11 lipidmetabolism
TRANSCRIPT
1
Lipid Metabolism
2
Fatty Acids
CH3(CH2)nCH2CO2H
O
O
CH3(CH2)nCH2C-O-R
CH3(CH2)nCH2C-OH H-O-R
O
O
CH3(CH2)nCH2C-OH H-S-R
CH3(CH2)nCH2C-S-R
Ester Thioester
3
Fatty Acids as Stored Energy
• Fatty acids are the body’s principal
form of stored energy
• Carbon almost completely reduced
as CH2
• Very closely packed in storage
tissues - not hydrated as sugars are
4
Dietary Fatty Acids
• Comprise 30-60% of caloric intake in
average American diet
• Triacylglycerols, phospholipids,
sterol esters
• Principal sources: dairy products,
meats
5
Digestion of Dietary
Triacylglycerols• Occurs in duodenum
• Facilitated by • Bile salts (emulsification)
• Alkaline medium (pancreatic juice)
Pancreatic
lipasesOH
OH
TAG MAG
Intestinal
lipases Glycerol
+
Fatty Acids
Blocked by Orlistat (“Fat Blocker”) - Xenical/Alli
6
Epithelial Cell (Intestinal Wall)
Intestinal lumen
MAG Glycerol Fatty Acids
TAG
Lipoprotein
ChylomicronsLymphatics
Blood (bound to albumin)Adipose Tissue
And Muscle
7
Fat Storage
• Mainly as triacylglycerols
(triglycerides) in adipose cells
• Constitute 84% of stored energy• Protein - 15%
• Carbohydrate (glucose or glycogen) - <1%
8
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
Release of Fatty Acids from
TriacylglycerolsO
O
O
O O O
+
HOC-R3 HOC-R2 HOC-R1
Triacylglycerol Glycerol
Lipases
CH2OH
CHOH
CH2OHCH2OC-R1
CHOC-R2
CH2OC-R3
10Adipose Cell
Hormone
(Adrenalin, Glucagon, ACTH)
Receptor (7TM)
ATP c-AMP
Adenylyl
Cyclase
Activates
Activates lipase
Triacylglycerols Glycerol +
Fatty acids Blood
Lipolysis
Insulin
blocks this
step
11
ATP c-AMP AMP
Inactive Kinase Activated Kinase
Inactive Lipase Activated Lipase
P
Triacyl-
glycerol
Glycerol +
Fatty Acids
Phosphatase(Hormone-sensitive
Lipase)
Insulin favors formation
of the inactive lipase
Adenylyl cyclase Phosphodiesterase
Enhanced by insulinEnhanced by glucagon
12
Acylglycerol Lipases
Triacylglycerol
Lipase
Diacylglycerol
Lipase
OH
OH
OH
Monoacylglycerol
Lipase
OH
OH
OH
Triacylglycerol (TAG)
Diacylglycerol (DAG)
Monoacylglycerol
(MAG)
Glycerol
13
Fate of Glycerol
OH
OH
OH
Glycerol
In Liver:
Dihydroxyacetone
Phosphate
Pyruvate
Glucose
Glycolysis
Gluconeogenesis
14
Beta Oxidation
• Cleavage of fatty acids to acetate in
tissues
• Occurs in mitochondria
9 CH3COSCoACO2H
[O] [O] [O] [O] [O][O] [O] [O]
15
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)
16
Fatty Acid Activation by
Esterification with CoASH
CoASH + RCO2H + ATP RCOSCoA + AMP + PPi
AcylCoA
Synthetase
2 Pi
Pyrophos-
phatase
Occurs in outer mitochondrial
membrane for long chain fatty acids
ATP AMP + PPi -32.3
CoASH + RCO2H RCOSCoA +31.5
PPi 2 Pi -33.6
G0’(KJ/mole)
-34.4
17
Membrane Transport of
Fatty Acyl CoA Esters
Transported across inner mitochondrial
membrane by translocase
(CH3)3NO
O -
OH
(CH3)3NO
O -
O2CR
Carnitineacyltransferase II(matrix side of inner mitochondrialmembrane)
