Biochemistry Exam Iii - Eicosanoids

Front 1

Include prostaglandins (PG), thromboxanes (TX), and leukotrienes (LT)

Potent regulators of cellular function

Act as “local” hormones

Have a major role in the inflammatory response (e.g. infection or injury)

Also have roles in smooth muscle contraction and regulation of blood pressure

Many have very short half-lives

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Eicosanoids

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Small protein molecules

Signal other cell types for communication with one another

Regulated by eicosanoids, which regulate wich cells come in/out

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Know that cells will be releasing cytokines.

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EPA and DHA are linked to synthesis of eicosanoids.

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EPA/DHA suppress/repress inflammation

Omega 6 are proinflammatory

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Most common precursor is arachidonic acid (eicosatetraenoic acid – n-6 polyunsaturated fatty acid – PUFA)

Arachidonic acid is synthesized from the essential fatty acid ________ (plant oils)

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linoleate

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1. Arachidonic acid is released from the lipid bilayer as a consequence of activation of membrane bound phospholipase A2 or phospholipase C

2. This occurs in response to the action of histamine or cytokines

3. Phospholipase A2 is specific for sn-2 position of phospholipids

4. Phospholipase C hydrolyzes phosphorylated inositol from phosphatidylinositols (DAG containing arachidonic acid)

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Action of phosolipases

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Denotes type of prostaglandin

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PG 'letter'

R7 = seven linear carbons attached to ring

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Denotes whether hydroxyl gorup is coming out/into the plane

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alpha

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Where the prostaglandin came from:

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Number subscript

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From Eicosatrienoic acid

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Subscript 1

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From arachadonic acid

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Subscript 2

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From DHA or EPA

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Subscript 3

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Six membered ring

Differ in location of the oxygen

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Thromboxanes

TXA2 most common thromboxane

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PGH2 can be interconverted

Isomerases
- Can obtain a variety of prostaglandins

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From PGH2

1. Thromboxanes (TXA2)
2. PGI2 (prostacyclin)
3. PGE2 -> FGF2a
4. PGD2

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Increase:
- Vasodilation
- cAMP

Decrease

Platelet aggregation   

Leukocyte aggregation 
IL-1a and IL-2 (cytokines with a role in lymphocyte proliferation)

T-cell proliferation (specific subsets have specific roles)

Lymphocyte migration

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PGI2 (procyclin)

PGE2

PGD2

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Increases

Vasoconstriction

Bronchoconstriction

Smooth muscle contraction

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PGF2α

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Increases
- Vasconstriction
- Platelet aggregation
- Lymphocyte proliferation
- Bronchoconstriction

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Thromboxane A2

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NSAIDs - Target COX 1 and 2

COX-2: Production is enhanced only in inflammatory tissue in response to a particular type of inflammation.

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Problem with drugs that target both Cox enzymes:
- Lining of gut is destroyed.

Cox-2 - advantage, only expressed by specific inflammatory tissues

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5-lipooxygenase
12-lipooxygenase
15-lipooxygenase

What does the number represent?

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The number denotes where the enzyme puts the hydroperoxi group.

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Only this enzyme gives rise to lipoxins

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5-lipooxygenase

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Increases
- Leukocyte aggregation
- INF-y (cytokine)
- IL-1, IL-2 (cytokines)
- T-cell proliferation
- Vascular permeablity

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LTB4

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Increase

- Vascular permeability
- INF-y, IL (interleukin)
- Bronchoconstriction

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LTC4 and LTD4

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Cytochrome P450 - very large and diverse superfamily of hemoproteins.

Cytochromes P450 use both exogenous and endogenous compounds as substrates in enzymatic reactions.

Usually part of multicomponent electron transfer chain called P450-containing systems.

Involved in synthesis and action of epoxides, HETEs, and diHETES

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Epoxides produce HETEs and 5,6 diHETEs

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Generated through free radical damage.
- Occurs at SN-2 position
- Used in diagnosis of oxidative stress, ie, Alzheimers.

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Non-enzymatic production of isoprostanes

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Has a role in protecting from inflammatory insults to brain and other tissue.

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Protectins

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Major components of fish oil are the n-3 polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)

EPA and DHA are involved in the production of resolvins and protectins

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EPA (20:5),

DHA (22:6)

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(20:5),

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EPA

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(22:6)

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DHA

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Main points:
- GIve rise to protectins and resolvins

- Cross talk exists between DHA and EPA

- Role in leukocyte migration (cell-cell signaling and communication)

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Importance of EPAs and DHAs

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