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Lipid Metabolism

Rosdiana Natzir
Dep.of Biochemistry
Faculty of Medicine, Hasanuddin University

Fatty Acids
CH3(CH2)nCH2CO 2H
O

CH3(CH2)nCH2C-OH

H-O-R

CH3(CH2)nCH2C-OH

CH3(CH2)nCH2C-O-R
Ester

H-S-R

CH3(CH2)nCH2C-S-R
Thioester
2

Fatty Acids as Stored Energy


Fatty acids are the bodys principal form of
stored energy
Carbon almost completely reduced as CH2
Very closely packed in storage tissues - not
hydrated as sugars are

Dietary Fatty Acids


Comprise 30-60% of caloric intake in
average American diet
Triacylglycerols, phospholipids,
sterol esters
Principal sources: dairy products,
meats

Digestion of Dietary
Triacylglycerols
Occurs in duodenum
Facilitated by

Bile salts (emulsification)


Alkaline medium (pancreatic juice)
Pancreatic
lipases

OH

OH

TAG

MAG

Intestinal
lipases

Glycerol
+
Fatty Acids
5

Epithelial Cell (Intestinal Wall)


Intestinal lumen

MAG Glycerol Fatty Acids

Lipoprotein

TAG
Lymphatics
Blood (bound to albumin)

Chylomicrons
Adipose Tissue
And Muscle

Fat Storage
Mainly as triacylglycerols
(triglycerides) in adipose cells
Constitute 84% of stored energy

Protein - 15%
Carbohydrate (glucose or glycogen) - <1%

Processing of Lipid Reserves: Overview


1. Lipid Mobilization:
In adipose tissue TAGs hydrolyzed to
fatty acids plus glycerol
2. Transport of Fatty Acids in Blood
To Tissues
3. Activation of Fatty Acids as CoA Ester
4. Transport into Mitochondria
5. Metabolism to Acetyl CoA
8

Release of Fatty Acids from


Triacylglycerols
O

CH 2OC-R1
O

CHOC-R 2

CH 2OH

Lipases

CHOH

CH 2OC-R3

CH 2OH

Triacylglycerol

Glycerol
+

HOC-R 1

HOC-R 2

HOC-R 3

Lipolysis

Hormone
(Adrenalin, Glucagon, ACTH)

Receptor (7TM)
Activates

ATP
Insulin
blocks this
step

Adenylyl
Cyclase

c-AMP

Activates lipase
Triacylglycerols

Glycerol +
Fatty acids

Adipose Cell

Blood

10

ATP

Adenylyl cyclase

Enhanced by glucagon

Phosphodiesterase

c-AMP

Inactive Kinase

AMP

Enhanced by insulin

Activated Kinase
P

Inactive Lipase

Activated Lipase

Phosphatase
Insulin favors formation
of the inactive lipase

Triacylglycerol

(Hormone-sensitive
Lipase)

Glycerol +
Fatty Acids
11

Acylglycerol Lipases

Diacylglycerol (DAG)

Triacylglycerol
Lipase
OH
Triacylglycerol (TAG)
OH
OH
OH

Monoacylglycerol
Lipase

Diacylglycerol
Lipase
OH

OH

Monoacylglycerol
(MAG)

Glycerol
12

Fate of Glycerol

Pyruvate

In Liver:
OH
OH
OH

Glycolysis

Dihydroxyacetone
Phosphate
Gluconeogenesis

Glycerol
Glucose

13

Beta Oxidation
Cleavage of fatty acids to acetate in
tissues
Occurs in mitochondria
[O]

[O]

[O]

[O]

[O]

[O]

[O]

[O]
CO 2 H

9 CH3COSCoA

14

Steps in Beta Oxidation


Fatty Acid Activation by Esterification
with CoASH
Membrane Transport of Fatty Acyl CoA
Esters
Carbon Backbone Reaction Sequence

Dehydrogenation
Hydration
Dehydrogenation
Carbon-Carbon Cleavage (Thiolase Reaction)
15

