prostaglandins - rose–hulman institute of technologybrandt/chem430/11_prostaglandins.pdf ·...
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Prostaglandins
(Let’s perturb pathways and see what happens!)
Production
“Particle Physics”
Consistency of dose
Stability
Size
Elegance
Fatty Acid Nomenclature
OHC
Oω9 fatty acids
Oleic acid(18:1 ∆9)
COH
O
5,8,11-Eicosatrienoic acid(20:3 ∆5,8,11)
Fatty Acid Nomenclature
COH
OLinoleic acid(18:2 ∆9,12)
COH
O
8,11,14-Eicosatrienoic acid(20:3 ∆8,11,14)
γ-Linolenic acid(18:3 ∆6,9,12)
COH
O
COH
O
Arachidonic acid5,8,11,14-Eicosatetraenoic acid(20:4 ∆5,8,11,14)
ω6 fatty acids
Fatty Acid Nomenclature
COH
O
α-Linolenic acid(18:3 ∆9,12,15)
COH
O
5,8,11,14,17-Eicosapentaenoic acid(20:5 ∆5,8,11,14,17)
ω3 fatty acids
Prostaglandin Synthesis
CO
O
H
OH
H
H
O
H
OH
H
OH
OH
H
OH
P OO
O
CH2 CH CH2
OC
O
Phosphatidylinositol
Phospholipase A2
COH
OC
OH
O
OOH
O
O
COH
O
OH
O
O
PGH2
PGG2Cyclooxygenase
Peroxidase
Prostaglandinsynthase
Prostaglandinsynthase
Arachidonic acid5,8,11,14-Eicosatetraenoic acid(20:4 ∆5,8,11,14)
Prostaglandin Synthesis
COH
O
OH
O
O
PGH2
Prostacyclinsynthase
Thromboxanesynthase
PGE isomerase
PGFsynthase
Non-enzymatic
OHHO
OC
HO
O
PGI2(Prostacyclin)
COH
O
OH
O
OTXA2 TXB2
COH
O
OH
O
OH
HO
COH
O
OH
O
HO
PGE2
COH
O
OH
HO
HO
PGF2α
Leukotrienes
COH
O
Arachidonic acid5,8,11,14-Eicosatetraenoic acid(20:4 ∆5,8,11,14)
5-lipoxygenase
OH
O
O 5-Hydroperoxy-ecosatetraenoicacid (5-HPETE)
HO
OH
OOH
OH
OH
OO
OH
OOH
S
H2N
O
HN
OH
O
OH
OOH
S
H2N
O
OH
O OH
OH
OOH
S
HN
O
HN
OH
O
OH2N
γ-glutamyltransferaseGlutamate
peptidase
Glycine
LeukotrieneA4 hydrolase
Glutathione
5-lipoxygenase
LTC4synthase
(glutathione S-transferase)
LTA4 LTB4
LTD4
LTC4
LTE4
Lipoxins
OH
OOH
OH
HO
OH
O
OH
15-lipoxygenase (15S)-HETE hydrolase
Aspirin-acetylatedcyclooxygenase-2
OH
O
OH
(15R)-HETE OH
OOH
OH
HO
5-lipoxygenase LXA4
COH
O
Arachidonic acid5,8,11,14-Eicosatetraenoic acid(20:4 ∆5,8,11,14)
hydrolase5-lipoxygenase
15-epi-LXA4
Nuclear Receptors
HO
1α,25-Dihydroxy-vitamin D3(Calcitriol)
OH
OH
O
OH
O
OHHOOH
HO
O
NH3
OO
I
I
I
HO
3,5,3´-triiodothyronine(Thyroid hormone T3)
OO9-cis-Retinoic acid
Cortisol Estradiol
G-Protein Coupled Receptors
OH
HO
OH
NH3
NorepinephrineOH
HO
OH
NH2
CH3
Epinephrine
cAMP-DependentProtein KinasePhosphorylase
KinasePhosphorylaseKinase
