42 Eicosanoids---------------------------------------END Flashcards
where does the arachidonic acid bind?
to the fatty acid that is bound to the phospholipid in the cell membrane at position 2
what are the two mechanisms for the stimulation of the enzyme phospholipase A2 for the liberation of arachidonic acid? what makes the signal stronger?
direct and indirect; Smooth muscle contractions due to Ca2+ make the signal stronger too
what is the direct mechanism for the stimulation of the enzyme phospholipase A2 for the liberation of arachidonic acid?
Direct: Phospholipase A2 cleaves phosphatidylcholine in the membrane to form free arachidonic acid
PLA2 is activated by the binding of a stimulus (histamine or cytokinase) to the receptor
Steroidal anti-inflammatory agents inhibits phospholipase A2
what is the indirect mechanism for the stimulation of the enzyme phospholipase A2 for the liberation of arachidonic acid?
Phospholipase C cleaves PIP2 to create IP3 and DAG. The creation of IP3 increases intracellular calcium. The release of calcium activates phospholipase A2 which can then cleave the phospholipid to create free arachidonic acid in the cell. In addition, DAG left over after the liberation of IP3 can interact with DAG lipase that also cleaves arachidonic acid at position 2
The activation of phospholipase C converts phosphatidylinositol bisphosphate to 1,2-diacylglycerol. 1,2-diacylglycerol is then converted into arachidonic acid via diacylglycerol lipase
what are the three forms of Cyclooxygenase enzymes?
COX1
COX2
COX3
what is COX1?
constitutive, found in nearly all tissues
what is COX2?
inducible during inflammatory disease states
what is COX3?
splice variant of COX 1 with same function
what is the mechanism of NSAIDs treatment?
NSAIDs (Non-steroidal anti-inflammatory agents) block prostaglandin formation by irreversibly inhibiting COX
Aspirin acylates an active site serine while other NSAIDs bind non-covalently to COX to inhibit them
Aspirin is the only COX inhibitor to covalently modify COX resulting in suicide inhibition
what is the mechanism of steroid treatment?
Steroidal anti-inflammatory drugs such as hydrocortisone and prednisone block prostaglandin formation by inhibiting phospholipase A2 so arachidonic acid cannot be liberated. More complete shut down of all pathways. HPETE’s and Epoxides too
describe the prostaglandins? what part of the molecule is key for activation?
20 carbon atoms with an internal, saturated 5-carbon ring with a hydroxyl group at carbon 15 and a double bond between carbons 13 and 14.
The hydroxyl group at position 15 is key for activation and inactivation.
what is the inactive prostaglandin?
Prostaglandin G (PGG2) is the inactive form and is recognized due to the -OOH at position 15
how is Prostaglandin G (PGG2) converted to the active form?
PGH2 is the active and is converted from inactive to active via peroxidase due to the reduction of -OOH to -OH at position 15
what happens to the PGH2?
may be converted to several other molecules such as TXA synthase in the Thromboxane Synthesis Pathway or Prostacyclin in the PGI Synthesis Pathway
what happens if a ketone is formed?
its degraded
In very general terms – what is the major structural feature of prostaglandins versus thromboxanes?
20 carbon atoms Internal, saturated 5 carbon ring Hydroxyl group at carbon 15 A double bond between carbons 13 and 14 Various substituents on the ring
is the thromboxane structure similar to prostaglandins?
Thromboxanes structure similar to prostaglandins but they contain a 6-membered ring
Some thromboxanes have an additional oxygen atom bridging carbons 9 and 11 of the ring
What is the enzyme pathway that leads to prostaglandins? Thromboxanes? HETEs and leukotrienes?
Arachidonic acid may be converted into PGG2, HPETE, or Epoxides
Arachidonic acid to PGG2 via cycle-oxygenase
Arachidonic acid to HPETE via lipo-oxygenase
Arachidonic acid to Epoxides via cytochrome P450
what is the enzyme for Arachidonic acid to PGG2?
cycle-oxygenase, creates prostaglandins, thromboxanes
what is the enzyme for Arachidonic acid to HPETE
lipo-oxygenase creates leukotrienes, HETE, Lipoxins
what is the enzyme for Arachidonic acid to Epoxides
cytochrome P450 creates diHETE and HETE
Arachidonic acid is converted to the 5-HPETE, 12-HPETE, and 15-HPETE via this enzyme? describe the mechanism and how active is it?
lipooxygenase enzymes, it incorporates an oxygen molecule onto a carbon of one of several double bonds (position 5, 12, or 15). The activity of these enzymes are tissue dependent.
The conversion from arachidonic acid to the 5-HPETE, 12-HPETE, and 15-HPETE are inactive due to the position of the peroxyl group. HPETEs are reduced to corresponding hydroxyl metabolites (HETEs) or metabolized to form leukotrienes or lipoxins.
What structural feature of prostaglandins makes the series 1 vs series 2 vs series 3? Can you recognize this from a picture shown?
Series one contains one double bond
Series two contains two double bonds
Series 3 has 3 double bonds
