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BIOCHEMISTRY > ME04 - Unsaturated Fatty Acids and Eicosanoids > Flashcards

ME04 - Unsaturated Fatty Acids and Eicosanoids Flashcards

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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
What is the mechanism of action of the insulin sensitizer Rosiglitazone (Avandia), a PPAR-gamma agonist
PPAR thus promotes TG synthesis even when insulin is low and little glycerol-3- phosphate is produced from glucose
26
What are the Most prominent Eicosanoids
Prostaglandins (PG)
27
Collectively identified as prostanoids
PG and thromboxanes (TX)
28
Origin of Eicosanoids
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
29
Differentiate the ring structure of Eicosanoids
In PG, the ring structure is cyclopentane Prostaglandin E2 In TX, the ring is a cyclic ether (Oxane ring)
30
The principal eicosanoids of biological significance to humans are derived from ________?
Arachidonic Acid
31
All mammalian cells except erythrocytes synthesize eicosanoids. True or False?
True.
32
How are eicosanoids referred as local hormones
All eicosanoids function locally at the site of synthesis, thus they are also referred to as local hormones
33
SYNTHESIS OF ARACHIDONIC ACID FROM LINOLEIC ACID
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
Rate-limiting enzyme of eicosanoid biosynthesis
Phospholipase A2
35
FUNCTION OF EICOSANOIDS
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
Two main pathways are involved in the biosynthesis of eicosanoids
The prostaglandins and thromboxanes are synthesized by the cyclic pathway The leukotrienes and lipoxins are synthesized by the linear pathway.
37
CYLCIC PATHWAY
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
How is the The cyclic pathway initiated?
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
2 Forms of COX Activity
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
Causes and Effects of INCREASE in prostaglandin synthesis
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
A widely used class of drugs that act upon the cyclooxygenase activity, inhibiting both COX- 1 and COX-2
Non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, indomethacin, naproxen, phenylbutazone and aspirin
42
How does Aspirin work inhibiting Cyclooxygenase>
Aspirin acts by acetylation of the serine residue of cyclooxygenase (irreversible)
43
Rationale behind why pharmaceutical companies have developed drugs targeted exclusively against the inducible COX-2 activity e.g. Celecoxib
Because inhibition of COX-1 activity in the gut is associated with NSAID-induced ulcerations
44
Drugs that act to inhibit phospholipase A2
The corticosteroidal drugs Act to inhibit phospholipase A2 >> thereby inhibiting the release of arachidonate from membrane phospholipids and the subsequent synthesis of eicosanoids.
45
Prostaglandins have varied receptors thus acting on a variety of cells, what are these variety of actions:
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
Released by aggregating platelets
THROMBOXANE A2 Constricts blood vessels and activates platelets Actions last only 30-60s
47
Antagonist of Thromboxane A2
PGI2 or prostacyclin, which has a half life of 3 minutes
48
Vasodilators formed by endothelial cells
PROSTAGLANDIN E2 AND I2
49
Vasodilator used in infants with pulmonary stenosis to maintain the patency of the ductus arteriosus prior to surgery
PGE1
50
Vasodilator that raises cAMP in platelets and vascular smooth muscle for the treatment of pulmonary hypertension
PGI2 (epoprostenol)
51
Vasodilator involved in gastric mucosa that stimulates mucus secretion and suppresses gastric acid secretion Reduces peptic ulcer risk
Prostaglandin E
52
A synthetic PGE1 analogue, is used to prevent gastric ulcer in patients given NSAIDS
Misoprostol
53
Vasodilator that is Synthesized in the endometrium Induces uterine contraction Induces abortion
PGE2 and PGF2alpha
54
What stimulates PGE2 and PGF2alpha?
Levels increase at parturition
55
Excessive production of PGE2 and PGF2alpha results to:
Menstrual cramps
56
What vasodilators and hormones participates in induction of labor?
PGE2 and PGF2alpha + OXYTOCIN
57
Difference of PGE2 and PGF2alpha from OXYTOCIN
Unlike oxytocin induces uterine contraction at all times, not just during term pregnancy
58
Formed by WBC as mediators of inflammation
PGE2 and TXA2
59
Mediates fever A product of activated monocytes and macrophages
IL-1
60
Mechanism of action of IL-1?
Binds to vascular receptors in the preoptic area of the hypothalamus where it induces PGE2 formation
61
Activates the thermoregulatory center
PGE2
62
MOA of Aspirin
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
Side effect of people who regularly take aspirin
Suffer from excessive bleeding whenever the skin is perforated.
64
What is sustained during long- term dosing
Maximal inhibition of platelet thromboxane A2 production is sustained during long- term dosing with controlled-release aspirin
65
What falls only slightly during long-term dosing
Basal prostacyclin biosynthesis
66
What stimulates the systemic synthesis of prostacyclin
Bradykinin
67
How does Aspirin inhibits platelet
Aspirin inhibits thromboxane without much inhibition of prostacyclin, resulting in platelet inhibition
68
Linear Pathway
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
What initiates the linear pathway?
Action of lipoxygenases
70
In the Linear Pathway, what gives rise to the leukotrienes?
5-lipoxygenase
71
The leukotrienes that are known as the peptidoleukotrienes (cysteinyl leukotrienes) because of the presence of amino acids
LTC4, LTD4, LTE4 and LTF4
72
The peptidoleukotrienes which are components of slow-reacting substance of anaphylaxis (SRS-A),
LTC4, LTD4 and LTE4
73
MOA of peptidoleukotrienes?
Mediate inflammatory responses and are involved in the pathophysiology of asthma
74
What are used in the treatment of asthma?
5-lipoxygenase inhibitors and leukotriene inhibitors
75
Produced in leukocytes, platelets, mast cell and heart and lung vascular tissues
LTA4 (Leukotriene A4)
76
LTC4 >> LTD4 >> LTE4
Contraction of smooth muscle Bronchoconstriction - Vasoconstriction - Increased vascular permeability - Components of slow-reacting substance of anaphylaxis (SRS-A)
77
Produced primarily by platelets Promotes platelet aggregation Vasoconstriction Mobilizes intracellular calcium Contraction of smooth muscle
TXA2 (Thromboxane A2)
78
Increased chemotaxis of polymorphonuclear leukocytes Release of lysosomal enzymes Adhesion of WBC
LTB4 (Leukotriene B4)
79
Produced primarily by endothelium of vessels Vasodilation Inhibits platelet aggregation
PGI2 (Prostacyclin)
80
Produced by most tissues Vasoconstriction Contraction of smooth muscle Stimulates uterine contractions
PGF2 (Prostaglandin F2alpha)
81
Produced by most tissues, especially kidney Vasodilation Relaxes smooth muscle Used to induce labor
PGE2 (Prostaglandin E2)

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