Fatty Acid Activation by


Esterification with CoASH
CoASH + RCO2H + ATP

AcylCoA

RCOSCoA + AMP + PPi

Synthetase

Occurs in outer mitochondrial


membrane for long chain fatty acids

Pyrophosphatase

2 Pi
G0(KJ/mole)

ATP
AMP + PPi
CoASH + RCO2H RCOSCoA
PPi
2 Pi

-32.3
+31.5
-33.6
-34.4

16

Membrane Transport of
Fatty Acyl CoA Esters
RCOSCoA +

+
(CH 3)3 N

Carnitine
acyltransferase II
(matrix side of
inner mitochondrial
membrane)

Carnitine

+
(CH 3)3 N

O
OH

OCarnitine
acyltransferase I
(outer part of mitochondrial
inner membrane)

O
O2CR

O-

O-Acylcarnitine

Transported across inner mitochondrial


membrane by translocase

17

Translocase

Carnitine acyltransferase I

Carnitine acyltransferase II
18

Source:http://cellbio.utmb.edu/cellbio/mitochondria_1.htm

Beta Oxidation
Reaction Sequence
H H
R-CH 2 -C-C-COSCoA
H H

Acyl CoA
Dehydrogenase

R-CH 2 -C=C-COSCoA

FAD

-Ketoacyl CoA
H
R-CH 2 -C-C-COSCoA
OH

FADH 2

L--Hydroxyacyl
CoA
Dehydrogenase
NADH
+ H+

CoASH

NAD +

Thiolase
(-ketothiolase)
R-CH 2 -C-SCoA
O

CH 3 -C-SCoA

trans- 2 -enoyl CoA


H2 O
Enoyl CoA Hydratase
H H

R-CH 2 -C-C-COSCoA
HO H

L--Hydroxyacyl CoA

Occurs in Mitochondria

Repeat Sequence

19

Complete Beta Oxidation


of Palmitoyl CoA
CH 3 CH 2 --CH2 CH 2 --CH2 CH 2 --CH2 CH 2 --CH2 CH 2 --CH2 CH 2 --CH2 CH 2 --CH2 COSCoA

7 Cycles
8 CH3COSCoA + 7 FADH2 + 7 NADH + 7 H

20

Energetics of Complete
Oxidation of Fatty Acids
High Energy Phosphate
Bonds Generated

Palmitic Acid

Palmitoyl CoA

TCA Cycle

CH3COSCoA

-2

CO2 + H2O

108

Net

106

106 High Energy Phosphate Bonds

For Palmitic Acid


CO2:
G0 = - 9,790 KJ/Mole

G0 = 3,233 KJ/Mole
Efficiency
of -Oxidation = 33%
21

Complete Oxidation
Fatty Acids: 9 kcal/g
Carbohydrates: 4 kcal/g
Protein:

4 kcal/g

22

Beta Oxidation of Odd


Carbon Fatty Acids
CH 3 CH 2 CH 2 --CH2 CH 2 --CH2 CH 2 --CH2 CH 2 --CH2 CH 2 --CH2 COSCoA

5 Cycles
5 CH3COSCoA + CH3CH2COSCoA
Propionyl CoA

TCA Cycle
Mutase

HO 2 CCH 2 CH 2COSCoA

Succinyl CoA

Vit. B12

CO 2 H
CH 3-C-H

Epimerase

COSCoA

L-Methylmalonyl
CoA

Propionyl CoA
Carboxylase
ATP/CO2

CO 2 H
H-C-CH 3
COSCoA

D-Methylmalonyl
CoA

23

Beta Oxidation of
Unsaturated Fatty Acids
H H
CH 3(CH 2 )7 -C=C-CH 2 (CH 2 )6 COSCoA

Oleoyl CoA
Beta Oxidation
(3 Cycles)

H
Isomerase
H H
CH 3(CH 2 )7 -CH 2 -C=C-COSCoA
CH 3(CH 2)7-C=C-CH 2COSCoA
2
H
trans-
3
cis-

