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liveonearthWhat is arachidonic acid? It's a 20 carbon fatty acid that is unsaturated in four places. It is also known as eicosatetraenoic acid. 20:4 delta 4, 8, 11, 14. It's a precursor to local (autocrine & paracrine) signalling molecules known as Eicosanoids.
Arachidonic acid is central to the synthesis of which lipids? Eicosanoids which are (again) local, and work on cell surface receptors, often via the cGMP pathway. E's have a short half life and are not carried in the blood.
Eicosanoids
--produced from fatty acids released from membrane phospholipids
--signaling molecules made by oxygenation of twenty-carbon essential fatty acids, either omega-3 (ω-3) or omega-6 (ω-6) EFAs
--have short half lives, are inactivated by hydroxyl at C15 converting to ketone
--four families of eicosanoids—prostaglandins, prostacyclins, thromboxanes and leukotrienes
--For each of the four above, there are two or three separate series, derived either from an ω-3 or ω-6 EFA.
--These series' different activities largely explain the health effects of ω-3 and ω-6 fats.
Where is arachidonic acid "stored" in the cells? in membranes, commonly in the middle position on glycerol backbone of a phospholipid.
What enzymes release arachidonic acid from "storage"? via a 2nd messenger system involving a stimulus that binds to a receptor on the cell, triggering phospholipase A2 (which requires Ca++) to liberate A.acid from phosphatidyl choline, or phospholipase C to libertate it from phosphatidylinositol biphosphate via a 2-3 step process.
How do cyclooxygenase and lipooxygenase systems for the synthesis of eiconsanoids differ? First, sameness: both are made/activate?? in platelets in plasma.
The cyclooxygenase system converts arachidonate into PGG2 then PGH2, precurors for prostaglandins (PGs) and thromboxanes (TXs). "cyclic pathway"
The lipoxygenase system converts arachidonate into HPETEs, precursor for leukotrienes. "linear pathway"
What are NSAIDS? Non-steroidal anti-inflammatory agents such as aspirin (irreversible) and ibuprofen (reversible) which inhibit cyclooxygenase.
Low dose aspirin therapy (COX 1) permanently blocks cyclooxygenase to avoid clots.? Aspirin impacts endothelial cells they make more what??? Up regulate production of what?? Have to make new platelets via megakaryocytes to get more platelets to get more active cyclooxygenase.
At what step do NSAIDS interfere with eicosanoid production? They interfere with the conversion of freed arachidonic acid via cyclooxygenase to prostaglandins. Arachidonic acid can still be converted to epoxides and leukotrienes.
At what step do steroidal anti-inflammatory agents interfere with eicosanoid production? They stop the arachidonic acid from being freed from the membrane, by synthesizing a protein (lipocortin) that inhibits phospholipase A2.
Explain the naming of prostaglandins and thromboxanes (together known as prostanoids). PGs, TXs and LTs are grouped according to the number of double bonds in their hydrocarbon chains, ie by series.
How do thromboxanes differ from prostaglandins?
THROMBOXANES
--from platelets
--aggregation of cells (which cells??)
--vasoconstriction
--increase BP
PROSTAGLANDINS
--made in many tissues
--pro and anti inflam
--contractions of smooth muscle
--lowers BP
--regulates gastric secretion
--regulates body temp
--regulates platelet aggregation
--control of inflammation
--vascular permability
--aspirin inhibits production of these
What are some prostaglandins labeled "pro-inflammatory" and others "anti-inflammatory"? Of the PGs, Series 1 and 3 are anti-inflammatory, series 2 are pro-inflammatory.
WIKI: The ω-6 eicosanoids are generally pro-inflammatory; ω-3's are much less so. The amounts and balance of these fats in a person's diet will affect the body's eicosanoid-controlled functions, with effects on cardiovascular disease, triglycerides, blood pressure, and arthritis. Anti-inflammatory drugs such as aspirin and other NSAIDs act by downregulating eicosanoid synthesis.
What are the precursors of series 1, series 2, and series 3 eicosanoids? First: trans double bonds are at position 13, cis double bonds at positions 5 and 17. The hydroxyl group at C15 is required for biological activity.
SERIES 1
--has double bond at 13-14
--precursor is 8, 11, 14-Eicosatrienoic acid, aka linoleic omega 6
--is anti-inflammatory
SERIES 2
--has double bond at 13-14 and 5-6
--is pro-inflammatory
--precursor is regular arachidonic acid, C20:delta 5, 8, 11, 14
SERIES 3
--has double bond at 13-14 and 5-6 and 17-18
--is anti-inflammatory
--precursor is Eicosapenaenoic acid, C20 delta 5, 8, 11, 14, 17, aka linolenic omega 3
Be able to use the name of a prostaglandin or a thromboxane to identify the series to which it belongs. OK. Let's see. The name will be PG or TX plus a letter, plus a delta and some numbers. The delta and numbers indicated where the double bonds are. All have 13-14 bonds, so if that's the only one it's series 1. 2nd series has 5-6 unsats. 3rd has 17-18 unsats. Memorize memorize memorize.