Carnitineacyltransferase I(outer part of mitochondrial inner membrane)
O-Acylcarnitine
Carnitine
+
+RCOSCoA +
18Source: http://cellbio.utmb.edu/cellbio/mitochondria_1.htm
Carnitine acyltransferase I Carnitine acyltransferase II
Translocase
19
Beta Oxidation
Reaction Sequence
Occurs in Mitochondria
Repeat Sequence
H H
H H
H
H
H
H
HO HO
H
O
H
O
Enoyl CoA Hydratase
R-CH2-C-C-COSCoA R-CH2-C=C-COSCoA
R-CH2-C-C-COSCoAR-CH2-C-C-COSCoA
R-CH2-C-SCoA CH3-C-SCoA
Acyl CoADehydrogenase
FAD FADH2trans-2-enoyl CoA
H2O
L--Hydroxyacyl CoA
L--Hydroxyacyl CoADehydrogenase
NAD+NADH
+ H+
CoASH
+
Thiolase
-Ketoacyl CoA
(-ketothiolase)
20
Complete Beta Oxidation
of Palmitoyl CoA
CH3CH2--CH2CH2--CH2CH2--CH2CH2--CH2CH2--CH2CH2--CH2CH2--CH2COSCoA
7 Cycles
8 CH3COSCoA + 7 FADH2 + 7 NADH + 7 H+
21
Energetics of Complete
Oxidation of Fatty Acids
Palmitic Acid Palmitoyl CoA -2
CH3COSCoA CO2 + H2O 108
High Energy Phosphate
Bonds Generated
Net 106
TCA Cycle
106 High Energy Phosphate Bonds G0’ = 3,233 KJ/Mole
For Palmitic Acid CO2:
G0’ = - 9,790 KJ/MoleEfficiency
of -Oxidation = 33%
22
Complete Oxidation
Fatty Acids: 9 kcal/g
Carbohydrates: 4 kcal/g
Protein: 4 kcal/g
23
Beta Oxidation of Odd
Carbon Fatty Acids
CH3CH2CH2--CH2CH2--CH2CH2--CH2CH2--CH2CH2--CH2COSCoA
5 Cycles
5 CH3COSCoA + CH3CH2COSCoA
Propionyl CoA
CO2H
COSCoA
H-C-CH3
CO2H
COSCoA
CH3-C-HHO2CCH2CH2COSCoA
D-Methylmalonyl
CoA
L-Methylmalonyl
CoA
Succinyl CoA
TCA Cycle
Propionyl CoA
Carboxylase
ATP/CO2
EpimeraseMutase
Vit. B12
24
Beta Oxidation of
Unsaturated Fatty Acids
H H
CH3(CH2)7-C=C-CH2(CH2)6COSCoA
H H
CH3(CH2)7-C=C-CH2COSCoA
H
H
CH3(CH2)7-CH2-C=C-COSCoA
Oleoyl CoA
Beta Oxidation
(3 Cycles)
cis-3
Isomerase
trans-2
Continuation of Beta Oxidation
25
Ketogenesis: Formation of
Ketone Bodies
2 CH3COSCoA CH3COCH2COSCoA
Thiolase
CH3COSCoA
Acetoacetyl CoA
HO2C-CH2-C-CH2COSCoA
OH
CH3
-Hydroxy--methylglutaryl CoA
(HMG CoA)
HMG CoA
Synthase
Cholesterol
(in cytosol)
Several
steps
Ketogenesis
(in liver: mitochon-
drial matrix)
See Slide 78
26
Ketogenesis: Formation
of Ketone Bodies (Cont’d.)
HO2C-CH2-C-CH2COSCoA
OH
CH3
HMG CoA
Acetoacetate
HMG CoA
lyase
- CH3COSCoA
- CO2
CH3COCH3
Acetone
(volatile)
CH3CHCH2CO2
OH
-Hydroxybutyrate
NADH + H+
NAD+
Dehydrogenase
Ketone bodies are important sources
of energy, especially in starvation
CH3COCH2CO2
27
-Hydroxybutyrate Acetoacetate Succinyl CoA
SuccinateAcetoacetyl CoA
-Ketoacyl CoA
transferase
2 Acetyl CoA
Thiolase
TCA Cycle
Ketone Bodies As Energy SourcesIn liver
Acetoacetate is major energy
source in cardiac muscle and
renal cortex; also in brain in
starvation and diabetes
Not found in liver
Combines with
oxaloacetate
28
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
29
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
30
CH3COCH2CO2H pKa = 3.6 Acetoacetic Acid
CH3CHCH2CO2H pKa = 4.7 -Hydroxybutyric acid
OH
Concentration of acetoacetic acid can result in metabolic
acidosis (pH 7.1) affinity of Hb for O2.