Continuation of Beta Oxidation

24

Ketogenesis: Formation of
Ketone Bodies
2 CH3COSCoA

Thiolase

CH3COSCoA

CH3COCH2COSCoA
Acetoacetyl CoA

HMG CoA
Synthase
Cholesterol
(in cytosol)
See Slide 78

(in liver: mitochondrial matrix)


Ketogenesis

Several
steps

OH

HO2C-CH2-C-CH2COSCoA
CH3

-Hydroxy--methylglutaryl CoA
(HMG CoA)
25

Ketogenesis: Formation
of Ketone Bodies (Contd.)
OH

HO2C-CH2-C-CH2COSCoA
CH3

HMG CoA

HMG CoA
lyase
- CH3COSCoA

CH3COCH2CO2
Acetoacetate

NADH + H+
Dehydrogenase
NAD+

OH
CH3CHCH2CO2
-Hydroxybutyrate
Ketone bodies are important sources
of energy, especially in starvation

- CO2
CH3COCH3
Acetone
(volatile)
26

Ketone Bodies As Energy Sources


In liver
-Hydroxybutyrate

Acetoacetate

Acetoacetate is major energy


source in cardiac muscle and
renal cortex; also in brain in
starvation and diabetes

Succinyl CoA

-Ketoacyl CoA
transferase
Not found in liver

Thiolase

2 Acetyl CoA

Acetoacetyl CoA

Succinate

Combines with
oxaloacetate
TCA Cycle

27

Ketones in Diabetes Mellitus


In presence of insulin:
Enhanced glucose uptake by tissues
Decreased mobilization of lipids by
adipocytes
In absence of insulin:
Decreased glucose uptake by tissues
Increased mobilization of lipids by
adipocytes

28

Ketones in Diabetes Mellitus


Biochemical consequences of decreased
insulin production:

Glucose not taken up by liver

Decreased oxaloacetate to combine with


acetyl CoA to enter TCA

Adipocytes release fatty acids into blood

Increased production of ketone bodies in liver

29

Metabolic Acidosis in
Untreated Diabetes Mellitus
CH3COCH2CO2H pKa = 3.6
Acetoacetic Acid

OH
CH3CHCH2CO2H pKa = 4.7
-Hydroxybutyric acid

Concentration of acetoacetic acid can result in metabolic


acidosis (pH 7.1)
affinity of Hb for O2.
30

Fatty Acid Biosynthesis

31

Fatty Acid Synthesis vs.


Degradation
Synthesis

Degradation

Intermediates

Linked to SH in
Proteins
(Acyl Carrier Proteins)

Linked to CoASH

Site

Cytosol

Mitochondria

Enzymes

Components of
Single Peptide

Redox
Coenzymes

NADP / NADPH

Separate Polypeptides
+

NAD / NADH
32

Fatty Acid Biosynthesis


Occurs in cytosol
Starts with acetyl CoA
Problem:

Most acetyl CoA produced in mitochondria


Acetyl CoA unable to traverse mitochondrial
membrane

33

Citrate As Carrier of Acetate Groups


Cytosol
Glucose

Mitochondria

Pyruvate

Pyruvate

Malic enzyme

Pyruvate Acetyl
Dehydrogenase

Malate
Malate
dehydrogenase

Acetyl CoA

Citrate

CoA

Oxaloacetate

Oxaloacetate

ATP-Citrate
Lyase

Note: Acetyl CoA


cannot be converted
to glucose

Citrate
Mitochondrial
membrane

34

Fatty Acid Biosynthesis:


Formation of Malonyl CoA
Acetyl CoA
Carboxylase

CH3COSCoA + ATP + HCO3-

Malonyl CoA

O2CCH2COSCoA

+ ADP + Pi + H+

Committed step in fatty acid synthesis


Reaction is irreversible
Regulation of acetyl CoA carboxylase activity:
by palmitoyl CoA
by citrate
by insulin
by epinephrine and glucagon
Malonyl CoA inhibits carnitine acyl transferase I
Blocks beta oxidation

