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Y1S2 Biochemistry > Eicosanoid Metabolism > Flashcards

Eicosanoid Metabolism Flashcards

1
Q

What are eicosanoids?

A
  • Eicos means 20
  • Derivatives of fatty acids & are Synthesized in the body
  • They can do an action and its opposite, or two different actions at two different tissues
  • Their precursor is arachidonic acid (20 C), which is not essential but synthesized from the very essential linoleic acid
  • Considered as paracrine and autocrine (affects the cell that produces them or the neighboring ones)
  • Not stored and are synthesized by most tissues excluding RBCs
  • They bind to specific cell surface G-protein coupled receptors and generally increase the levels of cAMP
  • They might bind to nuclear receptors and alter gene transcription
  • They have a wide variety of functions
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2
Q

What are the groups of eicosanoids?

A

1) Prostaglandins (contain a 5C ring cycle)

2) Leukotrienes (linear)

3) Thromboxane (contains a ring cycle)

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3
Q

What is the difference between endocrines and paracrine/autocrine?

A

1) Eicosanoids have a shorter half-life (10-sec - 5 min), which means that their function is limited to nearby cells

2) They do not travel in the blood

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4
Q

Describe prostaglandins

A

1) It is a potent biological molecule

2) Acts like hormones in controlling the body’s processes

3) They are made in most tissues and exert their effects on cells that produce them and the cells in the immediate vicinity

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5
Q

What is the structure of prostaglandins?

A

1) Synthesized from 20-carbon unsaturated fatty acids

2) It is a cyclic compound that includes a 5-carbon ring

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6
Q

What is the meaning of the different things in the Name (Prostaglandins E1)

A

The letter “E” represents the functional group

The number beside it “1” reflects the number of double bonds

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7
Q

What are the biological processes that are regulated by eicosanoids?

A

1) Blood clotting

2) Inflammatory response

3) Reproductive system

4) GI tract

5) Kidneys

6) Respiratory tract

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8
Q

How do eicosanoids regulate blood pressure?

A

1) Thromboxane A2 stimulates the constriction of BV & platelet aggregation

2) Prostacyclin (PGI2) dilates BV and inhibits platelet aggregation

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9
Q

How do eicosanoids regulate the inflammatory response?

A

Prostaglandins mediate some aspects of the inflammatory response

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10
Q

How do eicosanoids mediate the reproductive system?

A

1) Stimulates the smooth muscle by PGE2 (smooth muscle contraction is important during labor)

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11
Q

What are the effects of eicosanoids on the GI tract?

A

1) Prostaglandins inhibit gastric secretions

2) Prostaglandins increase the secretion of protective mucus (which is inhibits by NSAID, causing ulcers)

3) Inhibition of hormone-sensitive lipases

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12
Q

What are the effects of eicosanoids on the kidneys?

A

1) Prostaglandins dilate renal blood vessels, which results in increased water and electrolyte excretion

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13
Q

What is the effect of eicosanoids on the respiratory tract?

A

1) Leukotrienes promotes the constriction of bronchi

2) Prostaglandins promote bronchodilation

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14
Q

What is the structure of thromboxanes?

A

Similar to prostaglandins but with a 6-membered ring instead of a 5

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15
Q

What are the receptors of prostaglandins?

A
  • Prostaglandin receptors can regulate at the second messenger level & the genetic level

1) Cell membrane/intracellular receptor: G-coupled protein receptors, which in turn either stimulate or inhibit the formation of cAMP “2nd messenger”, or it might activate a phosphatidylinositol signal pathway leading to the intracellular release of Ca+2

2) Nuclear receptor: PPAR-y, found in the nucleus, when the prostaglandins attach to them they will activate the transcriptional factors of many genes

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16
Q

Describe the receptors of prostaglandins

A
  • They are specified by the same letter code
  • Multiple receptors for a prostaglandin are specified by subscripts (EP1, EP2, EP3, etc)
  • Effects of a particular prostaglandin might vary in different tissues depending on which receptors are expressed
  • Different receptors for a particular prostaglandin might activate different signal cascades (in different cells PGE2 might activate or inhibit G-proteins leading to either an increase or decrease in cAMP formation)
  • E-class is for prostaglandins while T-class is for thromboxanes
17
Q

What is a phospholipase enzyme?

A
  • They are enzymes that release arachidonic acid (fatty acid) from phospholipids (cell membrane)
  • How do they attach? arachidonate is often esterified to OH on C2 of the phospholipids, especially phosphatidylinositol (PI)
18
Q

What are the types of phospholipases?

A

1) Phospholipase A2 (used for phosphatidylcholine), releasing the arachidonate from the Phospholipids will produce arachidonate & Lysophospholipid

2) Phospholipase C (used for phosphatidylinositol) it cleaves the phosphatidylinositol into diacylglycerol

3) Diacylglycerol Lipase releases Arachidonate linked to C2 of diacylglycerol

19
Q

What is the first step in the synthesis of prostaglandins?

A

The release of arachidonic acid

20
Q

What are the different mechanisms that release arachidonic acid?

