Biochemistry-Eicosanoids Flashcards
What is an eicosanoid?
20C polyunsaturated fatty acids w/ 3-5 double bonds
Most common precursor for human eicosanoids
Arachadonic acid
How do eicosanoids differ from hormones?
Autocrine/paracrine instead of endocrine. Act on GPCRs instead of nuclear receptors. Rapidly degraded instead of stable.
How does eicosanoid synthesis get initiated?
A ligand binds to a receptor. 1) Phospholipase A2 is activated and releases arachadonic acid from the plasma membrane. Eicosanoid synthesis begins. 2) Phospholipase C is activated and forms 1,2-DAG from phosphatidylinositol bisphosphate. Diacylglycerol lipase releases AA and a monoacylglycerol. Monoacylglycerol lipase releases arachadonic acid from the remaining monoacylglycerol. Eicosanoid synthesis begins.
How do we get arachadonic acid in the first place?
Linoleoyl-CoA in the diet. It is converted to arachidonyl-CoA in the liver where it is esterified to form membrane phospholipids in the liver. When we need it it is released by a phospholipase, which can be released at the different sites shown below.
How does the structure of thromboxanes differ from that of the prostaglandins?
Thromboxanes have a 6-membered ring. Prostaglandings have a 5-membered ring.
What are the differences between the two cyclooxygenases?
COX-1 is constitutively active. COX-2 is induced by pro-inflammatory stimuli (IL-1, IL-2 and TNF-alpha). This is why it is more desirable to inhibit COX-2, mitigating pain and leaving the stomach alone by leaving COX-1 alone.
What is the rate determining step in eicosanoid synthesis? What follows it? What inhibits this step?
The cyclooxygenase step. It incorporates 2 oxygens into AA that causes cyclization of AA and formation of a peroxide. This is followed by a peroxidase reaction at COX’s other site that uses glutathione to reduce the peroxide to a hydroxy group. NSAIDs inhibit the rate determining step.
What part of COX-1 and COX-2 is exploited by drug companies?
The active site. COX-1 has and Isoleucine where COX-2 has a Valine. COX-2 can accommodate bulkier drugs and thats how it gets exploited. Smaller structures tend to be more specific for COX-1.
Where is the COX enzyme located?
Buried in the lipid bilayer. This is good because this is where the arachidonic acid is also located.
What type of drugs are NSAIDs? How do they work?
Hydrophobic. This is so they can bind to the same active site that arachidonic acid does. Aspirin covalently binds to a Ser in the active site and irreversibly inhibits COX. Other COX inhibitors bind slowly and tightly to the active site and inhibit COX by drug-induced conformational change that is irreversible.
What things are produced by COX-1?
It is constitutively expressed in most cells. It produces TXA2 in platelets and PGE2 & PGI2 (stimulate mucin production)
What things are produced by COX-2?
It is induced in macrophages that were activated by cytokines. It produces PGE2 & PGI2 (modulate inflammation, pain, fever). Note that channeling these eicosanoids into angiogenic factors is implicated in colorectal cancer.
Why is the activity of eicosanoids so variable around the body?
There are different densities of receptors in different areas of the body and some receptors have opposing effects for binding of the same eicosanoid.
Why do we use low-dose aspirin to prevent myocardial infarction?
Platelets have COX-1 activity that produces TxA2, which promotes platelet aggregation. Aspirin irreversibly inhibits COX-1 in platelets, which are anucleate and cannot produce more COX-1, so the effects last 7-10 days. Additionally, you do low dose so you selectively inhibit platelet COX-1 while leaving enterocyte COX-1 alone.