Week 6: Eicosanoids Flashcards
What are eicosanoids, and what common chemical precursor are they derived from?
Eicosanoids are derived from arachidonic acid, and are short-lived signaling molecules. They include the prostaglandins and thromboxanes (cyclic), and leukotrienes and other eicosanoids (linear).
What are the essential dietary fatty acids that relate to eicosanoids?
Linoleate and a-linolenate are both essential dietary FAs
Which phospholipase is involved in the release of arachadonic acid from glycerophospholipids? What activates it and what inhibits it?
Phospholipase A2 is involved in cleaving arachidonate from parent glycerophospholipids. It is activated by hormonal, neuronal, or physical stimulation, and is inhibited by glucocorticoids.
What is the key enzyme involved in the formation of thromboxanes and other prostaglandins? What blocks its action, and how?
The cyclooxygenase (COX) enzyme is involved in a two-step prep process for prostaglandins and thromboxanes. Its function can be blocked when aspirin or other related NSAIDs add an acetyl group to a serine moiety at an active site on the COX enzyme.
What are the two isoforms of the main enzyme involved in the inflammatory response? What is the difference between the two? Why do we want to create drugs that only arrest the function of one of them?
COX1 and COX2.
COX1 is a “housekeeping” enzyme, that is constitutively expressed, and takes part in gastric protection, maintenance of renal bloodflow, and vascular homeostasis
COX2 is involved in tissue-specific inflammation, and produces molecules that recruit inflammatory mediating cells and other tissue repair elements to the site of inflammation.
Because COX1 is mostly unrelated to inflammation, we want to block the activity of COX2 ONLY, and not COX1.
What does arachadonic acid become, and what enzymes mediate this process?
Arachadonic acid becomes PGH2 via Cyclooxygenase and peroxidase, and from there can become the prostaglandins, thromboxanes, and other short-lived signaling molecules
What are prostaglandins?
They are cyclic, short-lived, hormone-like signaling molecules. The prostaglandins are a group of lipids made at sites of tissue damage or infection that are involved in dealing with injury and illness. They control processes such as inflammation, blood flow, the formation of blood clots and the induction of labour.
What are thromboxanes?
Thromboxanes are substances produced by platelets, and work in blood clotting, constriction of blood vessels, and platelet aggregation.
How do the prostaglandins and thromboxanes work counter to one another?
Some early prostaglandin/prostacyclin molecules have very brief anti-platelet aggregation properties, while thromboxanes have platelet aggregation properties. This helps prevent massive platelet buildup in blood vessels that would completely block off the vessel.
How does daily low-dose aspirin help prevent clot aggregation in patients with high BP?
Aspirin inhibits COX enzymes that are already present in the system. Thrombocytes/platelets, which are anucleated, do not contain the DNA or machinery necessary to produce new thromboxanes that cause platelets to aggregate, and their COX enzymes are thus constitutively inhibited by daily aspirin.
However, endothelial cells of blood vessels, which produce prostaglandins, are nucleated, and can therefore continue to produce signaling molecules once new COX enzymes are translated. This allows for continued expression of aggregation-reducing COX enzymes and their product prostaglandin molecules.
What is the function of leukotrienes? What is different about their formation pathway compared to the prostaglandins and thromboxanes? What are some other, similar molecules in this family?
The leukotrienes are short-lived signaling molecules that cause airway constriction, as well as the production of mucus and fluid. Production of these molecules is involved in the allergic and asthmatic response.
Leukotrienes, along with lipoxins, hepoxilins, and epi-lipoxins are all linear signaling molecules, whereas the prostaglandins and thromboxanes are cyclic.
What enzyme helps catalyze the formation of leukotrienes? What enzyme does it take the place of in the prostaglandin/thromboxane-forming pathway?
The COX enzyme normally used in the prostaglandin/thromboxane-forming pathway is replaced by lipoxygenase in the leukotriene/hepoxilin/lipoxin/epi-lipoxin formation pathway
What leukotriene is involved in the pro-inflammatory reaction? What does it cause?
Leukotriene B4 (LTB4) promotes inflammation that is involved in atherosclerosis.
What leukotrienes are involved in immune inflammatory reactions? What major systemic issue can arise from their action?
LTC4, LTD4 and LTE4 are all important mediators of immune-mediated inflammation, and can cause anaphylaxis.
How is asthma commonly treated as it relates to the leukotrienes?
Inhibition of the 5-lipoxygenase enzyme, and/or binding of activator proteins are common ways to reduce the production of the leukotrienes involved in the asthmatic response.
