Prostaglandins - Rose–Hulman Institute of Technologybrandt/Chem430/11_Prostaglandins.pdf ·...

21
Prostaglandins (Let’s perturb pathways and see what happens!)

Transcript of Prostaglandins - Rose–Hulman Institute of Technologybrandt/Chem430/11_Prostaglandins.pdf ·...

Page 1: Prostaglandins - Rose–Hulman Institute of Technologybrandt/Chem430/11_Prostaglandins.pdf · Prostaglandins (Let’s perturb pathways and see what happens!) Production “Particle

Prostaglandins

(Let’s perturb pathways and see what happens!)

Page 2: Prostaglandins - Rose–Hulman Institute of Technologybrandt/Chem430/11_Prostaglandins.pdf · Prostaglandins (Let’s perturb pathways and see what happens!) Production “Particle

Production

“Particle Physics”

Consistency of dose

Stability

Size

Elegance

Page 3: Prostaglandins - Rose–Hulman Institute of Technologybrandt/Chem430/11_Prostaglandins.pdf · Prostaglandins (Let’s perturb pathways and see what happens!) Production “Particle

Fatty Acid Nomenclature

OHC

Oω9 fatty acids

Oleic acid(18:1 ∆9)

COH

O

5,8,11-Eicosatrienoic acid(20:3 ∆5,8,11)

Page 4: Prostaglandins - Rose–Hulman Institute of Technologybrandt/Chem430/11_Prostaglandins.pdf · Prostaglandins (Let’s perturb pathways and see what happens!) Production “Particle

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

Page 5: Prostaglandins - Rose–Hulman Institute of Technologybrandt/Chem430/11_Prostaglandins.pdf · Prostaglandins (Let’s perturb pathways and see what happens!) Production “Particle

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

Page 6: Prostaglandins - Rose–Hulman Institute of Technologybrandt/Chem430/11_Prostaglandins.pdf · Prostaglandins (Let’s perturb pathways and see what happens!) Production “Particle

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)

Page 7: Prostaglandins - Rose–Hulman Institute of Technologybrandt/Chem430/11_Prostaglandins.pdf · Prostaglandins (Let’s perturb pathways and see what happens!) Production “Particle

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

Page 8: Prostaglandins - Rose–Hulman Institute of Technologybrandt/Chem430/11_Prostaglandins.pdf · Prostaglandins (Let’s perturb pathways and see what happens!) Production “Particle

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

Page 9: Prostaglandins - Rose–Hulman Institute of Technologybrandt/Chem430/11_Prostaglandins.pdf · Prostaglandins (Let’s perturb pathways and see what happens!) Production “Particle

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

Page 10: Prostaglandins - Rose–Hulman Institute of Technologybrandt/Chem430/11_Prostaglandins.pdf · Prostaglandins (Let’s perturb pathways and see what happens!) Production “Particle

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

Page 11: Prostaglandins - Rose–Hulman Institute of Technologybrandt/Chem430/11_Prostaglandins.pdf · Prostaglandins (Let’s perturb pathways and see what happens!) Production “Particle

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

Page 12: Prostaglandins - Rose–Hulman Institute of Technologybrandt/Chem430/11_Prostaglandins.pdf · Prostaglandins (Let’s perturb pathways and see what happens!) Production “Particle

More Signaling

Page 13: Prostaglandins - Rose–Hulman Institute of Technologybrandt/Chem430/11_Prostaglandins.pdf · Prostaglandins (Let’s perturb pathways and see what happens!) Production “Particle

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

Page 14: Prostaglandins - Rose–Hulman Institute of Technologybrandt/Chem430/11_Prostaglandins.pdf · Prostaglandins (Let’s perturb pathways and see what happens!) Production “Particle

Steroidal Anti-inflammatory Drugs

O

O

HO OH

OH

Cortisol

O

O

HO OH

OH

CH3

F Dexamethasone

O

O

O OH

OH

Prednisone

Page 15: Prostaglandins - Rose–Hulman Institute of Technologybrandt/Chem430/11_Prostaglandins.pdf · Prostaglandins (Let’s perturb pathways and see what happens!) Production “Particle

Non-steroidal Anti-inflammatory Drugs

OHO

OH

OHO

O CH3

O

Salicylic acid[2-hydroxybenzoic acid]

Aspirin[acetyl salicylic acid]

[2-acetoxybenzoic acid]

Page 16: Prostaglandins - Rose–Hulman Institute of Technologybrandt/Chem430/11_Prostaglandins.pdf · Prostaglandins (Let’s perturb pathways and see what happens!) Production “Particle

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]

Page 17: Prostaglandins - Rose–Hulman Institute of Technologybrandt/Chem430/11_Prostaglandins.pdf · Prostaglandins (Let’s perturb pathways and see what happens!) Production “Particle

COX Isoform Active Sites

Pharmacol Rev 56:387–437, 2004

Page 18: Prostaglandins - Rose–Hulman Institute of Technologybrandt/Chem430/11_Prostaglandins.pdf · Prostaglandins (Let’s perturb pathways and see what happens!) Production “Particle

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]

Page 19: Prostaglandins - Rose–Hulman Institute of Technologybrandt/Chem430/11_Prostaglandins.pdf · Prostaglandins (Let’s perturb pathways and see what happens!) Production “Particle

Acetaminophen

HNH3C

O

OH

AcetaminophenParacetamol

[p-acetaminophenol][N-(4-hydroxyphenyl)acetamide]

[4-hydroxylacetanilide]

Page 20: Prostaglandins - Rose–Hulman Institute of Technologybrandt/Chem430/11_Prostaglandins.pdf · Prostaglandins (Let’s perturb pathways and see what happens!) Production “Particle

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

Page 21: Prostaglandins - Rose–Hulman Institute of Technologybrandt/Chem430/11_Prostaglandins.pdf · Prostaglandins (Let’s perturb pathways and see what happens!) Production “Particle

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