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1
Lipid Metabolism
Hanley N. Abramson, Ph.D.Professor, Department of Pharmaceutical Sciences
Wayne State UniversityOctober 2010
2
Fatty AcidsCH3(CH2)nCH2CO2H
O
OCH3(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)
Pancreaticlipases
OH
OH
TAG MAG
Intestinallipases Glycerol
+Fatty Acids
Blocked by Orlistat (“Fat Blocker”) - Xenical/Alli
6
Epithelial Cell (Intestinal Wall)
Intestinal lumenMAG Glycerol Fatty Acids
TAG
Lipoprotein
ChylomicronsLymphatics
Blood (bound to albumin)Adipose TissueAnd Muscle
7
Adipocytes
8
Fat Storage
• Mainly as triacylglycerols (triglycerides) in adipose cells
• Constitute 84% of stored energy• Protein - 15%• Carbohydrate (glucose or glycogen) - <1%
9
Processing of Lipid Reserves: Overview
1. Lipid Mobilization:In adipose tissue TAGs hydrolyzed to
fatty acids plus glycerol
2. Transport of Fatty Acids in BloodTo Tissues
3. Activation of Fatty Acids as CoA Ester
4. Transport into Mitochondria
5. Metabolism to Acetyl CoA
Release of Fatty Acids from Triacylglycerols
O
O
O
O O O+
HOC-R3 HOC-R2 HOC-R1
Triacylglycerol Glycerol
Lipases
CH2OH
CHOH
CH2OHCH2OC-R1
CHOC-R2
CH2OC-R3
11Adipose Cell
Hormone(Adrenalin, Glucagon, ACTH)
Receptor (7TM)
ATP c-AMPAdenylylCyclase
Activates
Activates lipase
Triacylglycerols Glycerol + Fatty acids Blood
Lipolysis
Insulinblocks thisstep
12
ATP c-AMP AMP
Inactive Kinase Activated Kinase
Inactive Lipase Activated LipaseP
Triacyl-glycerol
Glycerol +Fatty Acids
Phosphatase(Hormone-sensitiveLipase)
Insulin favors formationof the inactive lipase
Adenylyl cyclase Phosphodiesterase
Enhanced by insulinEnhanced by glucagon
13
Acylglycerol Lipases
TriacylglycerolLipase
DiacylglycerolLipase
OH
OH
OH
MonoacylglycerolLipase
OH
OH
OH
Triacylglycerol (TAG)
Diacylglycerol (DAG)
Monoacylglycerol(MAG)
Glycerol
14
Fate of Glycerol
OH
OH
OH
Glycerol
In Liver:
DihydroxyacetonePhosphate
Pyruvate
Glucose
Glycolysis
Gluconeogenesis
15
Beta Oxidation
• Cleavage of fatty acids to acetate in tissues
• Occurs in mitochondria
9 CH3COSCoACO2H
[O] [O] [O] [O] [O][O] [O] [O]
16
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)
17
Fatty Acid Activation by Esterification with CoASH
CoASH + RCO2H + ATP RCOSCoA + AMP + PPi AcylCoA
Synthetase
2 Pi
Pyrophos-phatase
Occurs in outer mitochondrialmembrane for long chain fatty acids
ATP AMP + PPi -32.3CoASH + RCO2H RCOSCoA +31.5PPi 2 Pi -33.6
G0’(KJ/mole)
-34.4
18
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 +
19Source: http://cellbio.utmb.edu/cellbio/mitochondria_1.htm
Carnitine acyltransferase I Carnitine acyltransferase II
Translocase
