CC2 - Prostaglandins

Eicosanoid

• eicosa — Greek for "twenty"

• signaling molecules

• the networks of controls that depend upon eicosanoids are among the most complex in the human body

1. Eicosapentaenoic acid

2. Arachidonic acid

3. Dihomo-gamma-linolenic acid

The collective term for oxygenated derivatives of three different 20-carbon fatty acids

Eicosapentaenoic acid (EPA

an ω-3 fatty acid with 5 double bonds

Arachidonic acid (AA)

an ω-6 fatty acid, with 4 double bonds

Dihomo-gamma-linolenic acid (DGLA)

an ω-6 fatty acid, with 3 double bonds.

20-carbon fatty acids

eicosanoids are made by oxidation of ____________________

Omega 3 (ω-3) or omega-6 (ω-6)

Eicosanoids are derived from this types of fatty acids

ω-6 eicosanoids

pro-inflammatory eicosanoids

ω-3 eicosanoids

less pro-inflammatory

Effects of imbalance in eicosanoid-controlled functions

1. Cardiovascular disease

2. Triglycerides

3. Blood pressure

4. Arthritis

Aspirin (other NSAIDs)

anti-inflammatory drugs that down regulate eicosanoid synthesis

Sub-families of Eicosanoids (Prostaglandin)

Types of prostaglandin:

• Prostacyclins

• Thromboxanes

• Lipoxins

• Leukotrienes

Eicosanoids Sub-Families (Notes)

• For each, there are two or three separate series, derived from either an ω-3 or an ω-6 EFA

• In these series different activities largely explain the health effects of ω-3 and ω-6 fat

Classic Eicosanoids

Leukotrienes and Prostanoids

Three types of Prostanoids

• Prostaglandins (PG)

• Prostacyclins (PGI)

• Thromboxanes (TX)

Several other classes are also technically termed eicosanoid they includ

• Hepoxilins

• Resolvins

• Isofurans

• Isoprostanes

• Lipoxins

• Epi-lipoxins

• Epoxyeicosatrienoic acids (EETs) and Endocannabinoids.

A particular eicosanoid is denoted by a four-character abbreviation, composed of:

1. Its two-letter abbreviation (above)

2. One A-B-C sequence-letter and

3. A subscript, indicating the number of double bonds.

3 double bonds

The EPA-derived prostanoids have ________________ (e.g., PGG3, PGH3, PGI3, TXA3)

5 double bonds

EPA-derived leukotrienes have _____________ (LTB5).

2 double bonds

AA-derived prostanoids have ___________ (e.g. PGG2, PGH2, PGI2, TXA2)

4 double bonds

AA-derived Leukotrienes have _________ (LTB4)

Prostaglandin E₁ — The 5-member ring is characteristic of the class.

Thromoxane A₂ — Oxygens moved into the ring

Leukotriene B₄. — Note the 3 conjugated double bonds

Prostacyclin I₂ — The second ring distinguishes it from the prostaglandins.

Leukotriene E₄ — Example of a cysteine leukotriene

PGD₂

promotion of sleep

PGE₂

smooth muscle contraction; including pain, heat, fever; bronchoconstriction

PGE_2α

Uterine contraction

PGI₂

inhibition of platelet aggregation; vasodilation; embryo implantation

TXA₂

stimulation of platelet aggregation; vasoconstriction

15d-PGj₂

Adipocyte differentiation

LTB₄

leukocyte chemotaxis

Cysteinyl-LTs

Anaphylaxis; bronchial smooth muscle contraction

Inflammation; immunity

Eicosanoids are mainly in ___________ or ____________

Central Nervous System

As messengers in the ___________________. They are found in most living things

hormones

In humans, eicosanoids are local ____________ that are released by most cells, act on that same cell or nearby cells (i.e., they are autocrine and paracrine mediators), and then are rapidly inactivated

short half-life

Eicosanoids have a __________, ranging from seconds to minutes

Dietary antioxidants

Inhibit the generation of some inflammatory eicosanoids, e.g. trans-resveratrol against thromboxane and some leukotrienes.

