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BIOCHEMISTRY > ME04 - Unsaturated Fatty Acids and Eicosanoids > Flashcards

ME04 - Unsaturated Fatty Acids and Eicosanoids Flashcards

1
Q

Fatty acids which contain 1 double bond (monounsaturated, MUFA) or more than 1 double bond (polyunsaturated, PUFA) in their structure

A

UNSATURATED FATTY ACIDS | Generally derived from vegetables and fish

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2
Q

What happens when Unsaturated fatty acids substituted for saturated fats in the diet,

A

MUFA lowers LDL and increases HDL

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3
Q

Compounds derived from 20-carbon fatty acids (C20 eicosanoic acids)

A

EICOSANOIDS

  • Include prostanoids (prostaglandins, prostacyclins, and thromboxanes), leukotrienes, and lipoxins
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4
Q

What is the main precursor of eicosanoids

A

Arachidonic acid, which may be derived from cell membrane phospholipids or from the diet

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5
Q

Biochemical Importance of Unsaturated Fatty Acids

A

Unsaturated fatty acids maintain membrane fluidity
A high ratio of polyunsaturated fatty acids (PUFA) in the diet lowers cholesterol
Unsaturated fatty acids give rise to local hormones called prostaglandins that mediate pain and inflammation, reproduction, and blood coagulation
Leukotrienes have chemotactic properties that are important in allergic reactions (they are bronchoconstrictors and play a part in the pathophysiology of asthma)

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6
Q

Fatty Acids which Cannot be synthesized in the body

A

Essential Fatty Acids | found in high concentrations in vegetable oils (from plants)

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7
Q

Example of Essential Fatty Acids

A

Linoleic and linolenic acid (both are unsaturated)

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8
Q

Is Arachidonic Acid an essential fatty acid?

A

Arachidonic acid is also esssential, but it is only semi-essential because it can be formed from linoleic acid

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9
Q

Function of Essential Fatty Acids

A

EFAs are required for the synthesis of prostanoids, leukotrienes, and lipoxins
Also found as structural lipids in the cell which preserve membrane structure

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10
Q

FA that lower both plasma LDL and HDL (Seen in nuts, avocado, sesame oil)

A

Omega 6

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11
Q

FA found in plants and fish oils

A

Omega 3

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12
Q

Deficiency symptoms are produced when EFAs are absent from the diet (skin lesions, impaired lipid transport) True or False?

A

True.

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13
Q

Synthesized from a-linolenic acid or obtained directly from fish oils
Important for brain and retinal development

A

DHA (Docosahexanoic acid)

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14
Q

Unsaturated Fatty Acid Synthesis

A

Monounsaturated fatty acids are synthesized by a D9 desaturase system (located in the ER)

Double bonds can be introduced at the D4, D5, D6, and D9 positions but never beyond D9

Plants can synthesize fatty acids with double bonds at the D12 and D15 positions, but mammals cannot (which makes linoleic and linoleic acid essential fatty acids)

The first double bond introduced into a saturated fatty acid is nearly always in the D9 position (As in stearoyl-CoA desaturase)

Additional bonds are always separated by a methylene group

Chain elongation is accomplished by adding 2 carbons to the chain catalyzed by the enzyme elongase

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15
Q

Rate-limiting enzyme in the biosynthesis of monounsaturated fatty acids

A

Stearoyl-CoA desaturase (SCD)

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16
Q

Function of Stearoyl-CoA desaturase (SCD)

A

It catalyzes the 9-cis desaturation of acyl- CoA substrates, the preferred substrates being palmitoyl-CoA and stearoyl-CoA, which are converted to palmitoleoyl-CoA and oleoyl-CoA, respectively

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17
Q

What are the substrates for incorporation into membrane phospholipids, triglycerides, cholesterol esters, and wax esters

A

Palmitoleoyl-CoA and oleoyl-CoA

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18
Q

Function of MICROSOMAL D9 DESATURASE

A

Conversion of Stearoyl-CoA *18C saturated) to Oleoyl-CiA *18-c, unsaturated at d9 or w9)

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19
Q

Receptors which is expressed in the liver that when absent, the liver esterifies fatty acids
to triglycerides

A

PEROXISOME PROLIFERATOR- ACTIVATED RECEPTORS (PPARs)

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20
Q

FATE OF ESTERIFIED LIPIDS

A

Esterified lipids are either exported by lipoproteins, or accumulate in the liver