How do leukotrienes differ from prostaglandins and thromboxanes?
--they're an open ring structure, whereas prostaglandins are carbon cycles and thromboxanes are heterocycles
--naming involves numerical subscript denoting # of double bonds (unsats)
--LT's made via linear pathway, enzyme = lipooxygenase
----LINEAR: arachidonic acid --> 5-HPETE --> leukotrienes
--PGs & TXs synthesized via cyclic pathway, enzyme = cyclooxygenase (COX I and II)
--INHIBITION: steroids inhibit all of them, but aspirin doesn't inhibit lipoxygenase (it blox COX), so leukotrienes are not inhibited by aspirin (& other NSAIDS)
--leukotrienes are the only ones made & delivered by macrophages, neutrophiles, monocytes
--leukotrienes are the only ones that cause chemotaxis
--leukotrienes are the only ones that encourage cell to cell adhesions
LEUKOTRIENES (LTs)
--produced by macrophages incl neutrophils, monocytes
--LINEAR PATHWAY
--inflammatory
--Fx: chemotaxis (attract WBC's), vasoconstriction esp in bronchitis
--something about cell adhesions
--aspirin doesn't affect them
--have no ring
--open chain structure with 1 conjugated and 2 non-conjugated double bonds (1 C spacers)
--derived from HPETEs which is from arachidonic acid
--HPETE - hydroperoxyeicosatetraenoic acid (don't ask me to type it again)
--naming: LT plus additional letter that denotes modification of parent chain, subscript numeral is # of unsats
PROSTAGLANDINS (PGs)
--a carbon cycle plus two hydrocarbon tails of 7 and 8 carbons
--CYCLIC PATHWAY
--made by many tissues
--pro and anti-inflammatory
--lowers BP
--regulates gastric secretions: (not in SSL notes)
--regulates body temp
--regulates platelet aggregation
--controls imflam
--affects vascular permeability
--aspirin works on these
--from prostanoic acid, thromboxane comes from same parent compound
--bonds at 8 & 12 in trans relationship (tails can't stack, are offset)
--all natural prostaglandins have a hydroxyl at C15
--20 carbons, bend in the middle around a five sided ring, two lipidy tails
--naming: PG plus A, B, E, F, I, D, G, H plus a series that indicates where the unsaturations are in the tails The letter after PG denotes the attachments on the five membered ring that is the "head".
--PGA & B interconvert
THROMBOXANES
--made by platelets
--CYCLIC PATHWAY
--made from PG's so also blocked by aspirin, NSAIDS
--cause aggregations of cells. (which cells???)
--cause vasoconstriction
--increase BP
--inflammatory
--naming: TX plus extra letter denotes ring variation, numberical subscript gives # of dbl bonds in hydrocarbon tail chains
--series are the same as the prostaglandins, series 1 has unsats at 13-14, series 2 has unsats at 13-14 and 5-6, and series 3 has unsats at those plus 17-18
--TXA2 involved in platelet aggregation
--is a heterocycle because there is oxygen in the ring
ASPIRIN BLOCKS THE CYCLIC PATHWAY
--COX (cyclooxygenase) is made in platelets maybe other places too
--has two catalytic sites hence I and II
--aspirin acetylates an active site
----ARACHIDONIC acid --/--> PG's or TX's
--low dose aspirin therapy permanently blocks COX I, reduces ability to clot
----CYCLIC: arachidonic acid --> PGG2 --> PGH2 -->TX or PG
----to get more COX I you have to make more platelets (megakaryocytes)
--other NSAIDS such as ibuprofen REVERSIBLY block the pathway
EICOSANOIDS
--derived by folding arachidonic acid, which we can synthesize by elongating shorter unsaturated fatty acids, arachidonic is 20C has unsats at 5, 8, 11, 14.
--precursors for prostaglandins, leukotrienes, prostacyclines and thromboxanes
--speed of synthesis depends on concentration of arachidonic
--product made depends on what enzymes are present
--used for local signalling (auto or paracrine, not in blood)
--short half life
--work on cell surface receptors
--often use cGMP pathway
--Fx variable; smooth muscle action--control blood flow, local BP up or down, inflam up or down, secretins up or down, immune effectors
--stored in membrane phospholipids, on the middle carbon of the glycerol backbone
--linoleic and linoleic acids are also stored on the middle carbon in phospholipids
Arachidonic acid is central to the synthesis of which lipids? Eicosanoids which are (again) local, and work on cell surface receptors, often via the cGMP pathway. E's have a short half life and are not carried in the blood.