35

Fatty Acid Biosynthesis:


Role of Acyl Carrier Proteins
CH3COSCoA

Acetyl
Transferase

O2CCH2COSCoA

CH3CO-S-ACP
Acetyl ACP

Malonyl
Transferase

O2CCH2CO-S-ACP
Malonyl ACP

ACP = Acyl carrier protein

36

Fatty Acid Biosynthesis:


Formation of Acetoacetyl ACP
CH3CO-S-ACP + -O2CCH2CO-S-ACP
-Ketoacyl ACP
Synthetase

CH3COCH2CO-S-ACP + CO2
Acetoacetyl ACP

37

Fatty Acid Biosynthesis:


Formation of Butyryl ACP
-Ketoacyl ACP
reductase

CH3COCH2CO-S-ACP
Acetoacetyl ACP

OH

CH3CCH2CO-S-ACP

NADPH
+ H+

NADP+

H
-D-Hydroxybutyryl ACP

- H2O
NADP+

CH3CH2CH2CO-S-ACP
Butyryl ACP

NADPH
+ H+

2,3-transEnoyl ACP
reductase

-Hydroxyacyl ACP
dehydratase

CH3C=C-CO-S-ACP
H

Crotonyl ACP
38

Fatty Acid Biosynthesis:


Sources of NADPH
Pentose Phosphate Pathway:
CHO
HO

OH

NADP+

NADPH
+ H+

CO2-

HO

OH

NADP+

OH
OH
OP
6-Phosphogluconate

OH
OH
OP
Glucose-6phosphate

Malic Enzyme:

NADP+

HO-CH-CO2Malate

CH2CO2

NADPH
+ H+

CO2
NADPH
+ H+

Malic
Enzyme CO2

OH
O
OH
OH
OP
Ribulose-5phosphate

O
CH3CCO2Pyruvate
39

Fatty Acid Biosynthesis:


Chain Elongation
CH3CH2CH2CO-S-ACP

O2CCH2CO-S-ACP

CH3CH2CH2COCH2CO-S-ACP
H

OH

CH2CH2CH2CHCH2CO-S-ACP

CH3CH2CH2C=CCO-S-ACP
H
40

Fatty Acid Biosynthesis:


Chain Elongation (Contd)
H

NADPH
+ H+

CH3CH2CH2C=CCO-S-ACP

CH3(CH2)3CH2CO-S-ACP

CH3(CH2)13CH2CO2
Palmitate

NADP+

5 Cycles

CH3(CH2)13CH2CO-S-ACP

Thioesterase

Palmitoyl ACP

41

Fatty Acid Biosynthesis:


Fatty Acid Synthase
in Animals

Consists of a single polypeptide containing


three distinct domains

Conducts all steps in fatty acid synthesis


except function of acyl CoA carboxylase
42

Orlistat: A Fatty Acid


Synthase (FAS) Inhibitor
Inhibits thioesterase
domain of FAS
Anti-obesity
Anti-cancer (experimental):
FAS overexpressed in
several tumor types;
inhibition induces
apoptosis
43

Further Processing of Fatty


Acids: Elongation
CH3(CH2)13CH2COSCoA
Palmitate

In mitochondria and
at surface of
endoplasmic reticulum

CH3COSCoA
Thiolase

CH3(CH2)13CH2COCH2COSCoA
NADH + H+
NAD+

Dehydrogenase

OH

L- Configuration

CH3(CH2)13CH2CCH2COSCoA
H

44

Further Processing of Fatty


Acids: Elongation (Contd)
OH

CH3(CH2)13CH2CCH2COSCoA
- H2O
Hydratase

H
H

CH3(CH2)13CH2C=CCOSCoA
NADPH + H+
Dehydrogenase

NADP+

CH3(CH2)13CH2CH2CH2COSCoA
Stearoyl CoA
45

Further Processing of Fatty


Acids: Unsaturation
CH3(CH2)13CH2CH2CH2COSCoA
Stearoyl CoA

Stearoyl CoA
Desaturase

O2

CH3(CH2)7C=C(CH2)7COSCoA + H2O
Oleoyl CoA

This reaction occurs in eukaryotes


Endoplasmic reticulum membrane
46

Further Processing of Fatty


Acids: Polyunsaturation
9

CH3(CH2)7C=C(CH2)7CO2H
H H
Plants: Further unsaturation
occurs primarily in this region
12

