Week 5 TBL Flashcards
Prostaglandins are involved in what?
Carcinogenesis Bone remodelling Sleep Inflammation and pain Allergy and immunity Vascular homeostasis and haemostasis Fever generation Ovulation, fertilisation and parturition Gastrointestinal function Renal function
How do prostaglandins act?
5 basic types of receptor
Called P receptors and preceding letter indicated the natural prostanoid to which each receptor is most sensitive
e.g. EP, DP, DF
Subscript numerals indicate that receptor has subtypes e.g. EP1, EP4
IP receptor binds what?
What does it mediate?
PGI2
- vasodilation
- inhibits platelet aggregation
- Fibrinolysis
What are prostaglandins?
Polyunsaturated, oxygenated derivatives of three C20 fatty acids (AA, DGLA, EPA)
Classified into10 types (PGA-PGJ) according to:
- the code of ring variants (A-J) and
- number of double bonds in their side chain (1-3)
If R1 is a carbonyl and R2 is a hydroxyl group.
and the whole structure has 2 double bonds
What name of prostaglandin is it?
E2
IF R1 us a hydroxyl group and R2 us a carbonyl group
and the whole structure has 2 double bonds
What name of prostaglandin is it?
D2
If both R1 and R2 are hydroxyl groups
and the whole structure has 2 double bonds
What name of prostaglandin is it?
F2(alpha)
What is PGE2 involved in?
inflammatory
What is PGD2 involved in?
immunity
What is PGF2(alpha) involved in?
vasoconstriction
What is PGI2 involved in?
Potent vasodilator that inhibits platelet aggregation
What is a prostanoid?
Prostanoids are a subclass of eicosanoids consisting of the prostaglandins (mediators of inflammatory and anaphylactic reactions), the thromboxanes (mediators of vasoconstriction), and the prostacyclins (active in the resolution phase of inflammation.)
What is TXA2?
Thromboxane A2
a potent inducer of platelet aggregation
Draw Prostaglandin E?
ok
Draw Prostaglandin F?
ok
Draw Prostaglandin D?
ok
What are prostaglandins made of?
20C fatty acids Major substrate = ARACHIDONIC ACID (AA) (gives rise to ‘2’ series PG) But can also be derived from: Dihomogamma-linolenic acid (DGLA) (‘1’ series PG) or Eicosapentaenoic acid (EPA) (‘3’ series PG)
When DGLA is the precusor molecule, how many double bonds are in the resulting prostaglandin?
One
When arachodonic acid is the precusor molecule, how many double bonds are in the resulting prostaglandin?
Two
When EPA is the precusor molecule how many double bonds are in the resulting prostaglandin?
Three
How many double bonds in DGLA?
Three
How many double bonds in AA?
Four
How many double bonds in EPA?
Five
What kind of enzyme adds carbons?
elongase
What kind of enzyme adds double bonds?
Desaturase
Which pathways involve our cells all the time with regards to eiconasoids?
Fatty acid pathways omega-3, omega-6 and omega-9
EPA is what omega?
Omega-3 fatty acid
AA is what omega?
Omega-6 fatty acid
DGLA is what omega?
Omega-6 fatty acid
Omega means?
The end
Omega 3= double bond 3 carbons from the end
What are the essential fatty acids?
alpha-linolenic acid (ALA) linoleic acid (LA)
What will happen to your body if you have no fat?
- Skin red, unstable
- disorders that come from essential fatty acids
Why are they called essential fatty acids?
Mammals cannot make them, we must take them from our diet
Nutrients needed for ALA
flaxseed, rapeseed, soy oils
ALA is the start of which pathway?
omega-3
LA is the start of which pathway?
omega-6
Nutrients needed for LA
safflower, cottonseed, soy, cornoils
Why do people eat fish for brain power?
DHA is at the end of the omega-3 pathway and is used for brain-power
Babies are born with the correct amount of DHA (from their mothers) in their nervous system
in the omega-3 only a small amount (less than 5%)of ALA is converted to DHA and EPA
hence fish can increase the amount of EPA and then hence the amount of DHA –> brain power!