Eicosanoids
--produced from fatty acids released from membrane phospholipids
--signaling molecules made by oxygenation of twenty-carbon essential fatty acids, either omega-3 (ω-3) or omega-6 (ω-6) EFAs
--have short half lives, are inactivated by hydroxyl at C15 converting to ketone
--four families of eicosanoids—prostaglandins, prostacyclins, thromboxanes and leukotrienes
--For each of the four above, there are two or three separate series, derived either from an ω-3 or ω-6 EFA.
--These series' different activities largely explain the health effects of ω-3 and ω-6 fats.
Where is arachidonic acid "stored" in the cells? in membranes, commonly in the middle position on glycerol backbone of a phospholipid.
What enzymes release arachidonic acid from "storage"? via a 2nd messenger system involving a stimulus that binds to a receptor on the cell, triggering phospholipase A2 (which requires Ca++) to liberate A.acid from phosphatidyl choline, or phospholipase C to libertate it from phosphatidylinositol biphosphate via a 2-3 step process.
How do cyclooxygenase and lipooxygenase systems for the synthesis of eiconsanoids differ? First, sameness: both are made/activate?? in platelets in plasma.
The cyclooxygenase system converts arachidonate into PGG2 then PGH2, precurors for prostaglandins (PGs) and thromboxanes (TXs). "cyclic pathway"
The lipoxygenase system converts arachidonate into HPETEs, precursor for leukotrienes. "linear pathway"
What are NSAIDS? Non-steroidal anti-inflammatory agents such as aspirin (irreversible) and ibuprofen (reversible) which inhibit cyclooxygenase.
Low dose aspirin therapy (COX 1) permanently blocks cyclooxygenase to avoid clots.? Aspirin impacts endothelial cells they make more what??? Up regulate production of what?? Have to make new platelets via megakaryocytes to get more platelets to get more active cyclooxygenase.
At what step do NSAIDS interfere with eicosanoid production? They interfere with the conversion of freed arachidonic acid via cyclooxygenase to prostaglandins. Arachidonic acid can still be converted to epoxides and leukotrienes.
At what step do steroidal anti-inflammatory agents interfere with eicosanoid production? They stop the arachidonic acid from being freed from the membrane, by synthesizing a protein (lipocortin) that inhibits phospholipase A2.
Explain the naming of prostaglandins and thromboxanes (together known as prostanoids). PGs, TXs and LTs are grouped according to the number of double bonds in their hydrocarbon chains, ie by series.
How do thromboxanes differ from prostaglandins?
THROMBOXANES
--from platelets
--aggregation of cells (which cells??)
--vasoconstriction
--increase BP
PROSTAGLANDINS
--made in many tissues
--pro and anti inflam
--contractions of smooth muscle
--lowers BP
--regulates gastric secretion
--regulates body temp
--regulates platelet aggregation
--control of inflammation
--vascular permability
--aspirin inhibits production of these
What are some prostaglandins labeled "pro-inflammatory" and others "anti-inflammatory"? Of the PGs, Series 1 and 3 are anti-inflammatory, series 2 are pro-inflammatory.
WIKI: The ω-6 eicosanoids are generally pro-inflammatory; ω-3's are much less so. The amounts and balance of these fats in a person's diet will affect the body's eicosanoid-controlled functions, with effects on cardiovascular disease, triglycerides, blood pressure, and arthritis. Anti-inflammatory drugs such as aspirin and other NSAIDs act by downregulating eicosanoid synthesis.
What are the precursors of series 1, series 2, and series 3 eicosanoids? First: trans double bonds are at position 13, cis double bonds at positions 5 and 17. The hydroxyl group at C15 is required for biological activity.
SERIES 1
--has double bond at 13-14
--precursor is 8, 11, 14-Eicosatrienoic acid, aka linoleic omega 6
--is anti-inflammatory
SERIES 2
--has double bond at 13-14 and 5-6
--is pro-inflammatory
--precursor is regular arachidonic acid, C20:delta 5, 8, 11, 14
SERIES 3
--has double bond at 13-14 and 5-6 and 17-18
--is anti-inflammatory
--precursor is Eicosapenaenoic acid, C20 delta 5, 8, 11, 14, 17, aka linolenic omega 3
Be able to use the name of a prostaglandin or a thromboxane to identify the series to which it belongs. OK. Let's see. The name will be PG or TX plus a letter, plus a delta and some numbers. The delta and numbers indicated where the double bonds are. All have 13-14 bonds, so if that's the only one it's series 1. 2nd series has 5-6 unsats. 3rd has 17-18 unsats. Memorize memorize memorize.