20
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 FADH 2trans-2-enoyl CoA
H2O
L--Hydroxyacyl CoA
L--Hydroxyacyl CoADehydrogenase
NAD+NADH + H+
CoASH
+
Thiolase
-Ketoacyl CoA
(-ketothiolase)
21
Complete Beta Oxidation of Palmitoyl CoA
CH3CH2--CH2CH2--CH2CH2--CH2CH2--CH2CH2--CH2CH2--CH2CH2--CH2COSCoA
7 Cycles
8 CH3COSCoA + 7 FADH2 + 7 NADH + 7 H+
22
Energetics of Complete Oxidation of Fatty Acids
Palmitic Acid Palmitoyl CoA -2
CH3COSCoA CO2 + H2O 108
High Energy PhosphateBonds Generated
Net 106
TCA Cycle
106 High Energy Phosphate Bonds G0’ = 3,233 KJ/Mole
For Palmitic Acid CO2:G0’ = - 9,790 KJ/Mole
Efficiencyof -Oxidation = 33%
23
Complete Oxidation
Fatty Acids: 9 kcal/g
Carbohydrates: 4 kcal/g
Protein: 4 kcal/g
24
American Golden Plover
25
Arctic Tern
26
Camel
27
Beta Oxidation of Odd Carbon Fatty Acids
CH3CH2CH2--CH2CH2--CH2CH2--CH2CH2--CH2CH2--CH2COSCoA
5 Cycles
5 CH3COSCoA + CH3CH2COSCoAPropionyl CoA
CO2H
COSCoA
H-C-CH3
CO2H
COSCoA
CH3-C-HHO2CCH 2CH2COSCoA
D-MethylmalonylCoA
L-MethylmalonylCoA
Succinyl CoA
TCA Cycle
Propionyl CoA CarboxylaseATP/CO2
EpimeraseMutase
Vit. B12
28
Beta Oxidation of Unsaturated Fatty Acids
H HCH3(CH2)7-C=C-CH2(CH2)6COSCoA
H HCH3(CH2)7-C=C-CH2COSCoA
H
H
CH3(CH2)7-CH2-C=C-COSCoA
Oleoyl CoABeta Oxidation(3 Cycles)
cis-3
Isomerase
trans-2
Continuation of Beta Oxidation
29
Ketogenesis: Formation of Ketone Bodies
2 CH3COSCoA CH3COCH2COSCoAThiolase
CH3COSCoA
Acetoacetyl CoA
HO2C-CH2-C-CH2COSCoA
OH
CH3
-Hydroxy--methylglutaryl CoA(HMG CoA)
HMG CoASynthase
Cholesterol(in cytosol)
Severalsteps
Ketogenesis(in liver: mitochon-
drial matrix)
See Slide 78
30
Ketogenesis: Formation of Ketone Bodies (Cont’d.)
HO2C-CH2-C-CH2COSCoA
OH
CH3
HMG CoAAcetoacetate
HMG CoAlyase
- CH3COSCoA
- CO2
CH3COCH3
Acetone(volatile)
CH3CHCH2CO2
OH
-Hydroxybutyrate
NADH + H+
NAD+Dehydrogenase
Ketone bodies are important sources of energy, especially in starvation
CH3COCH2CO2
31
-Hydroxybutyrate Acetoacetate Succinyl CoA
SuccinateAcetoacetyl CoA
-Ketoacyl CoAtransferase
2 Acetyl CoAThiolase
TCA Cycle
Ketone Bodies As Energy SourcesIn liver
Acetoacetate is major energysource in cardiac muscle andrenal cortex; also in brain instarvation and diabetes
Not found in liver
Combines with oxaloacetate
32
Ketones in Diabetes MellitusIn 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
33
Ketones in Diabetes MellitusBiochemical 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
34
CH3COCH2CO2H pKa = 3.6 Acetoacetic Acid
CH3CHCH2CO2H pKa = 4.7 -Hydroxybutyric acid
OH
Concentration of acetoacetic acid can result in metabolicacidosis (pH 7.1) affinity of Hb for O2.