Metabolic Acidosis in
Untreated Diabetes Mellitus
31
Fatty Acid Biosynthesis
32
Fatty Acid Synthesis vs.
Degradation
Intermediates
Site
Enzymes
Redox
Coenzymes
Synthesis Degradation
Linked to SH in Linked to CoASH
Proteins
(Acyl Carrier Proteins)
Cytosol Mitochondria
Components of Separate Polypeptides
Single Peptide
NADP+
/ NADPH NAD+
/ NADH
33
Fatty Acid Biosynthesis
• Occurs in cytosol
• Starts with acetyl CoA• Problem:
» Most acetyl CoA produced in mitochondria
» Acetyl CoA unable to traverse mitochondrial
membrane
34
Mitochondrial
membrane
Cytosol Mitochondria
Glucose Pyruvate Pyruvate Acetyl CoA
Oxalo-
acetateCitrate
Citrate
Acetyl CoA
Pyruvate
Dehydrogenase
ATP-Citrate
Lyase
Malate
Oxaloacetate
Malic enzyme
Malate
dehydrogenase
Note: Acetyl CoA
cannot be converted
to glucose
Citrate As Carrier of Acetate Groups
35
Fatty Acid Biosynthesis:
Formation of Malonyl CoA
CH3COSCoA + ATP + HCO3- -O2CCH2COSCoA
Acetyl CoA
Carboxylase
+ ADP + Pi + H+
Malonyl CoA
• 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
36
Fatty Acid Biosynthesis:
Role of Acyl Carrier Proteins
CH3COSCoA CH3CO-S-ACP
-O2CCH2COSCoA -O2CCH2CO-S-ACP
Acetyl
Transferase
Malonyl
Transferase
Acetyl ACP
Malonyl ACP
ACP = Acyl carrier protein
37
Fatty Acid Biosynthesis:
Formation of Acetoacetyl ACP
CH3CO-S-ACP + -O2CCH2CO-S-ACP
CH3COCH2CO-S-ACP + CO2
Acetoacetyl ACP
-Ketoacyl ACP
Synthetase
38
Fatty Acid Biosynthesis:
Formation of Butyryl ACP
CH3COCH2CO-S-ACP CH3CCH2CO-S-ACP
OH
HAcetoacetyl ACP
-D-Hydroxybutyryl ACP
-Ketoacyl ACP
reductase
NADPH
+ H+
NADP+
CH3C=C-CO-S-ACP
H
H
-Hydroxyacyl ACP
dehydratase- H2O
Crotonyl ACP
CH3CH2CH2CO-S-ACP
Butyryl ACP2,3-trans-
Enoyl ACP
reductase
NADPH
+ H+
NADP+
39
Fatty Acid Biosynthesis:
Sources of NADPH
Pentose Phosphate Pathway:
CHO
OH
OHOHOP
HO
CO2-
OH
OHOHOP
HO
NADP+NADPH
+ H+ NADP+
NADPH
+ H+
CO2
OH
OHOHOP
O
Ribulose-5-
phosphate6-Phospho-
gluconateGlucose-6-
phosphate
Malic Enzyme:
HO-CH-CO2-
CH2CO2-Malate
CO2
NADP+
NADPH
+ H+
Malic
Enzyme
CH3CCO2-
O
Pyruvate
40
Fatty Acid Biosynthesis:
Chain Elongation
CH3CH2CH2CO-S-ACP -O2CCH2CO-S-ACP+
CH3CH2CH2COCH2CO-S-ACP
CH2CH2CH2CHCH2CO-S-ACP CH3CH2CH2C=CCO-S-ACP
H
H
OH
41
Fatty Acid Biosynthesis:
Chain Elongation (Cont’d)
CH3(CH2)3CH2CO-S-ACPCH3CH2CH2C=CCO-S-ACP
H
H
NADPH
+ H+NADP+
CH3(CH2)13CH2CO-S-ACP
5 Cycles
Palmitoyl ACP
CH3(CH2)13CH2CO2
-
PalmitateThioesterase
42
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