Having a lot of plant oils will not give you the amount of DHA you need
What things can you eat to increase the amount of EPA in the omega-3 fatty acid pathway?
oily fish
fish oils
krill oil
algae
What things can you eat to increase the amount of gamma linoleic acid at the start of the omega-6 pathway?
borage and evening primrose oils
What things can you eat to increase the amount of DGLA in the omega-6 pathway?
liver, organ meats
What things can you eat to increase the amount of AA in the omega-6 pathway?
animal fats, butter, egg yolks
Full name of DGLA
(‘1’ series PG)
Dihomogamma-linolenic acid
Full name of EPA?
3 series PG
Eicosapentaenoic acid
Full name of AA?
2 series PG
Arachodonic acid
What does a phospholipase enzyme do?
Convert membrane-bound phospholipid into Arachodonic acid
What inhibits a phosopholipase enzyme?
Corticosteroids
What does a COX enzyme do?
Convert AA to the Cyclic endoperoxides
i.e.
PGG2 and PGH2
What inhibits a COX enzyme?
Coxibs and NSAIDs
What does COX stand for?
Cyclooxygenase
What does NSAID stand for?
Non-steroidal anti-inflammatory drug
The cyclic endoperoxides PGG2 and PGH2 go on to make what important molecules?
PGD2 PGE2 PGF2 PGI2 TXA2 (Thromboxane)
What do prostaglandins generally mediate?
mediators of inflammatory and anaphylactic reactions
What do prostacyclins generally do?
They’re active in the resolution phase of inflammation
What do thromboxanes do?
Mediators of vasoconstriction
True or false, AA is toxic in high concentrations
Why/why not?
True
it also explains why AA is metabolised by COX1 immediately after being cleaved why PLA2.
It is not free in the cell.
What does PLA2 do?
Phospholipase A2 frees (cleaves) arachodonic acid from the cell
NSAIDs inhibit what enzyme?
COX (cyclo-oxygenase)
How do cyclooxygenases make Prostanoids?
Cox1 and cox2 work one after the other once AA is released from the membrane
Cox transforms AA to unstable intermediate(s)
And then depending where the reaction takes place and what the system wants, other prostaglandins are made
Too much prostaglandin being made uncontrollably can stimulate activity, causing health issues such as…?
PGE2 and COX2 over expression
Cancer
Cancer has overexpression of what?
COX2 enzyme
PGE2
Why are coxibs bad? What do they do?
Specialist inhibitors of COX2
Side effect was cardiovascular disease
people in clinical trials had heart attacks
COX2 also needed in CVS
Difference between the isoforms COX1 and COX2
COX-1 - constitutive - in all cells, does basic housekeeping
COX-2 - induced (by cytokines, inflammatory stimuli, induced when cells need a lot of PGs) If you don’t switch it off then there will be inflammation etc
low levels of COX-1 needed for
homeostasis, vital for cell function
Some cell types need COX2 such as
CVS cells
When a physiological stimulus is there, what happens to AA?
COX-1 pathway activated -TXA2 and PGI2 made Control of platelet aggregation and vascular tone -PGE2 also made Cytoprotection
What happens when PGs are no longer needed?
They are metabolised by other enzymes in the body
into inactive metabolites
Uncontrolled overexpression of PGs you get inflammation that cannot resolve
Uncontrolled overexpression of PGs you get what?
Inflammation that cannot resolve
What is a knock-out mice model?
mice bred so certain information is removed from the genome
e.g. COX2 knockout mice have no COX2 enzyme
Phenotypic changes in COX1 knockout mice?
- reduced platelet aggregation
- Decreased amino acid-induced inflammation
- sensitive to radiation injury
- resistant to indomethacin-induced gastric ulceration
Phenotypic changes in COX2 knockout mice?
- Defective ovulation, fertilisation, implantation, decidualisation
- Decreased brain injury induced by ischaemia
- supression of tumourgenesis
- renal nephropathy
- cardiac fibrosis
- peritonisis
- failure of patent ductus arteriosus closure
How many domains does a GPCR have?
Seven
How many types of prostaglandin are there?
5
PG receptors are…
G-protein coupled transmembrane receptors
Linked to cAMP and/or Ca2+ signalling
AA is converted to PGG2 via COX
What does PGG2 make?
PGH2
PGH2 activates what GPCR transmembrane domains?