Oleic acid
(18:19)

Animals: Further unsaturation


occurs primarily in this region
9

CO 2 H

Linoleic acid (18:29, 12)

Essential dietary
fatty acids in mammals
15

12

Linolenic acid (18:312, 15)

CO 2H
47

Formation of Arachidonate
in Mammals
CO 2 H
Linoleic acid

14

11

As CoA ester:
1) Elongation
2) Desaturation x 2
8

CO 2H

Arachidonic acid (20:48, 11, 14)


(Eicosa-5,-8,11,14-tetraenoic acid)

Prostaglandins

48

Omega-3 Fatty Acids


CO 2H
-3 double bond

Eicosapentaenoic acid (20:58, 11, 14, 17)


CO 2H

Docahexaenoic acid (22:67, 10, 13, 16, 19)


Found in fish oils, esp. cold water fish
Important in:
Growth regulation
Modulation of inflammation
Platelet activation
Lipoprotein metabolism
49

Metabolite Regulation of Fatty


Acid Synthesis and Breakdown
Glucose

Citrate
Stimulates

Pyruvate

Acetyl CoA

Malonyl CoA

Blocks

Beta
Oxidation

Inhibits
Palmitoyl CoA

50

Hormonal Regulation of Fatty


Acid Synthesis and Breakdown
ATP

Adenylyl cyclase

cAMP

Stimulates
Glucagon and
epinephrine

Inhibition of
fatty acid
synthesis

Phosphodiesterase

Stimulates
Insulin

Activates Protein Kinase

Inactivates ACC by
phosphorylation

AMP

Inactivates
lipase

Activates triacylglycerollipase
51

Synthesis of Phosphatidate
Dihydroxyacetone
Phosphate
(from glycolysis)

CH 2OH

CH 2O2C-R1

CH 2OH

C=O

CHO 2C-R2

CHOH

Glycerol

CH 2O-P-O-

CH 2O-P-O
O-

O-

CH 2OH

Phosphatidate (formed in endoplasmic reticulum)


O

CH 2O2C-R1
Diacylglycerol
(important in
cell signaling)

CHO 2C-R2
CH 2OH

CH 2OC-R1
R3COSCoA

CHOC-R 2

Diacylglycerol
O
acyltransferase
(liver)
CH 2OC-R3

Triacylglycerol
(transported to
adipocytes and
muscle)
52

Synthesis of
Glycerophospholipids
NH2

CH 2O2C-R1
CHO 2C-R2
CH 2OH
Diacylglycerol

CH 2O2C-R1

O
+
R3NCH 2 CH 2OPOPO O

Transferase

CHO 2C-R2
O

OH OH

CH 2O-P-O-CH 2CH 2R3

R=H; CDP ethanolamine


R=CH3; CDP choline

O-

CDP = cytidine diphosphate

R3=NH3; Phosphatidylethanolamine
+

R3=N(CH3)3; Phosphatidylcholine

CH 2O2C-R1

HOCH 2 CHNH 3

CHO 2C-R2
O

CH 2O-P-O-CH 2CHNH 3
O-

Phosphatidylserine

CO 2-

HOCH 2 CH 2 NH3

CO 2 -

Serine

Ethanolamine
53

Respiratory Distress
Syndrome
Most frequently seen in premature infants
Also called hyaline membrane disease
Failure to produce sufficient dipalmitoyl phosphatidylcholine,
which normally is found in the extracellular fluid surrounding
alveoli; decreases surface tension of fluid to prevent lung
collapse
Treatment in infants born before 30 weeks includes
administration of artificial lung surfactant

