Download Biochemistry Ch 35 663-676 [4-20

Biochemistry Ch 35 663-676
Metabolism of Eicosanoids
Arachidonic acid, a polyunsaturated 20C compound is the most common source of eicosanoids,
and is normally found esterified to phospholipids in the plasma membrane
-must be obtained in the diet as arachidonic acid or linoleate (plant oils)
-AA is released from bilayer through activation of phospholipase A2 (PLA2) or PLC and
occurs after a stimulus such as histamine/cytokines interact with membrane receptor
LinoleateAA (bound)AA unbound epoxides (cyt450), leukotrienes (lipoxygenase), prostaglandins (cyclooxygenase)
-Most obvious symptom of fatty acid deficiencies is red/scaly dermatitis
-enzymes that make eicosanoids differ in tissues, sometimes producing PGE2, PGI2, or TxA2, 12HETE
-3 pathways are cyclooxygenase pathway, lipoxygenase pathway, and Cyt P450 pathway
Cyclooxygenase Pathway: Synthesis of Prostaglandins and Thromboxanes
1. Structure of Prostaglandins – 20C fatty acids with 5C ring. Nomenclature is a PG with an E for
structure different with a subscript of 1, 2, or 3 for number of double bonds
2. Structure of Thromboxanes – closely resemble prostaglandins except they have 6 membered
ring with an O atom
3. Biosynthesis of Prostaglandins and Thromboxanes –
AA (COX)  PGG2 (Peroxidase)  PGH2  PGD2, E2, I2, and TxA2 (PGD synthase etc..)-Functions of prostaglandins:
-PGI2, E2, and D2 – increase vasodilation and cAMP; decreases platelet aggregation,
WBC aggregation, IL-1 and 2, T cell proliferation, and lymphocyte migration
-PGF2a – increases vasoconstriction, bronchoconstriction, and smth muscle contraction
-TxA2 – produced by platelets to stimulate aggregation and vasoconstriction
-cyclooxygenase enzymes were found to exist in 2 isoformes: COX1 and COX2. COX1 is
constitutive while COX2 is inducible through growth factors and cytokines, and COX2 mRNA is
elevated in inflamed tissue
-COX1 involved in platelet aggregation and stomach cytoprotection
-COX2 involved in inflammation and hyperalgesia
-COX enzymes blocked by all NSAID drugs like aspirin, which is irreversible.
-other NSAIDs are reversible (Tylenol, ibuprofen)
-COX-2 selective inhibitors would get rid of GI ulcers and antiplatelet activity (celecoxib
and rofecoxib)
4. Inactivation of Prostaglandins and Thromboxanes – these molecules have short half lives
(seconds-minutes).
-prostaglandins inactivated by oxidation of 15-OH group to a ketone and double bond at
C13 reduced, allowing urine excretion
-TxA2 is metabolized to TxB2 by cleavage of O2 bridge between C9 and 11 to form 2 OH
groups; TxB2 has no activity
Lipoxygenase Pathway – Synthesis of leukotrienes, hydroxyeicosatetraenoic acid, lipoxins
-LOX catalyzes incorporation of O2 molecule into a carbon of double bond in AA, and may act on
carbons 5, 12, and 15
-type of LOX varies from tissue to tissue: polymorphonuclear leukocytes have 5-LOX, whereas
platelets have 12-LOX and eosinophilic leukocytes have 15-LOX
1. Leukotriene synthesis – begins with formation of HPETEs which are later reduced to HETEs or
metabolized into leukotrienes or lipoxins
-major leukotrienes produced by 5-LOX.
-AA + 5-LOX  5-HPETE  LTA4 + glutathione S-transferase  LTC4 + g glutamyl transpeptidase
 LTD4  LTE4
- LTA4 also converted to LTB4
Functions of LTB4: increases vascular permeability, t-cell proliferation, leukocyte aggregation,
INF-g, IL-1, 2
Functions of LTC4 and LTD4: increases bronchoconstriction vascular permeability, INF-g
2. Lipoxin Synthesis and Actions – lipoxins are formed through 15-LOX followed by 5-LOX on
arachidonic acid followed by a series of reductions to lipoxins such as LXA4
-lipoxins induce chemotaxis ad stimulate superoxide anion production in leukocytes
Cytochrome P450 Pathway: synthesis and actions of epoxides, HETEs and diol HETEs
-AAcytochrome P450 to yield epoxides, HETEs, and diHETEs and are implicated in ocular,
vascular, endocrine, and renal systems
Isoprostane Synthesis – derived from AA by lipid peroxidation and initiated by free radicals.
There is no enzymatic mechanism for their production.
-AA undergoes free radical damage; PLA2 removes it from membrane and releases into
circulation. Levels can be measured in the urine and can indicate oxidative stress
-best studied isoprostane is similar to PGF2a, and has similar effects on cultured cells as does
PGF2
Endocannabinoid Synthesis – endogenous ligands or cannabinoid receptors (CB1 and CB2) with
effects primarily in the nervous system
-anandamide – synthesized in neurons from phosphatidylethanolamine and is unique in
transferring an AA group from 2 position to free amino group on ethanolamine, and then using a
unique phospholipase D to cleave the modified ethanolamine from the phospholipid
-Synthesis is regulated by agonists that cause Ca influx into the neuron
-it acts as a retrograde messenger, binding to receptors on presynaptic membrane that later ion
fluxes such that neurotransmitter release from presynaptic neuron can be increased and an
analgesic effect obtained
-degraded by the enzyme fatty acid amide hydrolase, and inhibiting this enzyme can prolong
analgesic effects induced by anandamide
Mechanism of Action of Eicosanoids – target eicosanoid receptors on plasma membrane of
target cell, which activates adenylyl cyclase cAMP- protein kinase A system or causes an influx of
Ca2+ into the cytosol of target cells
-in some systems, eicosanoids modulate degree of adenylyl cyclase activation in response to
other stimuli, where eicosanoid may bind regulatory subunit of GTP binding proteins within
plasma membrane of target cell
-if eicosanoid binds stimulatory subunit, effect of stimulus is amplified, and vice versa
-Eicosanoids can work in a paracrine fashion, such as contraction of vascular smooth muscle by
TxA2, as well as autocrine by TxA2 to exhibit platelet aggregation