
Lipoxygenase inhibitors
Zyflo/zileutron
Cardiovascular benefits of omega-3 EPA and DHA
. Lower Triglycerides
. Prevent arrhythmia
. Dec. platelet aggregation
. Dec. bp