43
Orlistat: A Fatty Acid
Synthase (FAS) Inhibitor
Anti-obesity (Inhibits
pancreatic lipase in git)
Inhibits thioesterase
domain of FAS
Anti-cancer (experimental):
FAS overexpressed in
several tumor types;
inhibition induces
apoptosis
44
Further Processing of Fatty
Acids: Elongation
CH3(CH2)13CH2COSCoAPalmitoyl CoA
CH3(CH2)13CH2COCH2COSCoA
CH3(CH2)13CH2CCH2COSCoA
OH
H
NADH + H+
NAD+
Thiolase
Dehydrogenase
L- Configuration
CH3COSCoA
In mitochondria and
at surface of
endoplasmic reticulum
45
Further Processing of Fatty
Acids: Elongation (Cont’d)
CH3(CH2)13CH2CCH2COSCoA
OH
H
CH3(CH2)13CH2C=CCOSCoA
H
H
- H2O
Hydratase
CH3(CH2)13CH2CH2CH2COSCoA
Stearoyl CoA
NADPH + H+
NADP+
Dehydrogenase
46
Further Processing of Fatty
Acids: Unsaturation
CH3(CH2)13CH2CH2CH2COSCoA
CH3(CH2)7C=C(CH2)7COSCoA + H2O
H H
Stearoyl CoA
Oleoyl CoA
This reaction occurs in eukaryotes
Endoplasmic reticulum membrane
Stearoyl CoA
DesaturaseO2
47
Further Processing of Fatty
Acids: Polyunsaturation
CH3(CH2)7C=C(CH2)7CO2H
H H
Oleic acid
Plants: Further unsaturation
occurs primarily in this region
Animals: Further unsaturation
occurs primarily in this region
CO2H
(18:19)
9
Linoleic acid (18:29, 12)
12 9
Linolenic acid (18:39, 12, 15)
15 12 9
Essential dietary
fatty acids in mammals
CO2H
48
Formation of Arachidonate
in Mammals
Linoleic acid
CO2H
14 11 8 5
Arachidonic acid (20:45, 8, 11, 14)
(Eicosa-5,-8,11,14-tetraenoic acid)
As CoA ester:
1) Elongation
2) Desaturation x 2
Prostaglandins
CO2H
49
Omega-3 Fatty Acids
CO2H
CO2H
-3 double bond Eicosapentaenoic acid (20:55, 8, 11, 14, 17)
Docahexaenoic acid (22:64, 7, 10, 13, 16, 19)
• Found in fish oils, esp. cold water fish
• Important in:
Growth regulation
Modulation of inflammation
Platelet activation
Lipoprotein metabolism
50
Metabolite Regulation of Fatty
Acid Synthesis and Breakdown
Pyruvate Acetyl CoA Malonyl CoA
Palmitoyl CoA
Citrate
Inhibits
Stimulates
Beta
Oxidation
Blocks
Glucose
51
Hormonal Regulation of Fatty
Acid Synthesis and Breakdown
ATP cAMP AMPAdenylyl cyclase
Glucagon and
epinephrine
Stimulates
Phosphodiesterase
Insulin
Stimulates
Activates Protein Kinase
Inactivates ACC by
phosphorylation
Inhibition of
fatty acid
synthesis
Activates triacyl-
glycerollipase
Inactivates
lipase
52
Synthesis of Phosphatidate
O-
O
O-
O
O
O
O
CH2OC-R1
CHOC-R 2
CH2OC-R3
CHO 2C-R2
CH2O2C-R1
CH2OH
CH2O-P-O-
CH2O2C-R1
CHO 2C-R2C=O
CH2OH
CH2O-P-O-