PGI2 PGD2 PGE2 PGF2alpha PGF2 TXA2 PGD2
How many receptors are used by PGE?
Why?
Four
(EP1, EP2, EP3, EP4)
For ten properties
Complete this
DP receptor binds ___ and mediates what?
PGD2
- vasodilation
- inhibits platelet aggregation
- GI relaxation
FP receptor binds ___ and mediates….
PGF2(alpha)
- luteolysis (degradation of corpus luteum in menstral cycle)
- bronchoconstriction
IP receptor binds ___ and mediates…
PGI2
- vasodilation
- inhibits platelet aggregation
- fibrinolysis
TP receptor binds ___ and mediates..
TXA2 (Thromboxane)
- vasoconstriction
- platelet aggregation
- bronchoconstriction
What does the EP1 receptor mediate?
GI contraction
Pyrexia (fever)
What does EP2 receptor mediate?
bronchodilation
vasodilation
stimulates GI fluid secretion
What does EP3 receptor mediate?
GI relaxation
inhibition of gastric acid secretion
inhibition of ANS transmitters
pyrexia
What does EP4 receptor mediate?
vasodilatation
bone homeostasis
pyrexia
Methods of relatting PGs to therapeutics?
substrate substitution
enzyme inhibitors
prostaglandin replacement therapy/use of synthetic, selective analogues
If you change your diet to eat less meat and more fish, what will happen?
Less omega-6 fatty acids produced (therefore less and DGLA AA)
More omega-3 fatty acids produced (therefore more EPA)
This will produce an anti-inflammatory environment
Not to trigger baseline inflammatory conditions
GLA comes from primose oil
what effect?
Calming effect as it promotes more PG1 instead of PG2
fish oil in diet is good because…
Fish oil is rich in DHA and EHA
it promotes PG3 instead of PG2
Omega-3 fatty acids were significant in clinical trails because fish oil supplementation resulted in
reduction of fasting blood triglycerides
(but not total HDL or LDL cholesterol) in hyperlipidaemic subjects
in only one condition Coxibs are still used
Which? Why?
Arthritis
Because risk of CVD is considered worth it to reduce pain
renal syndrome side effects of NSAIDs due to decrease in PGE2
- increase Na+ retention
- peripheral oedema
- increase in blood pressure
- increase in weight
- congestive heart failure (rarely)
renal syndrome side effects of NSAIDs due to decrease in PGI2
- hyperkalaemia
- acute renal failure
‘Prostaglandin replacement therapy’/use of synthetic, selective analogues
Arthrotec = diclofenac + misoprostol
(NSAID + reduced stomach acid)
Diclofenac: NSAID
Misoprostol: EP1/3 agonist, which restores cytoprotection; prevents stomach ulcers
Arthrotec is?
Diclofenac + misoprostol
NSAID + reduced stomach acid
What is Diclofenac?
NSAID
What is Misoprostol?
EP1/EP3 agonist, which restures cytoprotection and prevents stomach ulcers
PGE2 can lead to carcinogenesis,
how?
cAMP and calcium concentration induce:
1) direct targeting of gene transcription, inducing cell proliferation (growth) and migration (potential metastasis)
2) –> HIF-1alpha causes VEF transcription and angiogenesis
3) Production of Survivin which inhibits apoptosis
4) —> MMPs –> increase invasiveness
5) –> PKA and PKC–>MAPK—1)
How do prostacyclins reduce intra-ocular pressure in glaucoma?
Reduce intra-ocular pressure relieving the optic nerve; allow fluid to drain freely
Latanoprost – PGF2a analogue
Bimatoprost – PGF2a analogue
Additional therapeutic uses for PGE analogues
Adjuncts to mifepristone and other agents used to terminate pregnancy Cervical ripening Potential uses to manage: Preterm labour Dysmenorrhoea Airway disease
What are the stimuli which induce AA production from phospholipid A?
cPLA2
sPLA2
PGH2 and PGH3 make…
L-PGDS H-PGDS mPEGS-1 PGFS PGIS TXAS
L-PGDS and H-PGDS make what PG?
PGD2
mPEGS-1 makes what PG?
PGE2
PGFS makes what PG?
PGF2alpha
PGIS makes what PG?
PGI2
TXAS makes what?
TXA2
