Lecture 47 Eicosanoids Flashcards
What is an eicosanoid?
Signaling molecules made from unsaturated essential fatty acids.
Mediate physiologic (inflammation) and pathologic (hypersensitivity) reactions
All cells make them except for erythrocytes
They are produced rapidly and degraded rapidly and are not stored
They are short-lived and therefore only function locally in an autocrine or paracrine fashion
What types of eicosanoids are there and where are they made?
Prostaglandin
Prostacyclin: a prostaglandin with an extra ring
Thromboxane
Prostanoid: collective term for prostaglandin, prostacyclin, and thromboxane; produced in most cells
Leukotriene: made in leokocytes
Epoxide: made in macrophages
Eicosanoid nomenclature
First two letters abbreviate type
Third letter for components of the ring on prostaglandin
Number indicates series (denotes # of double bonds in the linear portion of the molecule)
Example: PGH2
What are the other names for omega-6 and omega-3 fatty acids?
omega-6: Linoleic acid
omega-3: Linolenic acid
Describe pathway from dietary fatty acids to eicosanoid release for signaling.
From diet: linolenic and linoleic acids
In body: the acids are metabolized into different types of fatty acids that become part of plasma membrane phospholipids; w-3 becomes EPA, w-6 becomes AA, DGLA
Signaling through GPCR’s activates phospholipase enzyme which liberates these fatty acids from membrane phospholipids to produce free AA, EPA, DGLA
Free fatty acids are used to make eicosanoids that are released from the cell to signal surrounding cells.
Which fatty acids do americans get more of in their diet?
w-6 linoleic acid
Which series of PG’s cause more inflammation and thrombosis?
Series 2 (PG’s that have two double bonds outside the ring)
These come from omega-6 linoleic acid and are AA
Series 1 is DGLA, and series 3 is EPA
PGI vs TXA in platelet activation
Platelets synthesize and secrete the prostanoid thromboxane (TXA) to stimulate neighboring platelets to enhance aggregation
Endothelial cells prevent too much platelet aggregation by making and secreting the prostaglandin prostacyclin (PGI)
PGI binds to platelets and interferes with thromboxane signaling to inhibit aggregation
The series of each prostanoid determines relative efficacy of each signaling molecule
What is the result if AA is used to synthesize prostanoids and their effect on platelet aggregation and inflammation.
AA produces series 2 prostanoids such as TXA2 and PGI2. This shifts the platelets/endothelium to a stronger platelet aggregation response.
What happens to the platelet response if EPA is used to synthesize prostanoids?
Series 3 prostanoids are synthesized such as TXA3 and PGI3.
Platelet response and aggregation will be weaker than the response of series 2 prostanoids.
What is PLA2?
Phospholipase A2
It breaks down membrane phospholipids to create the free fatty acids (AA,EPA,DGLA) that are used to make the eicosanoids
Describe the production of leukotrienes
They are called leukotrienes because they are made in leukocytes (white blood cells [and in mast cells]) and they have three double bonds in a row.
PLA2 breaks down membrane phospholipids to make AA
In leukocytes and mast cells, enzyme 5-lipoxygenase converts AA to leukotriene A4, and in some cells to a group called cysteinyl leukotrienes
What do cysteinyl leukotrienes do?
They act on cell surface receptors (CysLT receptors) of target cells to:
Contract bronchial and vascular smooth muscle
Enhance mucus secretion in airway and gut
Recruit leukocytes to site of inflammation
Increase capillary permeability
What is the function of Zyflo?
It is an example of a 5-lipoxygenase inhibitor
This inhibits the production of leukotrienes and treats asthma because leukotrienes are involved with bronchial constriction
What is the function of Singulair?
It is an example of a cysteinyl leukotriene receptor antagonist
This is a treatment for asthma, bronchoconstriction, and allergic rinitis because it prevents binding of cysteinyl leukotrienes to CysLT receptors on bronchial smooth muscle and inflammatory cells
What is PGH synthase?
It includes Cyclooxygenase (COX) and Peroxidase
Converts AA, EPA, DGLA into prostaglandins, prostacyclin, and thromboxanes
What is the rate limiting step of eicosanoid synthesis?
PLA2 hydrolyzing membrane phospholipids to produce the free fatty acids that are precursors to eicosanoids (AA,EPA,DGLA)
Explain the first committed step of eicosanoid synthesis
Synthesis of PGH2
AA–>Intermediate–>PGH2
First reaction catalyzed by cyclooxygenase, causes cyclization and oxygenation of AA and requires Heme and 2 oxygen atoms
Second catalyzed by Peroxidase, glutathione provides reducing power to form PGH2
What does cyclooxygenase (COX) do?
COX helps to convert AA into PGH2 which is the first committed step of eicosanoid synthesis
What types of receptors do PGs and TX interact with and what is the result of each?
PG’s are released by endothelial cells and they bind to Gs-linked GPCR’s. This stimulates adenylate cyclase and increased cAMP and inhibits aggregation of platelets
TX are released by platelets, bind to Gq-linked GPCR’s and stimulate IP3/DAG to increase Ca2+ levels, PKC activity and increase aggregation of platelets
Where are prostaglandins degraded and with what enzyme?
They become inactive near their site of origin, but they are degraded in the capillaries of the lungs.
The enzyme involved is 15-hydroxyprostaglandin dehydrogenase
General functions of COX-1 and COX-2
COX enzymes in general convert AA into PG’s
COX-1 is constitutively made in most cells and is required for healthy gastric tissues, renal homeostasis, and platelet function
COX-2 is expressed only in certain cells, it mediates inflammation, pain, and fever
Actions of Aspirin
An NSAID
Irreversible inhibitor of COX-1 and COX-2
Acts by acetylating serine in the active site of COX enzymes
3 Actions: anti-inflammatory, analgesic, antipyretic
Actions of ibuprofen (brand name Advil)
An NSAID
Reversible competitive inhibitor of COX that blocks the channel for the substrate of both COX enzymes
3 Actions: anti-inflammatory, analgesic, antipyretic
Function of celebrex
Celebrex binds to the active site of only COX-2 which has a wider substrate channel than COX-1. This allows celebrex to have the good actions of NSAID’s (but isn’t one?) without the side effects of gastrointestinal bleeding, but is linked to heart attacks
Actions of Tylenol (acetaminophen)
Inhibits Neither COX-1 nor COX-2
Acts on the CNS, is not an NSAID, reduces pain and fever but is not anti-inflammatory and does not affect platelet function
Actions of steroids
Glucocorticoids reduce inflammation and suppress immunity
Inhibit prostanoid synthesis by decreasing PLA2 activity which affects all eicosanoid synthesis, and they decrease COX-2 gene transcription which affects prostanoid synthesis.