A

1) Direct release of the arachidonic acid, not affecting the dynamics of the cell membrane, this is when we have a phosphatidylcholine in the cell membrane and one of the FA’s are arachidonic acid and we have phospholipase A2

2) If we have a phosphatidylinositol in the cell membrane & phospholipase C, we will remove the inositol and 1,2-diacylglycerol is kept, then arachidonic acid will be released in two different ways by two different enzymes the first one will be directly released from 1,2-diacylglycerol via the enzyme diacylglycerol lipase the other product (monoacylglycerol) will release a arachidonic acid via the enzyme monoacylglycerol lipase

  • Arachidonic acid will then go through different pathways to synthesize prostaglandins, leukotrienes, or thromboxanes, this is where NSAIDs come into play inhibiting the enzyme that converts arachidonic acid into prostaglandins, on the other hand SAIDs inhibits the makeup of compound further up the pathway like cortisone which is associated with many side effects
21
Q

What enzyme is targeted by coticosteroid a SAID?

A

Phospholipase A2 inhibits the release of arachidonate (from the beginning of the pathway)

22
Q

What are the two pathways in the synthesis of eicosanoids?

A

1) Cyclic/cyclooxygenase pathway (The committed step is catalyzed by prostaglandin H2 synthase (COX enzyme “inhibited by NSAIDs”), producing prostaglandins, prostacyclins & thromboxanes)

  • All tissues convert arachidonic acid into PGH2, but depending on the type of tissue PGH2 will be converted into different compounds (prostaglandins, prostacyclins, or thromboxanes

2) Lipoxygenase/linear pathway

23
Q

What are the reactions that convert arachidonic acid into PGH2?

A

1) PGH2 synthase adds O2 to the arachidonic acid in a “cyclooxygenase reaction” converting it to PGG2

2) The PGH2 synthase converts PGG2 to PGH2 via the addition of two electrons in a peroxidase rxn

24
Q

What is the metabolic role of PGH2?

A

1) It can be converted to Thromboxane TXA2 via TXA synthase

  • Produced by platelets
  • Stimulates the aggregation of platelets
  • Causes vasoconstriction

2) Converted to different prostacyclins PGI2 via (PGI synthase, PGE synthase, & PGD synthase)

  • Produced by the vascular endothelial cells
  • Inhibits platelet aggregation
  • Causes vasodilation
25
Q

Describe the action of ibuprofen

A

Ibuprofen and NSAIDs in general block the hydrophobic channel “active site” by which arachidonate enters the cyclooxygenase active site

  • They inhibit the cyclooxygenase activity of PGH2 synthase (meaning that they inhibit the formation of prostaglandins “involved in fever, pain & inflammation”, and thromboxane “formation of blood platelets)
  • They inhibit via competitive inhibition, increasing the substrate conc will overcome this inhibition
26
Q

How does aspirin inhibits the formation of prostaglandins?

A

They acetylate a serine residue near the active site of cyclooxygenase preventing the binding of arachidonate

This is a covalent modification inhibition that is irreversible, the only way to overcome it is for the enzyme to degrade and for new ones to come

27
Q

What are the different isoforms of COX-1 & -2?

A

1) COX-1 expressed everywhere in the body

2) COX-2 is Found in most tissues, but its expression is highly regulated via growth factors, cytokines, and endotoxins, on the other hand, cAMP enhances the expression of COX-2

28
Q

What is the function of COX-1?

A

It is essential for thromboxane formation in blood platelets and for maintaining the integrity of the GI epithelium

29
Q

Explain the importance of COX-2

A
  • Its levels increase in inflammatory diseases like arthritis
  • Causes angiogenesis (BV development) which is essential for the growth of tumors
  • COX-2 expression is increased in some cancer cells
30
Q

What are some examples of drugs that are selective inhibitors of COX-2?

A

1) Celebrex

2) Vioxx

31
Q

What is the advantage of using selective COX-2 inhibitors?

A

They are anti-inflammatory and block the pain

  • Less likely to cause gastric toxicity, associated with NSAID that blocks COX-1
32
Q

What causes the tendency to develop blood clots when taking some of the NSAIDs?

A

The decreased production of anti-thrombic (clot-blocking) prostaglandin (PGI2) by endothelial cells

33
Q

What is the third isoform of PGH2 synthase?

A
  • COX-3
  • Mediates pain and fever
  • It is subjected to inhibition by acetaminophen (because acetaminophen/paracetamol) has little effect on COX-1 & COX-2 it lacks an anti-inflammatory activity
34
Q

What are the steps in the synthesis of leukotrienes/linear pathway/lipoxygenase pathway?

A
  • Facilitated by one enzyme called lipoxygenase found in leukocytes

1) arachidonate - 5-HPETE

2) 5-HPETE - Leukotriene-A4 (precursor for other leukocytes)

  • Affected by the NSAIDs to a lesser extent
35
Q

What is the role of leukotrienes?

A
  • They have a role in inflammation
  • Implicated in asthmatic constriction of the bronchioles
36
Q

What are some examples of anti-asthma medications?

A

1) Inhibitor of lipoxygenase (the main drug is the anti-asthma inhaler)

2) Inhibitors of leukotriene-receptor interactions (blocks the binding of leukotrienes to their receptors on the plasma membrane of the airway)

Y1S2 Biochemistry (4 decks)

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