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21
Q

What are the potent activators of PPAR-alpha

A

Fibrates, which lower serum lipids,

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22
Q

Transcription Factor which is most important in adipose
tissues because it Stimulates synthesis of many proteins involved in lipid metabolism

A

PPAR-Y TRANSCRIPTION FACTOR

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23
Q

What activates PPAR-Y TRANSCRIPTION FACTOR

A

PUFA

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24
Q

How is PPAR-Y TRANSCRIPTION FACTOR involved in Type 2 DM

A

Involved in type 2 diabetes pathogenesis by inducing PEP carboxykinase, which increases the conversion of pyruvate and lactate to glycerol-3-phosphate in adipose tissue

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25
Q

What is the mechanism of action of the insulin sensitizer Rosiglitazone (Avandia), a PPAR-gamma agonist

A

PPAR thus promotes TG synthesis even when insulin is low and little glycerol-3- phosphate is produced from glucose

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26
Q

What are the Most prominent Eicosanoids

A

Prostaglandins (PG)

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27
Q

Collectively identified as prostanoids

A

PG and thromboxanes (TX)

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28
Q

Origin of Eicosanoids

A

Prostaglandins were originally shown to be synthesized in the prostate gland,

Thromboxanes from platelets (thrombocytes) and

Leukotrienes from leukocytes, hence the derivation of their names

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29
Q

Differentiate the ring structure of Eicosanoids

A

In PG, the ring structure is cyclopentane Prostaglandin E2
In TX, the ring is a cyclic ether (Oxane ring)

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30
Q

The principal eicosanoids of biological significance to humans are derived from ________?

A

Arachidonic Acid

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31
Q

All mammalian cells except erythrocytes synthesize eicosanoids. True or False?

A

True.

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32
Q

How are eicosanoids referred as local hormones

A

All eicosanoids function locally at the site of synthesis, thus they are also referred to as local hormones

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33
Q

SYNTHESIS OF ARACHIDONIC ACID FROM LINOLEIC ACID

A

The major source of arachidonic acid is through its release from cellular stores
Within the cell, it resides predominantly at the C-2 position of membrane phospholipids and is released from there upon the activation of phospholipase A2

34
Q

Rate-limiting enzyme of eicosanoid biosynthesis

A

Phospholipase A2

35
Q

FUNCTION OF EICOSANOIDS

A

Inflammatory responses (predominantly those of the joints, skin and eyes),

on the intensity and duration of pain and fever, and

on reproductive function (including the induction of labor)

ROLE IN inhibiting gastric acid secretion, regulating blood pressure through vasodilation or constriction, and inhibiting or activating platelet aggregation and thrombosis.

36
Q

Two main pathways are involved in the biosynthesis of eicosanoids

A

The prostaglandins and thromboxanes are synthesized by the cyclic pathway
The leukotrienes and lipoxins are synthesized by the linear pathway.

37
Q

CYLCIC PATHWAY

A

Synthesis of the clinically relevant prostaglandins and thromboxanes from arachidonic acid.

Numerous stimuli (e.g. epinephrine, thrombin and bradykinin) activate PLA2 which hydrolyzes arachidonic acid from cellular membrane phospholipids.

[ Bradykinin receptor (specifically BDKR2) is coupled to both Gi/0 and Gq G-protein activation with the net effect that there is increased intracellular calcium and activation of PKC. ]

[ Both PKC phosphorylation and the Ca2+ ions activate the ER membrane-associated cPLA2 isoforms which, when activated, hydrolyze arachidonic acid from PIP2. ]

Arachidonic acid is converted to PGH2via the action of the bi-functional enzymes COX-1 and COX-2 (also called prostaglandin G/H synthase, PGS or prostaglandin endoperoxide synthetase).

The prostaglandins are identified as PG and the thromboxanes as TX. Prostaglandin PGI2 is also known as prostacyclin.

PGE2 is synthesized from PGH2 via the action of one of several PGE synthases, where PGE synthase-1 (PGES1) appears to be the key enzyme.

Two forms of PGD2synthases have been identified that convert PGH2 to PGD2. One is encoded by the HPGDS (hematopoietic prostaglandin D synthase) gene and the other is encoded by the PTGDS (prostaglandin D2 synthase).

The enzyme encoded by the HPGDS gene is a member of the large family of cytosolic glutathione S-transferase enzymes. Prostacyclin (PGI2) is synthesized from PGH2 via the action of prostacyclin synthase (PTGIS). Prostaglandin F synthase 1 (PGFS) converts PGH2 to PGF2_ or PGD2 to 9,11-PGF2,.

