Physiology 3140A Lecture Notes - Lecture 24: Arachidonic Acid, Phospholipase A2, Essential Fatty Acid
2 May 2018
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Cell Physiology Lecture 24
Other Lipid-Derived Chemical Mediators
November 27 2017
- Two active parts come from PI:
o IP3
o DAG: stimulate full activation of PKC
- NOTE: PS serves as an anchor
- Glycerophospholipids have two fatty acids: C1 and C2 of glycerol backbone
o On the third carbon there is the phosphate head group
o On the middle carbon, the fatty acid you often find is arachidonic acid (cleaved by
phospholipase A2 – takes off the second FA, on C2)
- Phospholipase A1 takes off the first FA, the one on C1
Second messengers and mediators derived from membrane lipids
- Most lipid-derived mediators are produced from phospholipids PI and PC by phospholipases (most
important)
- PS does not serve as a good source of mediators – it needs to be sitting on the inside of the membrane
AND intact in order to attract PKC
o Mission for PS is to serve as an anchor for PKC – do not want to be chopping it off, will have
an issue with PKC activation
- PE does not participate a lot
- THEREFORE, PI + PC ARE THE ONES THAT CONTRIBUTE THE MOST (does not mean that the others
do not)
- Best characterized is generation of inositol triphosphate (IP3) and diacylgercerol by phospholipase C-
β from PI
- Other lipid mediators include:
o Mediators with both autocrine and endocrine functions (e.g. prostaglandins and platelet-
activating factor)
▪ AUTOCRINE: act on the cell that makes it + releases it
• Tells the cell that its intended job has been done
o Ex. Biologically active molecule must be released from the cell
• Autocrine factor is co-released and co-made with the hormone to bind the
cell surface receptors on the same cell to indicate to the cell that the other
molecule was released
o Other molecule being released is endocrine
▪ ENDOCRINE
• Can be made + released from the cell and travel throughout the body to
mediate an effect on more distant tissues
o Therefore, MORE STABLE MOLECULES
- Some are positive or negative mediators
o Anti-inflammatory or inflammatory
o Vasodilation or vasoconstriction
- NO made in the blood vessel endothelial cells + since it is a gas it can passively diffuse out of the cell it
is made in and passively diffuse into an adjacent cell to mediate an effect in adjacent cell
o Turns on guanylate cyclase in the adjacent cell BUT not in the cell it was made in
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o Form of endocrine function! But this is short lived and short distance NOT like a hormone
that is released and travels throughout the body through the bloodstream
o NO = short half life
▪ Therefore, has to find a local receptor because in a matter of seconds/minutes it will
be degraded into other nitrate molecules.
o Technically paracrine bc close by
Eicosanoids (including Prostaglandins)
- They are all called eicosanoids
- Large group of compounds including prostaglandins, thromboxanes, leukotrienes and prostacyclins
o These are families of molecules – many molecules in each category
- ALL formed from essential fatty acid arachidonic acid
o Essential FA = have to get it through your diet, you can not synthesize it in your own body by
converting another FA to it
▪ If you lack it in your diet you would have problems populating arachidonic acid on
your glycerophospholipid + making other molecules
o Initial starting point – a cascade of molecules are made from it
- Eicosanoids are not stored in cell, but made on demand by series of enzymatic steps following
stimulation of cell
o E.g. cAMP tends to have a basal concentration in the cell (10-7 )
▪ Many signaling molecules have basal concentrations in the cell BUT this is below the
concentration to elicit biological effects
▪ The cell has to quickly make a lot of the molecule to have an effect
o BUT EICOSANOIDS ARE NOT SITTING AROUND IN THE CELL – THEY ARE MADE ON
DEMAND
- Arachidonic acid in the cell is esterified to membrane lipids on the second carbon
o It is NOT free inside the cell because it could be metabolized into biologically active
eicosanoids
o Do not find a free pool of arachidonic acid sitting around in the cell – not stored as a pool in
the cell