G protein-coupled receptor

Most eicosanoid receptors are members of the __________________ superfamily

Specific receptors of Leukotriene:

• CysLT1 (Cysteinyl leukotriene receptor type 1)

• CysLT2 (Cysteinyl leukotriene receptor type 2)

• BLT1 (Leukotriene B4 receptor)

Specific receptors of Prostanoids:

• PGD2: DP-(PGD2)

• PGE2:

  • EP1-(PGE2)

  • EP2-(PGE2)

  • EP3-(PGE2)

  • EP4-(PGE2)

• PGF2α: FP-(PGF2α)

• PGI2 (prostacyclin): IP-(PGI2)

• TXA2 (thromboxane): TP-(TXA2)

COX and LOX

Two families of enzymes catalyse fatty acid oxygenation to produce the eicosanoids

Cyclooxygenase (COX)

generates the prostanoids

Lipoxygenase (LOX)

in several forms

5-lipoxygenase (5-LO)

generates the leukotrienes and via trans cellular biosynthesis is also involved in lipoxin generation.

synthesized

Eicosanoids are NOT stored within cells, but are ______________ as required.

cell membrane; nuclear membrane

Eicosanoids are derived from the fatty acids that make up the _____________ and ______________

Eicosanoid biosynthesis

Begins when a cell is activated by mechanical trauma, cytokines, growth factors or other stimuli. (The stimulus may even be an eicosanoid from a neighboring cell; the pathways are complex.)

Phospholipase

• Eicosanoid biosynthesis triggers the release of a _______________ at the cell membrane

• travels to the nuclear membrane

Phospholipase A₂

The phospholipase catalyses ester hydrolysis of phospholipid

Phospholipase C

The phospholipase catalyses ester hydrolysis of diacylglycerol

rate-determining step

Phospholipase frees a 20-carbon fatty acid. This hydrolysis appears to be the ______________________ for eicosanoid formation.

Phospholipase A2 ( cPLA2)

• The fatty acids may be released by any of several phospholipases.

• Of these, type IV cytosolic phospholipase A2 (cPLA2) is the key actor

• As cells lacking cPLA2 are, in general, devoid of eicosanoid synthesis.

SN2

phospholipase cPLA2 is specific for phospholipids that contain AA, EPA or GPLA at the ______ position

Platelet-activating factor

cPLA2 may also release the lysophospholipid that becomes ____________________

Peroxidation and reactive oxygen species

• The free fatty acid is oxygenated along any of several pathways

• The eicosanoid pathways (via lipoxygenase or COX) add molecular oxygen (O2)

chiral

Although the fatty acid is symmetric, the resulting eicosanoids are _______

Stereoselectivity

The oxidations proceed with high _____________ (enzymatic oxidations are considered practically stereospecific)

hazardous

The oxidation of lipids is _______________ to cells, particularly when close to the nucleus.

Reactive O2 notes

• There are elaborate mechanisms to prevent unwanted oxidation.

• COX, the lipoxygenases and the phospholipases are tightly controlled

Isoforms

There are at least eight proteins activated to coordinate generation of Leukotrienes. Several of these exist in multiple __________

Reactive oxygen species (ROS)

Oxidation by either COX or lipoxygenase releases _______________________ and the initial products in eicosanoid generation are themselves highly reactive peroxides

adducts

LTA4 can form _________ with tissue DNA.

Cellular damage

Other reactions of lipoxygenases generate ____________

atherosclerosis

Rat(murine) model studies have shown to implicate 15-lipoxygenase in the pathogenesis of

compartmentalized

The oxidation in eicosanoid generation is ___________; this limits the peroxides' damage.

DNA; protein

In biology, an adduct is a complex that forms when a chemical binds to a biological molecule, such as ________ or ________

exposure to carcinogens

DNA adducts are altered forms of DNA that occur as the result of ____________________ (in the case of smokers these would be the carcinogens present in cigarette smoke)

DNA adduct

once formed, can be repaired, resulting in a return to the original DNA structure or be mis-repaired, resulting in a mutation.

Protein adduct

DO NOT have adverse biological effects but can be used as a measure of exposure to a foreign substance

detoxification of ROS

• The enzymes that are biosynthetic for eicosanoids -- e.g., glutathione-S-transferases, epoxide hydrolases, and carrier proteins belong to families whose functions are involved largely with cellular detoxification.

• This suggests that eicosanoid signalling might have evolved from the ________________