The principal thromboxanes (TXA2 and TXB2) are derived PGH2 via the action if thromboxane synthase. The three most physiologically significant cyclic eicosanoids are enclosed in the red boxes.

Green arrows denote positive effects. The subscript 2 in each molecule refers to the number of carbon-carbon double bonds present.

LPI: lysophosphoinositol.

38
Q

How is the The cyclic pathway initiated?

A

The cyclic pathway is initiated through the action of prostaglandin GH synthase
[PGS (also called prostaglandin endoperoxide synthetase)]
This enzyme possesses two activities, cyclooxygenase (COX) and peroxidase

39
Q

2 Forms of COX Activity

A
  1. COX-1 (PGS-1) is expressed constitutively in gastric mucosa, kidney, platelets, and vascular endothelial cells
  2. COX-2 (PGS-2) is inducible and is expressed in macrophages and monocytes in response to inflammation.
40
Q

Causes and Effects of INCREASE in prostaglandin synthesis

A

The increase in prostaglandin synthesis due to the induction of COX-2 mediates the pain, heat, redness, and swelling of inflammation, and the fever of infection

41
Q

A widely used class of drugs that act upon the cyclooxygenase activity, inhibiting both COX- 1 and COX-2

A

Non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, indomethacin, naproxen, phenylbutazone and aspirin

42
Q

How does Aspirin work inhibiting Cyclooxygenase>

A

Aspirin acts by acetylation of the serine residue of cyclooxygenase (irreversible)

43
Q

Rationale behind why pharmaceutical companies have developed drugs targeted exclusively against the inducible COX-2 activity e.g. Celecoxib

A

Because inhibition of COX-1 activity in the gut is associated with NSAID-induced ulcerations

44
Q

Drugs that act to inhibit phospholipase A2

A

The corticosteroidal drugs

Act to inhibit phospholipase A2&raquo_space; thereby inhibiting the release of arachidonate from membrane phospholipids and the subsequent synthesis of eicosanoids.

45
Q

Prostaglandins have varied receptors thus acting on a variety of cells, what are these variety of actions:

A

Cause constriction or dilatation in vascular smooth muscle cells
Cause aggregation or disaggregation of platelets
Sensitize spinal neurons to pain
Constrict smooth muscle
Regulate inflammatory mediation
Regulate calcium movement
Regulate hormone regulation
Control cell growth
Together with oxytocin participates in induction of labor
Unlike oxytocin induces uterine contraction at all times, not just during term pregnancy

46
Q

Released by aggregating platelets

A

THROMBOXANE A2

Constricts blood vessels and activates platelets
Actions last only 30-60s

47
Q

Antagonist of Thromboxane A2

A

PGI2 or prostacyclin, which has a half life of 3 minutes

48
Q

Vasodilators formed by endothelial cells

A

PROSTAGLANDIN E2 AND I2

49
Q

Vasodilator used in infants with pulmonary stenosis to maintain the patency of the ductus arteriosus prior to surgery

A

PGE1

50
Q

Vasodilator that raises cAMP in platelets and vascular smooth muscle for the treatment of pulmonary hypertension

A

PGI2 (epoprostenol)

51
Q

Vasodilator involved in gastric mucosa that stimulates mucus secretion and suppresses gastric acid secretion
Reduces peptic ulcer risk

A

Prostaglandin E

52
Q

A synthetic PGE1 analogue, is used to prevent gastric ulcer in patients given NSAIDS

A

Misoprostol

53
Q

Vasodilator that is Synthesized in the endometrium
Induces uterine contraction
Induces abortion

A

PGE2 and PGF2alpha

54
Q

What stimulates PGE2 and PGF2alpha?

A

Levels increase at parturition

55
Q

Excessive production of PGE2 and PGF2alpha results to:

A

Menstrual cramps

56
Q

What vasodilators and hormones participates in induction of labor?

A

PGE2 and PGF2alpha + OXYTOCIN

57
Q

Difference of PGE2 and PGF2alpha from OXYTOCIN

A

Unlike oxytocin induces uterine contraction at all times, not just during term pregnancy

58
Q

Formed by WBC as mediators of inflammation

A

PGE2 and TXA2

59
Q

Mediates fever
A product of activated monocytes and macrophages

A

IL-1

60
Q

Mechanism of action of IL-1?

A

Binds to vascular receptors in the preoptic area of the hypothalamus where it induces PGE2 formation

61
Q

Activates the thermoregulatory center

A

PGE2

62
Q

MOA of Aspirin

A

Inhibits the ability of the COX enzyme to synthesize the precursors of thromboxane within platelets.
It inhibits the COX enzyme both non-competitively and irreversibly.