54

Synthesis of Glycerophospholipids (Contd)


CH 2O2C-R1
CHO 2C-R2
O

CH 2O2C-R1

CH 2O2C-R1
CHO 2C-R2

CHO 2C-R2

CH 2O-P-O
-

CH 2O-P-O
O-

Phosphatidate

O-

CH 2O-CDP

OH OH

Cytidine diphosphate (CDP)


diacylglycerol

HO

Phosphorylation
of 4 & 5 OH groups

OH
OH

Phospholipase C
(plasma membrane)
CH 2O2C-R1

OH OH

Both IP3 and DAG are


important second messengers
in cell signaling pathways

Phosphatidylinositol

OPO3H2
H2O3PO

OPO3H2
OH

Inositol-1,4,5triphosphate (IP3)

CHO 2C-R2
CH 2OH

Diacylglycerol (DAG)
55

Synthesis of Glycerophospholipids (Contd)


CH 2O2C-R1

CH 2O2C-R1

CH 2O2C-R4

CHO 2C-R2

CHO 2C-R2

CHO 2C-R3

CH 2O-CDP
Cytidine diphosphate
(CDP) diacylglycerol

CH 2O-P-O-CH 2CHCH 2-O-P-O-CH 2


O-

OH

O-

Cardiolipin: formed in inner


mitochondrial membrane;
plays role in oxidative
phosphorylation
56

Synthesis of Glycerophospholipids (Contd)


CH 2OH

CH 2-O-CH=CHR 1

C=O

CHO 2C-R2
O

CH 2O-P-O
O-

Dihydroxyacetone
Phosphate
(from glycolysis)

CH 2O-P-O-CH 2CH 2NH 3


O-

Plasmalogens
(Abundant in cardiac
tissue and CNS)
57

Synthesis of Sphingolipids
CH3(CH2)14COSCoA +

HOCH 2 CHNH 3

Serine

CO 2 -

Palmitoyl CoA

3-Ketosphingosine
synthase
CoASH

HCO3-2

CH3(CH2)14CO-CHCH2OH
NH3+
3 Steps

2S,3-Ketosphinganine

OH
trans

CH3(CH2)12CH=CH-CH-CH-CH2OH

Ceramide

CH3(CH2)nCONH
58

Synthesis of Sphingolipids
(Contd)
CH 2O2C-R1
trans

OH

CH3(CH2)12CH=CH-CH-CH-CH2OH

CHO 2C-R2
O

CH3(CH2)nCONH

CH 2O-P-O-CH 2CH 2N(CH 3)3


O-

Ceramide

Phosphatidylcholine
Diacylglycerol
trans

OH

CH3(CH2)12CH=CH-CH-CH-CH2O-P-OCH2CH2N(CH3)3
CH3(CH2)nCONH
Gangliosides

O-

Sphingomyelin

Cerebrosides

59

Synthesis of Gangliosides
OH

trans

CH3(CH2)12CH=CH-CH-CH-CH2OH
CH3(CH2)nCONH

Ceramide

OH
trans

CH3(CH2)12CH=CH-CH-CH-CH2O-Sugar
CH3(CH2)nCONH

Glucose or
galactose

Cerebroside

Ceramide - Sugar - Sugar - GalNAc - Gal


NAN = N-acetylneuraminate
GalNAc = N-acetylgalactose

NAN

Ganglioside

60

Lipid Storage Diseases


(Gangliosidoses)

61

Tay-Sachs Disease
GM2 (a ganglioside):
Ceramide - O - Glucose - Galactose - N-Acetylgalactose
Hexoseaminidase A
catalyzes cleavage of this
glycoside linkage
Autosomal recessive disorder characterized by deficiency
of hexoseaminidase A; accumulation of gangliosides in brain
Most prevalent in Jews from Eastern Europe
For further information see:
http://www.marchofdimes.com/professionals/681_1227.asp