Metabolic Acidosis in Untreated Diabetes Mellitus
35
Fatty Acid Biosynthesis
36
Fatty Acid Synthesis vs. Degradation
Intermediates
Site
Enzymes
RedoxCoenzymes
Synthesis DegradationLinked to SH in Linked to CoASHProteins (Acyl Carrier Proteins)
Cytosol Mitochondria
Components of Separate PolypeptidesSingle Peptide
NADP+ / NADPH NAD+ / NADH
37
Fatty Acid Biosynthesis
• Occurs in cytosol• Starts with acetyl CoA
• Problem:» Most acetyl CoA produced in mitochondria» Acetyl CoA unable to traverse mitochondrial
membrane
38Mitochondrial
membrane
Cytosol Mitochondria
Glucose Pyruvate Pyruvate Acetyl CoA
Oxalo-acetate
Citrate
Citrate
Acetyl CoA
PyruvateDehydrogenase
ATP-CitrateLyase
Malate
Oxaloacetate
Malic enzyme
Malate dehydrogenase
Note: Acetyl CoAcannot be convertedto glucose
Citrate As Carrier of Acetate Groups
39
Fatty Acid Biosynthesis: Formation of Malonyl CoA
CH3COSCoA + ATP + HCO3- -O2CCH2COSCoA
Acetyl CoACarboxylase
+ 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 (feed-forward allosteric activation)
by insulin by epinephrine and glucagon
• Malonyl CoA inhibits carnitine acyl transferase I • Blocks beta oxidation
40
Fatty Acid Biosynthesis:Role of Acyl Carrier Proteins
CH3COSCoA CH3CO-S-ACP
-O2CCH2COSCoA -O2CCH2CO-S-ACP
AcetylTransferase
MalonylTransferase
Acetyl ACP
Malonyl ACP
ACP = Acyl carrier protein
41
Fatty Acid Biosynthesis:Formation of Acetoacetyl ACP
CH3CO-S-ACP + -O2CCH2CO-S-ACP
CH3COCH2CO-S-ACP + CO2Acetoacetyl ACP
-Ketoacyl ACPSynthetase
42
Fatty Acid Biosynthesis:Formation of Butyryl ACP
CH3COCH2CO-S-ACP CH3CCH2CO-S-ACPOH
HAcetoacetyl ACP-D-Hydroxybutyryl ACP
-Ketoacyl ACPreductase
NADPH+ H+
NADP+
CH3C=C-CO-S-ACP
H
H
-Hydroxyacyl ACPdehydratase- H2O
Crotonyl ACPCH3CH2CH2CO-S-ACP
Butyryl ACP2,3-trans-Enoyl ACPreductase
NADPH+ H+
NADP+
43
Fatty Acid Biosynthesis:Sources of NADPH
Pentose Phosphate Pathway:CHO
OH
OHOHOP
HO
CO2-
OH
OHOHOP
HONADP+
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
44
Fatty Acid Biosynthesis:Chain Elongation
CH3CH2CH2CO-S-ACP -O2CCH2CO-S-ACP+
CH3CH2CH2COCH2CO-S-ACP
CH2CH2CH2CHCH2CO-S-ACP CH3CH2CH2C=CCO-S-ACP
H
H
OH
45
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 ACPCH3(CH2)13CH2CO2
-
PalmitateThioesterase
46
Fatty Acid Biosynthesis:Fatty Acid Synthase
in Animals• Consists of a single polypeptide containing seven distinct domains
• Conducts all steps in fatty acid synthesis except function of acyl CoA carboxylase
• Fatty acid synthase expression normally very low in most cells
47
Orlistat: A Fatty Acid Synthase (FAS) Inhibitor
Anti-obesity (Inhibitspancreatic lipase in git)
Inhibits thioesterase domain of FAS
Anti-cancer (experimental): FAS overexpressed in several tumor types; inhibition induces apoptosis
48
The Crystal Structureof a Mammalian Fatty Acid SynthaseTimm Maier, Marc Leibundgut, Nenad Ban*
Sept. 5, 2008
49
Further Processing of Fatty Acids: ElongationCH3(CH2)13CH2COSCoA
Palmitoyl CoA
CH3(CH2)13CH2COCH2COSCoA
CH3(CH2)13CH2CCH2COSCoA
OH
H
NADH + H+
NAD+
Thiolase
Dehydrogenase
L- Configuration
CH3COSCoA
In mitochondria andat surface of endoplasmic reticulum
50
Further Processing of Fatty Acids: Elongation (Cont’d)
CH3(CH2)13CH2CCH2COSCoAOH
H
CH3(CH2)13CH2C=CCOSCoAH
H
- H2O Hydratase
CH3(CH2)13CH2CH2CH2COSCoAStearoyl CoA
NADPH + H+
NADP+
Dehydrogenase
51