CH2OH
CHOH
CH2OH
Dihydroxyacetone
Phosphate
(from glycolysis)
Glycerol
Phosphatidate (formed in endoplasmic reticulum)
Diacylglycerol
(important in
cell signaling)
R3COSCoA
Diacylglycerol
acyltransferase
(liver)
Triacylglycerol
(transported to
adipocytes and
muscle)
53
Synthesis of
Glycerophospholipids
CH2OH
CH2O2C-R1
CHO2C-R2
N
N
NH2
O
O
OHOH
R3NCH2CH2OPOPO+
R=H; CDP ethanolamine
R=CH3; CDP choline
CDP = cytidine diphosphateDiacylglycerol
+ Transferase
R3=NH3; Phosphatidylethanolamine
R3=N(CH3)3; Phosphatidylcholine
O-
O
CO2-
CH2O-P-O-CH2CHNH3
CH2O2C-R1
CHO2C-R2
+
+
CO 2-
HOCH2CHNH3
HOCH 2CH 2NH3
+Serine
Ethanolamine
O-
O
CHO2C-R2
CH2O2C-R1
CH2O-P-O-CH2CH2R3
+
+
Phosphatidylserine
54
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 (e.g., Exosurf or
Pumactant)
55
Synthesis of Glycero-
phospholipids (Cont’d)
O-
O
CHO2C-R2
CH2O2C-R1
CH2O-P-O-
CH2O-CDP
CH2O2C-R1
CHO2C-R2
Phosphatidate Cytidine diphosphate (CDP)
diacylglycerol
Phosphatidyl-
inositol
O-
O
OH
OHHO
OH OH
CH2O-P-O
CH2O2C-R1
CHO2C-R2
OH
OPO3H2
H2O3PO
OH OH
OPO3H2
CH2OH
CH2O2C-R1
CHO2C-R2+
Diacylglycerol (DAG)
Phospholipase C
(plasma membrane)
Both IP3 and DAG are
important second messengers
in cell signaling pathways
Inositol-1,4,5-
triphosphate (IP3)
Phosphorylation
of 4 & 5 OH groups
56
Synthesis of Glycero-
phospholipids (Cont’d)
O-
O O
O-OH
CHO2C-R3
CH2O2C-R4
CH2O-P-O-CH2CHCH2-O-P-O-CH2
CH2O2C-R1
CHO2C-R2
CH2O-CDP
CH2O2C-R1
CHO2C-R2
Cytidine diphosphate
(CDP) diacylglycerolCardiolipin: formed in inner
mitochondrial membrane;
plays role in oxidative
phosphorylation
57
Synthesis of Glycero-
phospholipids (Cont’d)
O-
O
CH2O-P-O-
CH2OH
C=O
Dihydroxyacetone
Phosphate
(from glycolysis)
O-
O
CH2O-P-O-CH2CH2NH3
CH2-O-CH=CHR1
CHO2C-R2
+
Plasmalogens
(Abundant in cardiac
tissue and CNS)
58
Synthesis of Sphingolipids+
CO 2-
HOCH2CHNH3CH3(CH2)14COSCoA +
HCO3-2 CoASH
3-Ketosphingosine
synthase
CH3(CH2)14CO-CHCH2OH
NH3+
2S,3-Ketosphinganine
3 Steps
CH3(CH2)12CH=CH-CH-CH-CH2OH
OH
Ceramide
Palmitoyl CoA
Serine
trans
CH3(CH2)nCONH
59
Synthesis of Sphingolipids
(Cont’d)
CH3(CH2)12CH=CH-CH-CH-CH2OH
CH3(CH2)nCONH
OH
CeramideO-
O +
CH2O-P-O-CH2CH2N(CH3)3
CH2O2C-R1
CHO2C-R2
Phosphatidylcholine
Diacylglycerol
CH3(CH2)12CH=CH-CH-CH-CH2O-P-OCH2CH2N(CH3)3
CH3(CH2)nCONH
OH O
O-
+
Sphingomyelin
CerebrosidesGangliosides
trans
trans
60
Synthesis of Gangliosides
CH3(CH2)12CH=CH-CH-CH-CH2OH
CH3(CH2)nCONH
OH
Ceramide
