Other Lipid Derived Mediators

imissyou419's version from 2016-12-18 17:57


Question Answer
Most lipid derived mediators are produced from what 2 phospholipids?PI and PC
Mediators can have both ___ and ___ functionsautocrine and endocrine functions e.g. prostaglandins, PDGF - autocrine function for negative (you did your job so now don't do it anymore)/positive (you did your job) feedback (allow the cell to understand signalling took place), cell that made it needs RECEPTORS on cell surface for it
Eicosanoidslarge family of compounds including prostaglandins, thromboxanes, leukotrienes, prostacyclins, NOT STORED IN CELL, MADE ON DEMAND FROM ESSENTIAL (from diet) ARACHIDONIC ACID FOLLOWING STIMULATION OF CELL AND PL-A2 CUTTING GPI @ C2 TO RELEASE ARACHIDONIC ACID AND THROUGH SERIES OF ENZYMATIC STEPS TO CONVERT TO EICOSANOIDS (rate determining step is availability of FREE arachidonic acid released from membrane phospholipids by PL-A2, arachidonic in cell membrane is unavailable for eicosanoid biosynthesis)
What happens if we have deficient in arachidonic acid in our diet?cannot make eicosanoids because no arachidonic acid
What 3 phospholipids are sources of arachidonic acid?PI, PC, PE
How many double bonds does arachidonic acid have?4, important to release energy, isomerize, act as nucleophiles so you get oxidation
What must cells have for eicosanoids to have their effect?receptor on their surface
What are the 4 pathways for metabolism of Arachidonic acid?1) production of prostaglandins and thromboxanes (initiate is cyclooxygenase); 2) leukotrienes (initiator is lipoxygenase); 3) EET (initiator is cytochrome P-450, liver enzyme); HPETE (arachidonic acid undergoes auto-oxidation)
Do cells express all enzymes that metabolize arachidonic acid?No, not all cells in the body express genome from all enzymes, some cells make 1 compliment of eicosanoids, another cell makes an entire range of eicosanoids, PRODUCT GENERATED IS TISSUE AND CELL TYPE SPECIFICITY
What happens if PL-A2 is not active?will not produce arachidonic acids because arachidonic acid is made on demand by PL-A2, lipocortin regulate PLA2
How is eicosanoids produced?PI, PC, PE have abundance of arachidonic acid in C2 of glycerol backbone, PL-A2 chop off arachidonic acid (rate determining step, made on demand), initiator enzyme cyclooxygenase makes prostaglandins and thromboxanes through series of more enzymatic processes determined by enzyme present in that particular cell type (if blocked, push to lipoxygenase pathway - multiple points of entry)
What happens if you take NSAID (aspirin)? IMPORTANTNSAID inhibit cyclooxygenase IRREVERSIBLY, will not produce prostaglandins or thromboxanes (arachidonic acid pushed to other pathways - some people develop asthma b/c ultra sensitive to leukotrienes from lipoxygenase pathway [NSAID was called SRSA - slow reacting substances of anaphylaxis]); lipoxygenase pathway makes a variety of molecules depending on what enzymes are present; must make new cyclooxygenase
How is LP-A2 regulated? IMPORTANTNO SIGNAL -> Lipocortin normally has high binding affinity for LP-A2 and blocks catalytic enzyme of constitutively active LP-A2 when bound;
SIGNAL (chemoattractant) -> increase cytosolic Ca2+, PKA/PKC phosphorylate lipocortin and change conformation so now it has low affinity for LP-A2 so LP-A2 can express catalytic domain and seek out membrane glycerophospholipids and cut arachidonic acid off, generate lysophospholipids

Rise in cytosolic Ca2+ levels for sufficient period of time -> increase PL-A2 activity, inflammatory response (shut down by SAID)

Lipocortin normally near PM @ cytosol because bond to PL-A2 which is membrane-bound (seeks out glycerophospholipids)
How is Lipocortin regulated?
glucocorticoids (steroid anti-inflammatory hormone) induce production of lipocortin.

Normally, have low glucocorticoid level in our body, sufficient to have small amount of synthesis of lipocortin, PL-A2 activity suppressed by endogenous lipocortin;

if you take SAID, make more lipocortin and completely suppress PL-A2 activity blocking production of inflammatory mediators derived from arachidonic acids
Activation of neutrophils by treatment with chemoattractantsmacrophages produce iNOS, neutrophils produce inflammatory mediators -> lipocortin phosphorylated by PKA and PKC, thus inhibiting of PL-A2 by lipocortin regulated by protein kinase activation, phosphorylated lipocortin is less effect as inhibitor of PL-A2 than nonphosphorylated lipocortin, release arachidonic acid from phospholipids by PL-A2, produce eicosanoids (inflammation)

Rise in Ca2+ levels for sufficient period of time -> increase PL-A2 activity (amplification)

(taking glucocorticoids block this process - produce more lipocortin so block PL-A2)

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