Further Processing of Fatty Acids: UnsaturationCH3(CH2)13CH2CH2CH2COSCoA
CH3(CH2)7C=C(CH2)7COSCoA + H2OH H
Stearoyl CoA
Oleoyl CoA
This reaction occurs in eukaryotesEndoplasmic reticulum membrane
Stearoyl CoADesaturase
O2
52
Further Processing of Fatty Acids: Polyunsaturation
CH3(CH2)7C=C(CH2)7CO2H
H HOleic acid
Plants: Further unsaturationoccurs primarily in this region
Animals: Further unsaturationoccurs primarily in this region
CO2H
(18:19)
9
Linoleic acid (18:29, 12)
12 9
Linolenic acid (18:312, 15)
15 12 9
Essential dietaryfatty acids in mammals
CO2H
53
Formation of Arachidonate in Mammals
Linoleic acid
CO2H14 11 8 5
Arachidonic acid (20:48, 11, 14)(Eicosa-5,-8,11,14-tetraenoic acid)
As CoA ester:1) Elongation2) Desaturation x 2
Prostaglandins
CO2H
54
Omega-3 Fatty AcidsCO2H
CO2H
-3 double bond Eicosapentaenoic acid (20:58, 11, 14, 17)
Docahexaenoic acid (22:67, 10, 13, 16, 19)
• Found in fish oils, esp. cold water fish• Important in:
Growth regulationModulation of inflammationPlatelet activationLipoprotein metabolism
55
Metabolite Regulation of Fatty Acid Synthesis and Breakdown
Pyruvate Acetyl CoA Malonyl CoA
Palmitoyl CoA
Citrate
Inhibits
Stimulates
BetaOxidation
Blocks
Glucose
56
Hormonal Regulation of Fatty Acid Synthesis and Breakdown
ATP cAMP AMPAdenylyl cyclase
Glucagon andepinephrine
Stimulates
Phosphodiesterase
Insulin
Stimulates
Activates Protein Kinase
Inactivates ACC byphosphorylation
Inhibition offatty acidsynthesis
Activates triacyl-glycerollipase
Inactivateslipase
57
Synthesis of Phosphatidate
O-
O
O-
O
O
O
O
CH2OC-R1
CHOC-R2
CH2OC-R3
CHO2C-R2
CH2O2C-R1
CH2OH
CH2O-P-O-
CH2O2C-R1
CHO2C-R2C=O
CH2OH
CH2O-P-O-CH2OH
CHOH
CH2OHDihydroxyacetone
Phosphate(from glycolysis)
Glycerol
Phosphatidate (formed in endoplasmic reticulum)
Diacylglycerol(important incell signaling)
R3COSCoA
Diacylglycerolacyltransferase(liver)
Triacylglycerol(transported toadipocytes andmuscle)
58
Synthesis of Glycerophospholipids
CH2OH
CH2O2C-R1
CHO2C-R2
N
N
NH2
O
O
OHOH
R3NCH2CH2OPOPO+
R=H; CDP ethanolamineR=CH3; CDP cholineCDP = cytidine diphosphate
Diacylglycerol
+ Transferase
R3=NH3; Phosphatidylethanolamine
R3=N(CH3)3; Phosphatidylcholine
O-
O
CO2-
CH2O-P-O-CH2CHNH 3
CH2O2C-R1
CHO2C-R2
+
+
CO 2-
HOCH 2CHNH3
HOCH 2CH2NH3+ Serine
Ethanolamine
O-
O
CHO2C-R2
CH2O2C-R1
CH2O-P-O-CH2CH2R3
+
+
Phosphatidylserine
59
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 surroundingalveoli; decreases surface tension of fluid to prevent lungcollapse
Treatment in infants born before 30 weeks includes administration of artificial lung surfactant (e.g., Exosurf orPumactant)
60
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
OPO3H2H2O3PO
OH OH
OPO3H2
CH2OH
CH2O2C-R1
CHO2C-R2+
Diacylglycerol (DAG)
Phospholipase C(plasma membrane)
Both IP3 and DAG are important second messengersin cell signaling pathways
Inositol-1,4,5-triphosphate (IP3)
Phosphorylationof 4 & 5 OH groups
61
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) diacylglycerol
Cardiolipin: formed in innermitochondrial membrane;plays role in oxidativephosphorylation
62
Synthesis of Glycero-phospholipids (Cont’d)
O-
OCH2O-P-O-
CH2OH
C=O
Dihydroxyacetone Phosphate(from glycolysis)
O-
OCH2O-P-O-CH2CH2NH3
CH2-O-CH=CHR1
CHO2C-R2
+
Plasmalogens(Abundant in cardiactissue and CNS)
63
Synthesis of Sphingolipids+
CO 2-