62

Other Gangliosidoses
Gauchers disease:
Ceramide - O - Glucose
-glucosidase
Fabrys disease:
Ceramide - O - Glucose - O - Galactose - O - Galactose
Nieman-Pick disease:

-galactosidase

Ceramide - Phosphate - Choline


sphingomyelinase

63

Synthesis of Eicosanoids
CH 2O2C-R

In cell membrane

CHO 2C
O

CH 2O-P-O-CH 2CH 2NR'3


O-

R= H or CH3

Hydrolysis of sn-2 ester bond


by phospholipase A2 (PLA2)

-O C
2

Arachidonate

64

Synthesis of Eicosanoids:
PLA2 Activation
Various stimuli:
Hormones, autacoids, etc.

Activation of
Membrane-bound
Receptors

PLA2
Activity
Ca+2

Arachidonate release and eicosanoid synthesis


are important mediators of tissue injury and inflammation

65

Synthesis of Eicosanoids:
Prostaglandin Synthesis
CO 2 -

O
O

Prostaglandin
endoperoxide
synthetase
(Cyclooxygenase)
Cyclic
endoperoxide

CO 2-

Hydroperoxidase

CO 2 -

O
O

O=O

Cyclooxygenase
CO 2 -

O
O

O
OH

PGH2

Hydroperoxide

O-O-H

Prostaglandin endoperoxide synthetase (also called cyclooxygenase)


possesses both cyclooxygenase and hydroperoxidase activity
Two forms of cyclooxygenase: COX -1 - constitutively expressed
COX -2 - inducible

PGG2

66

Cyclooxygenase (COX) Inhibitors


Nonsteroidal antiinflammatory drugs:
CO 2H

COX

COX

CO 2 H

HOH2C
OCOCH 3

Acetylsalicylic acid
(aspirin)

O - CCH 3

Ser-530

CH 2 OCOCH 3

Irreversible inhibition of COX by acetylation


of the active site

Actions of Aspirin:
Antiinflammatory (COX-2 inhibition)
GI injury (COX-1 inhibition)

67

COX-2 Selective Inhibitors


F3C

O
O

N
N

SO2 CH 3

Rofecoxib (Vioxx)

CH 3

SO2NH2

Celecoxib (Celebrex)

Glucocorticoids block COX-2 expression


68

Prostaglandins
O
CO 2H

CO 2 -

O
O

PGH2

HO

PGE2

OH

HO
CO 2H

OH
O

PGD2

OH

HO

Prostaglandins exhibit a variety


of actions on different tissues

CO 2 H

HO

OH

PGF2

69

Prostacyclin and Thromboxanes


OH

CO 2 -

Prostacyclin
synthase

O
PGH2

HO2C

OH
O

OH

Prostacyclin (PGI2):
Blocks platelet
aggregation

Thromboxane
synthase
CO 2 -

O
O

OH

Thromboxane A2 (TxA2):
Promotes platelet
aggregation (t1/2 = 30 sec.)

OH

Non-Enzymatic
HO

CO 2O

OH

Thromboxane B2 (TxB2):
inactive

70

Leukotriene Biosynthesis
OOH

CO 2H

5-Lipoxygenase
Arachidonic acid

OH

e
A
LT olas
dr
y
H

5-Hydroperoxyeicosa6,8,11,14-tetraenoic acid
(5-HPETE)

CO 2 H

5-Lipoxygenase
O

CO 2 H

Leukotriene A4 (LTA4)

Leukotriene B4 (LTB4)
Gly

Cys

OH

Leukotrienes are
important mediators
of inflammation

CO 2H

CO 2 H

Leukotriene E4 (LTE4)

- Glu
- Gly
Cysteinyl leukotrienes

Cys

Glu

Glutathione
LTC4 synthase
CO 2H

OH

Leukotriene C4 (LTC4)
71

Leukotriene Biosynthesis
(Contd)
CO 2H

CO 2 H

12-Lipoxygenase

HOO
Arachidonic acid

12-Hydroperoxyeicosa5,8,10,14-tetraenoic acid
(12-HPETE)