- Eicosanoids are made through a series of enzymatic steps that are initiated when a cell is stimulated
by a particular piece of information from the extracellular environment
- Major determinant of rate of synthesis is availability of free arachidonic acid
o If there is no arachidonic acid in the free state, a signal could arrive at the cell that might
normally elicit the production of eicosanoid BUT NO eicosanoid being produced
o Therefore, the first step is to liberate arachidonic acid from the lipid membrane BY
activation of phospholipase A2
o Cell gets signal from extracellular environment that is trying to relay information into the
cell that requires the production of an eicosanoid
▪ The first thing that has to happen is get free arachidonic acid
• Arachidonic acid is esterified to PI or PC in the membrane
• Need activation of phospholipase A2 – mechanism to liberate arachidonic
acid from the glycerophospholipid
- Therefore, the cell has to have good mechanisms for regulating phospholipase A2 activity
o Do not want a lot of activation of phospholipase A2 under normal conditions because it
would chop the glycerophospholipids and release arachidonic acid on a sustained basis
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▪ Get a lot of eicosanoids made and they have a wide range of biological activities
• E.g. inflammation, vasodilation
▪ Therefore, want a regulated response to that
o PhospholipasA2 creates lysophospholipid, which can act as a detergent to lyse the cell
▪ Lipids are hydrophobic –detergents are hydrophilic
▪ Do not want a lot of lysophospholipid in the cell membrane because it can lead to
cell lysis
▪ Enhance the fluidity of the PM where it becomes leaky
- HAS TO BE VERY CONTROLLED
o Take off some arachidonic acid, just enough to make the amount of eicosanoid you need to
send a signal to the target cell
- Arachidonic acid is found in cell membranes in lipid bound form, esterified to phospholipids at the
second carbon and unavailable for eicosanoid biosynthesis
- Arachidonic acid is normally released from membrane phospholipids by phospholipase A2
PC, PI and PE are sources of arachidonic acid
- 3 carbon glycerol backbone, phosphate head group (usually PC, PS), FA on C1 and C2
- Phospholipase A2 cleaves at the ether carbon 2, creating a hydroxyl group
o Releases FA + lysophospholipid
- Can tell the FA is arachidonic acid because it has double bonds (unsaturated)
o Makes it flexible
o Places the opportunity for the enzymes to work with the double bonds – oxygen or hydroxyl
groups
o Double bonds makes it subject to oxidation leading to many different structures
o 20 C extended conformation of arachidonic acid (usually folds b/c of its structure hair pin
structure)
▪ Goes through a series of enzymatic steps
- Depending on how it gets modified with the double bounds, it will produce a number of different
eicosanoids
1. Phospholipase A2 cleaves; liberate FA + lysophospholipid
a. Yield hydroxyl group on second C (in the lysophospholipid)
2. Arachidonic acid, due to its level of unsaturation can change its confirmation of hair-pin
structure
3. Due to double bonds it can be oxidized – end with different structures
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Document Summary
Ip3: dag: stimulate full activation of pkc. Phospholipase a1 takes off the first fa, the one on c1. Second messengers and mediators derived from membrane lipids important) And intact in order to attract pkc an issue with pkc activation. Most lipid-derived mediators are produced from phospholipids pi and pc by phospholipases (most. Therefore, pi + pc are the ones that contribute the most (does not mean that the others do not: mediators with both autocrine and endocrine functions (e. g. prostaglandins and platelet- Best characterized is generation of inositol triphosphate (ip3) and diacylgercerol by phospholipase c- Other lipid mediators include: activating factor: autocrine: act on the cell that makes it + releases it, tells the cell that its intended job has been done, ex. Some are positive or negative mediators: anti-inflammatory or inflammatory, vasodilation or vasoconstriction. Eicosanoids (including prostaglandins: essential fa = have to get it through your diet, you can not synthesize it in your own body by.