CH3(CH2)12CH=CH-CH-CH-CH2O-Sugar
CH3(CH2)nCONH
OH
Cerebroside
Ganglioside
trans
transGlucose or
galactose
Ceramide - Sugar - Sugar - GalNAc - Gal
NANNAN = N-acetylneuraminate
GalNAc = N-acetylgalactose
61
Lipid Storage Diseases
(Gangliosidoses)
62
Tay-Sachs Disease
Ceramide - O - Glucose - Galactose - N-Acetylgalactose
Hexoseaminidase A
catalyzes cleavage of this
glycoside linkage
GM2 (a ganglioside):
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
63
Other Gangliosidoses
Gaucher’s disease:
Fabry’s disease:
Nieman-Pick disease:
Ceramide - O - Glucose
Ceramide - O - Glucose - O - Galactose - O - Galactose
Ceramide - Phosphate - Choline
-glucosidase
-galactosidase
sphingomyelinase
64
Synthesis of Eicosanoids
O-
O+
CH2O-P-O-CH2CH2NR'3
CH2O2C-R
CHO2C
R’= H or CH3
In cell membrane
Hydrolysis of sn-2 ester bond
by phospholipase A2 (PLA2)
-O2C
Arachidonate
65
Synthesis of Eicosanoids:
PLA2 Activation
Various stimuli: Activation of
Hormones, autacoids, etc. Membrane-bound
Receptors
PLA2
Activity
Ca+2
Arachidonate release and eicosanoid synthesis
are important mediators of tissue injury and inflammation
66
Synthesis of Eicosanoids:
Prostaglandin Synthesis
CO2-O
O
CO2-
H
O=O
O
O
Cyclic
endoperoxide
Hydroperoxide
Prostaglandin
endoperoxide
synthetase
(Cyclooxygenase)
Cyclooxygenase
Hydroperoxidase
Prostaglandin endoperoxide synthetase (also called cyclooxygenase)
possesses both cyclooxygenase and hydroperoxidase activity
Two forms of cyclooxygenase: COX -1 - constitutively expressed
COX -2 - inducible
PGH2
PGG2
CO2-
O-O-H
O
O
CO2-
OH
O
O
67
Cyclooxygenase (COX) Inhibitors
Nonsteroidal antiinflammatory drugs:
OCOCH3
CO2H
Acetylsalicylic acid
(aspirin)
O - CCH3
CO2H
O
HOH2C
COX
Ser-530 CH2OCOCH3
COX
Irreversible inhibition of COX by acetylation
of the active site
Actions of Aspirin:
Antiinflammatory (COX-2 inhibition)
GI injury (COX-1 inhibition)
68
COX-2 Selective Inhibitors
O
O
SO2CH3
Rofecoxib (Vioxx)
N
N
SO2NH2
CH3
F3C
Celecoxib (Celebrex)
Glucocorticoids block COX-2 expression
69
ProstaglandinsO
HO
CO2H
OH
HO
O
CO2H
OH
HO
HO
CO2H
OH
CO2-
OH
O
O
PGH2
PGE2
PGD2
PGF2
Prostaglandins exhibit a variety
of actions on different tissues
70
Prostacyclin and Thromboxanes
O
HO2C OH
OH
CO2-
OH
O
O
PGH2 Prostacyclin (PGI2):
Blocks platelet
aggregation
Prostacyclin
synthase
O
OCO2
-
OH
Thromboxane
synthase
Thromboxane A2 (TxA2):
Promotes platelet
aggregation (t1/2 = 30 sec.)