63
Q

Side effect of people who regularly take aspirin

A

Suffer from excessive bleeding whenever the skin is perforated.

64
Q

What is sustained during long- term dosing

A

Maximal inhibition of platelet thromboxane A2 production is sustained during long- term dosing with controlled-release aspirin

65
Q

What falls only slightly during long-term dosing

A

Basal prostacyclin biosynthesis

66
Q

What stimulates the systemic synthesis of prostacyclin

A

Bradykinin

67
Q

How does Aspirin inhibits platelet

A

Aspirin inhibits thromboxane without much inhibition of prostacyclin, resulting in platelet inhibition

68
Q

Linear Pathway

A

Synthesis of the clinically relevant leukotrienes from arachidonic acid.

The leukotrienes are identified as LT.
Numerous stimuli (e.g. epinephrine, thrombin and bradykinin) activate PLA2 which hydrolyzes arachidonic acid from cellular membrane phospholipids.

Bradykinin receptor (specifically BDKR2) is coupled to both Gi/0 and Gq G-protein activation with the net effect that there is increased intracellular calcium and activation of PKC.

Both PKC phosphorylation and the Ca2+ ions activate the ER membrane-associated cPLA2 isoforms which, when activated, hydrolyze arachidonic acid from PIP2.

The enzyme, 5-lipoxygenase (5-LOX) in association with the protein, 5-LOX activating protein (FLAP), catalyzes the conversion of arachidonic acid, first to 5-hydroperoxyeicosatetraenoic acid (5-HPETE) which spontaneously reduces to 5-hydroxyeicosatetraenoic acid (5-HETE), and then to LTA4.

LTA4 is unstable and is converted to LTB4 in neutrophils and monocytes harboring LTA4 hydrolase. LTB4 is enclosed in a red box to denote its critical significance as one of the most potent inflammation-mediating lipids.

In mast cells and eosinophils, which harbor LTC4 synthase, LTA4 is converted to LTC4.

The leukotrienes LTC4, LTD4, LTE4 and LTF4 are known as the peptidoleukotrienes or the cysteinyl leukotrienes because of the presence of amino acids.

The peptidoleukotrienes, LTC4, LTD4 and LTE4 are components of slow-reacting substance of anaphylaxis (SRSA).

SRSA was originally identified as an activity released from sensitized lung after immunologic challenge.

69
Q

What initiates the linear pathway?

A

Action of lipoxygenases

70
Q

In the Linear Pathway, what gives rise to the leukotrienes?

A

5-lipoxygenase

71
Q

The leukotrienes that are known as the peptidoleukotrienes (cysteinyl leukotrienes) because of the presence of amino acids

A

LTC4, LTD4, LTE4 and LTF4

72
Q

The peptidoleukotrienes which are components of slow-reacting substance of anaphylaxis (SRS-A),

A

LTC4, LTD4 and LTE4

73
Q

MOA of peptidoleukotrienes?

A

Mediate inflammatory responses and are involved in the pathophysiology of asthma

74
Q

What are used in the treatment of asthma?

A

5-lipoxygenase inhibitors and leukotriene inhibitors

75
Q

Produced in leukocytes, platelets, mast cell and heart and lung vascular tissues

A

LTA4 (Leukotriene A4)

76
Q

LTC4&raquo_space; LTD4&raquo_space; LTE4

A

Contraction of smooth muscle
Bronchoconstriction
- Vasoconstriction
- Increased vascular permeability
- Components of slow-reacting substance of anaphylaxis (SRS-A)

77
Q

Produced primarily by platelets
Promotes platelet aggregation
Vasoconstriction
Mobilizes intracellular calcium
Contraction of smooth muscle

A

TXA2 (Thromboxane A2)

78
Q

Increased chemotaxis of polymorphonuclear leukocytes
Release of lysosomal enzymes
Adhesion of WBC

A

LTB4 (Leukotriene B4)

79
Q

Produced primarily by endothelium of vessels
Vasodilation
Inhibits platelet aggregation

A

PGI2 (Prostacyclin)

80
Q

Produced by most tissues
Vasoconstriction
Contraction of smooth muscle
Stimulates uterine contractions

A

PGF2 (Prostaglandin F2alpha)

81
Q

Produced by most tissues, especially kidney
Vasodilation
Relaxes smooth muscle
Used to induce labor

A

PGE2 (Prostaglandin E2)

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