Biochemistry-Eicosanoids Flashcards Preview

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Flashcards in Biochemistry-Eicosanoids Deck (25):

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.


Why don’t you want to take Vioxx after a motorcycle accident?

COX-2 opposes the pro-thrombotic activity of COX-1 and TxA2 by synthesizing anti-thrombotic PGI2. If you take Vioxx, which inhibits COX-2, you are increasing your risk for thrombosis after vascular injury.


Why are you less likely to feel pain in a stressful situation?

Stress = release of cortisol. Cortisol activates lipocortin (Annexin) which inhibits phospholipase A2 activity and prevents release of arachadonic acid. Less AA release = less input into cyclooxygenase pathway = less inflammatory eicosanoids. Additionally, it decreases expression of COX-2 mRNA and thus reduces COX-2 expression.


What enzymes are responsible for the rapid inactivation of prostaglandins?

1) PG Dehydrogenase oxidizes OH to ketone 2) Beta and omega oxidation finishes the job so that it can be more soluble and be excreted in the urine.


What reactions help to deactivate TxA2?

1) Add H2O and it will get rid of the epoxide 2) Beta-oxidation will make it more soluble so it can be excreted in the urine


How are the pulmonary bronchoconstrictors generated from arachadonic acid?

5-lipoxygenase -> -> LTC4 -> LTD4 -> LTE4. These all bind to the cys-LT receptors in the lungs to induce inflammation.


Why do 10% of asthmatics who take NSAIDs develop bronchospasms?

Strong inhibition of the COX pathway shunts excess AA to the lipoxygenase pathway and you get increased production of leukotrienes that cause increased bronchospasms.


What eicosanoids have anti-inflammatory effects?

Lipoxins. Note that COX-2 can induce production of these that is triggered by aspirin acetylation of COX-2.


What molecules are good markers for oxidative stress?

Isoprostanes. AA is injured by ROS in the plasma membrane, phospholipase A2 is activated to chop out the injured fatty acid and forms and isoprostane. Isoprostanes have activity similar to other eicosanoids and are excreted in the urine and can be measured.


How does arachadonic acid work with marijuana?

AA + ethanolamine = anandamide. Anandamide has targets in the brain that have analgesic effects that counter other eicosanoids, THC works on the same endocannabinoid receptors in the brain.


Why does sarin gas have analgesic effects?

It inhibits the enzymes that break down the anandamides and endocannabinoids.