CO 2 H
HO

12-Hydroxyeicosa5,8,10,14-tetraenoic acid
(12-HETE)

72

Leukotriene Biosynthesis
Inhibition
OH

CH-N-CONH 2
CH 3
Zileuton (Zyflo)
An inhibitor of 5-lipoxygenase
Used in the treatment of asthma

73

Cholesterol Biosynthesis:
Formation of Mevalonate
Liver is primary site of cholesterol biosynthesis

2 CH3COSCoA

Thiolase

CH3COCH2COSCoA
Acetoacetyl CoA

OH

HO2C-CH2-C-CH2CH2OH
CH3

3R-Mevalonic acid

HMGCoA
reductase

CH3COSCoA
HMG CoA
Synthase
OH

HO2C-CH2-C-CH2COSCoA

CoASH NADP + NADPH


+ H+

CH3

-Hydroxy--methylKey control step glutaryl CoA (HMG CoA)


in cholesterol
74
biosynthesis

Cholesterol Biosynthesis:
Processing of Mevalonate
OH
-

O2C-CH2-C-CH2CH2OH
CH3
Mevalonate

OH
2 Steps
ATP

O2C-CH2-C-CH2CH2OPOP
CH3
5-Pyrophosphomevalonate
- CO2
- H 2O

CH3
Isomerase
CH3-C=CH2CH2OPOP
CH2=C-CH2CH2OPOP
Isopentenyl
Dimethylallyl
CH3
pyrophosphate
pyrophosphate
75

Cholesterol Biosynthesis:
Isoprenoid Condensation
Dimethylallyl
pyrophosphate

Tail
OPOP
OPOP

Head
Head

Head to tail
Condensation

Tail

Tail

OPOP

Geranyl transferase

Geranyl
Pyrophosphate (GPP)

Isopentenyl
Pyrophosphate (IPP)

Isoprenes
Tail to tail
condensation
of 2 FPPs

Squalene

Head

Squalene
synthase

Geranyl
transferase

Head to tail
condensation
of IPP and GPP
OPOP

Head

Tail

Farnesyl
Pyrophosphate (FPP)

76

Isoprenoids
Widely distributed in nature
Generally contain multiple of 5 carbons:
Monoterpene; 10 carbons
Sesquiterpene: 15 carbons
Diterpene: 20 carbons

OH

OH

Menthol: a monoterpene

Lycopene: a tetraterpene

77

Conversion of Squalene to Cholesterol


Squalene2,3-epoxide

Squalene
monooxygenase
O2
Squalene

H+

2,3-Oxidosqualene
cyclase
CH3

CH3
CH3

HO

CH3

Cholesterol
Acyl-CoA:
cholesterol
acyltransferase

CH3

20 Steps

CH 3
HO
H3 C

CH 3

Lanosterol

RCO 2

Cholesterol esters
(principal transport form in blood)

78

Inhibition of Cholesterol Biosynthesis


HO
CH 3

CO 2 COSCoA

HMGCoA
reductase

HO
CH 3

HMG CoA

CO 2H
C -S -CoA
OH

Intermediate
HO

HO
CH 3

CO 2 OH

Mevalonate

CO 2 -

OH

Atorvastatin (Lipitor):
resembles intermediate

CH 2CH 2
N

C6 H5NHCO
79

Transformations of
Cholesterol: Bile Salts
HO

CH3

CH3

CO 2 -

CH3

CH3

HO

HO

Cholesterol

OH

Cholic acid

CH3

CONHCH 2 R

Taurocholate
R = CO2- Glycocholate
R = CH2SO3-

Detergents

80

Transformations of
Cholesterol: Steroid Hormones
OH

CH3

HO

OH

CH3

HO

Cortisol

Cholesterol

Progesterone

OH
OH

OH
O
HO

Testosterone

CH 2

Estradiol

HO

OH

Vitamin D

81