P
ATP ADP
cAMP
GlycogenPhosphorylase
ATP
ADP
GlycogenPhosphorylase
P
More Signaling
Phosphatidyl Inositol
CO
O
H
OH
H
H
O
H
OH
H
OH
OH
H
OH
P OO
O
CH2 CH CH2O
O
COH
O
OH
O
O
PGH2
Phosphatidylinositol
Phospholipase A2
Phospholipase C
OH
O
ProstaglandinSynthase(cyclooxygenase)
PI 4-Kinase
PIP 5-Kinase
CO
O
H
OH
H
H
O
H
OH
H
OH
O
H
O
P OO
O
CH2 CH CH2O
O
P
PO O
O
O
O
O
Phosphatidylinositol-4,5-bisphosphate
H
OH
H
H
O
H
OH
H
OH
O
H
O
P OO
O
P
PO O
O
O
O
O
Inositol-1,4,5-trisphosphate(IP3)
CO
O
OH
CH2 CH CH2O
O
Diacylglycerol
PI 3-KinasePhosphatidylinositol-3-phosphate
O
P OO
O
CO
O
H
OH
H
H
O
H
OH
H OH
H
OH
P OHO
O
CH2 CH CH2O
O
Steroidal Anti-inflammatory Drugs
O
O
HO OH
OH
Cortisol
O
O
HO OH
OH
CH3
F Dexamethasone
O
O
O OH
OH
Prednisone
Non-steroidal Anti-inflammatory Drugs
OHO
OH
OHO
O CH3
O
Salicylic acid[2-hydroxybenzoic acid]
Aspirin[acetyl salicylic acid]
[2-acetoxybenzoic acid]
Non-steroidal Anti-inflammatory Drugs
H3CCH3
CH3
OHO
O
CH3
OH
O
H3C
Naproxen[2-(6-methoxynaphthyl)
propionic acid]
N
Cl
O
CH3
O
OHO
CH3
Indomethacin
Ibuprofen[2-(4-isobutylphenyl)propionic acid]
COX Isoform Active Sites
Pharmacol Rev 56:387–437, 2004
Non-steroidal Anti-inflammatory Drugs
NS
O
O
H2NN CF3
CH3
S
O
O
H3CO
O
Rofecoxib[Vioxx]
Celecoxib[Celebrex]
S
O
O
H2NN
O
H3C
Valdecoxib[Bextra]
Etodolac[Lodine]
N
O
CH3
HO
O
CH3H
SN
NH
O
N
S
CH3
O O
OH
CH3 Meloxicam[Mobic]
Acetaminophen
HNH3C
O
OH
AcetaminophenParacetamol
[p-acetaminophenol][N-(4-hydroxyphenyl)acetamide]
[4-hydroxylacetanilide]
Acetaminophen Metabolism
UDP-Glucuronic acid
O H
H
OH
OH
H
H
OH
C
H
O
O N
NH
O
O
P
O
OO
OHHO
CH2OP
O
O
O
O
O H
H
OH
OH
H
H
OH
C
H
O
O
O
NHCH3
O
NHCH3
O
HO
Acetaminophen
N
NH
O
O
P
O
OO
OHHO
CH2OP
O
O
OO
O P
O
O
O
O S
O
OO
OH
CH2O
N
N N
N
NH2
P
O
O
O
3´-phosphoadenosine5´-phosphosulfate (PAPS)
glucuronyltransferase
sulfotransferase
NHCH3
O
HO
Acetaminophen
O S
O
O
O NHCH3
O
O P
O
O
O
O
OH
CH2O
N
N N
N
NH2
P
O
O
O
UDP
adenosine3´,5´-bisphosphate
Acetaminophen Metabolism
NHCH3
O
HO
Acetaminophen cytochrome P450(CYP2E1)
NH3C
O
OHHO
NH3C
O
O
Acetimidoquinone
SpontaneousH2O
HN
O
HN
O
O
OH3N
O O
HS
γ-Glu
Cys Gly
Glutathione(reduced form)HN
O
HN
O
O
OH3N
O O
S
HNH3C
O
OH
Cys-Protein
S
HNH3C
O
OHProtein-Cys-SH
Spontaneous
Spontaneous
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