How do leukotrienes differ from prostaglandins and thromboxanes?
--they're an open ring structure, whereas prostaglandins are carbon cycles and thromboxanes are heterocycles
--naming involves numerical subscript denoting # of double bonds (unsats)
--LT's made via linear pathway, enzyme = lipooxygenase
----LINEAR: arachidonic acid --> 5-HPETE --> leukotrienes
--PGs & TXs synthesized via cyclic pathway, enzyme = cyclooxygenase (COX I and II)
--INHIBITION: steroids inhibit all of them, but aspirin doesn't inhibit lipoxygenase (it blox COX), so leukotrienes are not inhibited by aspirin (& other NSAIDS)
--leukotrienes are the only ones made & delivered by macrophages, neutrophiles, monocytes
--leukotrienes are the only ones that cause chemotaxis
--leukotrienes are the only ones that encourage cell to cell adhesions
LEUKOTRIENES (LTs)
--produced by macrophages incl neutrophils, monocytes
--LINEAR PATHWAY
--inflammatory
--Fx: chemotaxis (attract WBC's), vasoconstriction esp in bronchitis
--something about cell adhesions
--aspirin doesn't affect them
--have no ring
--open chain structure with 1 conjugated and 2 non-conjugated double bonds (1 C spacers)
--derived from HPETEs which is from arachidonic acid
--HPETE - hydroperoxyeicosatetraenoic acid (don't ask me to type it again)
--naming: LT plus additional letter that denotes modification of parent chain, subscript numeral is # of unsats
PROSTAGLANDINS (PGs)
--a carbon cycle plus two hydrocarbon tails of 7 and 8 carbons
--CYCLIC PATHWAY
--made by many tissues
--pro and anti-inflammatory
--lowers BP
--regulates gastric secretions: (not in SSL notes)
--regulates body temp
--regulates platelet aggregation
--controls imflam
--affects vascular permeability
--aspirin works on these
--from prostanoic acid, thromboxane comes from same parent compound
--bonds at 8 & 12 in trans relationship (tails can't stack, are offset)
--all natural prostaglandins have a hydroxyl at C15
--20 carbons, bend in the middle around a five sided ring, two lipidy tails
--naming: PG plus A, B, E, F, I, D, G, H plus a series that indicates where the unsaturations are in the tails The letter after PG denotes the attachments on the five membered ring that is the "head".
--PGA & B interconvert
THROMBOXANES
--made by platelets
--CYCLIC PATHWAY
--made from PG's so also blocked by aspirin, NSAIDS
--cause aggregations of cells. (which cells???)
--cause vasoconstriction
--increase BP
--inflammatory
--naming: TX plus extra letter denotes ring variation, numberical subscript gives # of dbl bonds in hydrocarbon tail chains
--series are the same as the prostaglandins, series 1 has unsats at 13-14, series 2 has unsats at 13-14 and 5-6, and series 3 has unsats at those plus 17-18
--TXA2 involved in platelet aggregation
--is a heterocycle because there is oxygen in the ring
ASPIRIN BLOCKS THE CYCLIC PATHWAY
--COX (cyclooxygenase) is made in platelets maybe other places too
--has two catalytic sites hence I and II
--aspirin acetylates an active site
----ARACHIDONIC acid --/--> PG's or TX's
--low dose aspirin therapy permanently blocks COX I, reduces ability to clot
----CYCLIC: arachidonic acid --> PGG2 --> PGH2 -->TX or PG
----to get more COX I you have to make more platelets (megakaryocytes)
--other NSAIDS such as ibuprofen REVERSIBLY block the pathway
EICOSANOIDS
--derived by folding arachidonic acid, which we can synthesize by elongating shorter unsaturated fatty acids, arachidonic is 20C has unsats at 5, 8, 11, 14.
--precursors for prostaglandins, leukotrienes, prostacyclines and thromboxanes
--speed of synthesis depends on concentration of arachidonic
--product made depends on what enzymes are present
--used for local signalling (auto or paracrine, not in blood)
--short half life
--work on cell surface receptors
--often use cGMP pathway
--Fx variable; smooth muscle action--control blood flow, local BP up or down, inflam up or down, secretins up or down, immune effectors
--stored in membrane phospholipids, on the middle carbon of the glycerol backbone
--linoleic and linoleic acids are also stored on the middle carbon in phospholipids
