Eicosanoids Lecture Oct 3 Flashcards
What are the 6 classes of eicosanoids?
prostaglandins
thromboxanes
leukotrienes
HETE
lipoxins
Isoprostanes
What two eicosanoids are produced by the cyclooxygenase (cyclic) pathway?
prostaglandins and thromboxanes
What 3 eicosanoids are produced by the lipoxygenase (linear) pathway?
Luekotrienes
HETE
lipoxins
Which eicosanoid is produced by nonenzymatic free radical attack?
What is it’s clinical use?
Isoprostanes
There doesn’t seem to be a biological purpose for these yet, but they are great for lab test purposes because having elevated isoprostanes int h urine is indicative of oxidative stress and damage in the body
Which eicosanoids will be produced by the cytochorme p450 enzymes?
epoxides
HETE
diHETE
What is the method of action for prostaglandins?
they function as autocrine and paracrine hormones because htey have a very short half life
Which blood cell is the most affected by thromboxanes?
platelets - thromboxanes mediate vasoconstruction and platelet aggregaton
What is the precursor for the eicosanoids?
arachidonic acid
What do we need to take in from the diet to make arachidonic acid?
We have to eat linoleic and linolenic fatty acids because our fatty acyl desaturate enzyme can’t make double bonds if the desired location is too far away from the CoA end.
How is most of the arachidonic acid in the cell stored?
It’s stored in phospholipids located in the cytosolic side of the plasma membrane. PIP2 is the most common, but phosphtidylcholin often has it as well.
The arachidonic acid is usually attached to the 2nd carbon of the glycerol backbone
Different phospholipases cleave at different locations. WHere do the following cleave?
PLA1
PLA2
PLC
PLD
PLA2 cleaves at the 2 position on the glycerol
PLA1 cleaves on the 1 position
PLC cuts off the head group WITH the phosphate attached
PLD cuts off the head group WITHOUT the phosphate
What are the two methods for freeing arachidonic acid from the membrane in our cells?
- PLC will cleave the phosphoinositol bisohpate into DAG and IP3. DAG lipase will then cleave the arachidonic acid off of the DAG.
- PLA2 will directly clave the arachidonic acid off the phospholipid
What receptors activate the lipases required to free arachidonic acid from the membrane?
GPCRs on the membrane
Prostaglandin nomeclature provides what information?
PGI2
PG = prostaglading
I = the shape of the ring
2 = # of double bonds in the linear portions
What do ALL prostaglandins have structurally?
A hydrosyl at carobn 15
double bonds between carbons 13 and 14
a 5-carbon ring structure
What are the steps in prostaglanding and thromboxane synthesis?
- COX acts on arachidonic acid to make PGG2.
- PGG2 is acted on by peroxidase (using reduced glutathione) to form PGH2, which is the precursor
- PGH2 is converted to thromboxane by TXA synthease and prostaglandings by PG_ synthase (depends on what prostaglanding you want)
What makes thromboxanes different from prostacyclins structurally?
they have an epoxide oxygen bridge in the 6-C ring structure
How are leukotrienes synthesized? how are they different structurally from prostaglandings and thromboxanes?
They are synthesized through the linear pathway with lipoxygenase creating HPETE, which is then converted to HETE which has an epoxide, which is then reduced to make leukotrienes
Leukotrienes are structurally different because they do not have a run structure
Wha do prostaglandings do?
Trick question: some of them are pro-inflammatory and others are antiinflammatory
PGI, PGE, and PGD are anti-inflammatory and increase basodilation
PGF is pro-inflammatory and icnreases vasoconstriction, bronchoconstriction and smooth muscle
What is happenin gin terms of prostaglandin secretion/action in healthy blood vewwels?
The vascular endothelial cells are releasing PGI2, which prevents platelet clotting and keeps blood vessels open.
What happens when blood endothelia is damaged?
Damage reults in a proteolytic cascade which causes calcium release which culminates in thrombin activation
thrombin is a protease which cleaves soluble fibrinogen to form fibrin, which polymerizes into a wound covering matrix
When the platelets contact thrombin (or each other in a clot), they will release thromboxanes, which act as paracrine and autocrine hormones to induce platelet aggregation and other wound responses
What are endocannabinoids?
They are arachidonic acid with an attached ethanolamine
What is the protoypical endocannabinoid?
Anandamide
What receptors do endocannabinoids bind to?
CB1 and CB2
CB1 receptors are in nerve synapses, which is how endocannabinoids can have thei analgesic effects
CB2 receptors are in the spleen and immune cells
What effect does anandamide have on mast cells and macrophages?
It inhibits their release of TNF-alpha, thus blunting the signalling in the immune system and reducing inflammation
What do NSAIDs target?
They target cyclooxygenase so that you don’t get the formation of prostaglandins, which helps in treating pain, fever, and inflammation
What are the negative effects of COX inhibitors?
NSAIDs cannot selectively inhibit COX2 inhibitors (which would be nice because COX2 is what forms inflamatory PGs), so they inhibit COX1 as well.
COX1 forms prostaglandins that are anticlotting and stimulate mucin secretion in the gastric mucosa.
This is good in a way because it means NSAIDs have an anti-clotting ability, but it increases the risk of stomach ulcers
Describe the general structure of COX enzymes?
THe two isoforms have very similar active sites
they both act as homodimers
they have amphipathic domains that anchor them in the membrane of SR
they both contain heme catalytic domains
What does it mean to say that spirin is a suicide inhibitor?
It means it’s a noncompetitive inhibitor
The acetyl group from aspirin is transferred to the side chain of a serine amino acid near the active site of the COX enzyme
This is a covalent bond that permamently disables the enzyme and takes it out of circulation
Why does using aspirin for preventative purposes only require a minimum dose?
Because aspirin in that case is targeting platelets to block the formation of clots
since platelets do not have a nucleus, they are not capable of making for COX is need be. So that small amount of aspirin is effectively able to eliminate prostablanding synthesis for the lifetime of that platelet
WHat are some other NSAIDs that (unlike aspirin) do not covalently modify the COX enzymes?
ibuprofen (advil)
acetominophen (TYlenol)
Naproxen (Aleve)
What will aspiin do to the kinetics of COX?
It will reduce Vmax because it’s a suicide inhibitor
What were the adverse effects of the selective COX 2 inhibitors like celebrex and vioxx?
they have an increased risk of stroke and heart attack
How do prostaglandins prevent inflammation?
Hyrosycortisone, prednisones and dexamethasone interfere with the transcription of the genes for phospholipase 2 and cyclooxygenase
This prevents inflammation by blocking the production of both leukotrienes and prostalgandins
What were the corticosteroids we learned?
hydroxycortisone
prednisone
dexamethasone
What is the negative effect of systemic corticosteroid use?
They are gluconeogenic because they increase transcription of genes for PEP-CK synthesis and icnrease muscle protien breakdown
this leads to hyperglycemia
What are two ways we can treat the inflammation of asthma?
We can use inhaled corticosteroids (for acute attacks)
or we can use drugs that block the cys-leukotriene receptor (for daily use)
What were the cys-Leukotriene receptor blockers that we learned?
montelukast (singulair)
zafirlukast (accolate)