O
OH
HO
CO2-
OH
Non-Enzymatic
Thromboxane B2 (TxB2):
inactive
71
Leukotriene Biosynthesis
CO2H
Arachidonic acid
CO2H
OOH
5-Hydroperoxyeicosa-
6,8,11,14-tetraenoic acid
(5-HPETE)
5-Lipoxygenase
OCO2H
Leukotriene A4 (LTA4)
5-Lipoxygenase
OH
CO2H
Cys
GlyGlu
S
Glutathione
LTC4 synthase
Leukotriene C4 (LTC4)OH
CO2H
CysS
Leukotriene E4 (LTE4)
- Glu
- Gly
CO2HOH
Leukotriene B4 (LTB4)
Leukotrienes are
important mediators
of inflammation
Cysteinyl leukotrienes
72
Leukotriene Biosynthesis
(Cont’d)CO2H
Arachidonic acid
HOO
CO2H12-Lipoxygenase
12-Hydroperoxyeicosa-
5,8,10,14-tetraenoic acid
(12-HPETE)
HO
CO2H
12-Hydroxyeicosa-
5,8,10,14-tetraenoic acid
(12-HETE)
73
Leukotriene Biosynthesis
Inhibition
S
CH-N-CONH2
CH3
OH
Zileuton (Zyflo)
An inhibitor of 5-lipoxygenase
Used in the treatment of asthma
74
Cholesterol Biosynthesis:
Formation of Mevalonate
2 CH3COSCoA CH3COCH2COSCoA
Thiolase
CH3COSCoA
Acetoacetyl CoA
HO2C-CH2-C-CH2COSCoA
OH
CH3
-Hydroxy--methyl-
glutaryl CoA (HMG CoA)
HMG CoA
Synthase
HO2C-CH2-C-CH2CH2OH
OH
CH3
3R-Mevalonic acid
HMGCoA
reductase
CoASH NADP + NADPH
+ H+
Key control step
in cholesterol
biosynthesis
Liver is primary site of cholesterol biosynthesis
75
Cholesterol Biosynthesis:
Processing of Mevalonate
-O2C-CH2-C-CH2CH2OH
OH
CH3
Mevalonate
-O2C-CH2-C-CH2CH2OPOP
CH3
OH
2 Steps
ATP
5-Pyrophospho-
mevalonate
CH2=C-CH2CH2OPOP
CH3
- CO2
- H2O
Isopentenyl
pyrophosphate
CH3-C=CH2CH2OPOP
CH3
Dimethylallyl
pyrophosphate
Isomerase
76
Cholesterol Biosynthesis:
Isoprenoid Condensation
H
OPOP
OPOP
Head
TailHead
Tail
Isopentenyl
Pyrophosphate (IPP)
Dimethylallyl
pyrophosphate Head to tail
Condensation
OPOP
Geranyl
Pyrophosphate (GPP)
OPOP
Farnesyl
Pyrophosphate (FPP)
Head to tail
condensation
of IPP and GPP
Tail to tail
condensation
of 2 FPPs
Squalene
Head Tail
Head Tail
Isoprenes
Geranyl transferase
Geranyl
transferase
Squalene
synthase
77
Isoprenoids• Widely distributed in nature
• Generally contain multiple of 5 carbons:
• Monoterpene; 10 carbons
• Sesquiterpene: 15 carbons
• Diterpene: 20 carbons
OHOH
Menthol: a monoterpene
Lycopene: a tetraterpene
78
Conversion of Squalene to Cholesterol
O
H +
CH3H3C
CH3
HO
CH3
CH3
CH3
HO
CH3
CH3
RCO2
Squalene
Squalene
monooxygenase
2,3-Oxidosqualene
cyclase
Lanosterol
20 Steps
Cholesterol
Acyl-CoA:
cholesterol
acyltransferase Cholesterol esters
(principal transport form in blood)
O2
Squalene-
2,3-epoxide
79
Inhibition of Cholesterol Biosynthesis
COSCoA
HOCO2
-CH3
C -S -CoA
HOCO2
-CH3
H
OH
][HO
CO2-
CH3
OH
HOCO2
-
H
OH
CH2CH2
N
F
C6H5NHCO
Atorvastatin (Lipitor):
resembles intermediate
HMG CoA MevalonateIntermediate
HMGCoA
reductase
80
Transformations of
Cholesterol: Bile Salts
CO2-
HO
CH3
HO OHH
CH3
CONHCH2RCH3
CH3
HO
CH3
Cholesterol Cholic acid
R = CH2SO3- Taurocholate
R = CO2- Glycocholate
Detergents
81
Transformations of
Cholesterol: Steroid Hormones
O
O
O
OH
OHHO
O
CH3
HO
CH3
Cholesterol
Estradiol
Progesterone
Cortisol
O
OH
TestosteroneHO
OH
CH2
HO
OH
OHVitamin D