HOCH 2CHNH3CH3(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
64
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
65
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 orgalactose
Ceramide - Sugar - Sugar - GalNAc - Gal
NANNAN = N-acetylneuraminateGalNAc = N-acetylgalactose
66
Lipid Storage Diseases(Gangliosidoses)
67
Tay-Sachs Disease
Ceramide - O - Glucose - Galactose - N-Acetylgalactose
Hexoseaminidase Acatalyzes cleavage of this glycoside linkage
GM2 (a ganglioside):
Autosomal recessive disorder characterized by deficiencyof hexoseaminidase A; accumulation of gangliosides in brainMost prevalent in Jews from Eastern EuropeFor further information see: http://www.marchofdimes.com/professionals/681_1227.asp
68
Other GangliosidosesGaucher’s disease:
Fabry’s disease:
Nieman-Pick disease:
Ceramide - O - Glucose
Ceramide - O - Glucose - O - Galactose - O - Galactose
Ceramide - Phosphate - Choline
-glucosidase
-galactosidase
sphingomyelinase
69
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 bondby phospholipase A2 (PLA2)
-O2C
Arachidonate
70
Synthesis of Eicosanoids:PLA2 Activation
Various stimuli: Activation ofHormones, autacoids, etc. Membrane-bound
Receptors PLA2
Activity
Ca+2
Arachidonate release and eicosanoid synthesisare important mediators of tissue injury and inflammation
71
Synthesis of Eicosanoids:Prostaglandin Synthesis
CO2-O
O
CO2-
HO=O
O
O
Cyclicendoperoxide
Hydroperoxide
Prostaglandinendoperoxidesynthetase
(Cyclooxygenase)
Cyclooxygenase
Hydroperoxidase
Prostaglandin endoperoxide synthetase (also called cyclooxygenase) possesses both cyclooxygenase and hydroperoxidase activityTwo forms of cyclooxygenase: COX -1 - constitutively expressed COX -2 - inducible
PGH2
PGG2
CO2-
O-O-H
O
O
CO2-
OH
O
O
72
Cyclooxygenase (COX) InhibitorsNonsteroidal antiinflammatory drugs:
OCOCH3
CO2H
Acetylsalicylic acid(aspirin)
O - CCH3
CO2H
O
HOH2C
COX
Ser-530 CH2OCOCH3
COX
Irreversible inhibition of COX by acetylationof the active site
Actions of Aspirin:Antiinflammatory (COX-2 inhibition)GI injury (COX-1 inhibition)
73
COX-2 Selective Inhibitors
O
O
SO2CH3
Rofecoxib (Vioxx)
N
N
SO2NH2
CH3
F3C
Celecoxib (Celebrex)
Glucocorticoids block COX-2 expression
74
ProstaglandinsO
HO
CO2H
OH
HO
O
CO2H
OHHO
HO
CO2H
OH
CO2-
OH
O
O
PGH2
PGE2
PGD2
PGF2
Prostaglandins exhibit a varietyof actions on different tissues
75
Prostacyclin and Thromboxanes
O
HO2C OH
OH
CO2-
OH
O
O
PGH2 Prostacyclin (PGI2):Blocks platelet aggregation
Prostacyclinsynthase
O
O CO2-
OH
Thromboxane synthase
Thromboxane A2 (TxA2):Promotes platelet aggregation (t1/2 = 30 sec.)
O
OH
HO
CO2-
OH
Non-Enzymatic
Thromboxane B2 (TxB2):inactive
76
Leukotriene BiosynthesisCO2H
Arachidonic acid
CO2HOOH
5-Hydroperoxyeicosa-6,8,11,14-tetraenoic acid(5-HPETE)
5-Lipoxygenase
OCO2H
Leukotriene A4 (LTA4)
5-Lipoxygenase
OHCO2H
Cys
Gly Glu
S
GlutathioneLTC4 synthase
Leukotriene C4 (LTC4)OH
CO2H
CysS
Leukotriene E4 (LTE4)
- Glu- Gly
CO2HOH
LTA
Hydrolase
Leukotriene B4 (LTB4)
Leukotrienes areimportant mediatorsof inflammation
Cysteinyl leukotrienes
77
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)
78
Leukotriene Biosynthesis Inhibition
SCH-N-CONH2
CH3
OH
Zileuton (Zyflo)
An inhibitor of 5-lipoxygenaseUsed in the treatment of asthma
79
Cholesterol Biosynthesis: Formation of Mevalonate
2 CH3COSCoA CH3COCH2COSCoAThiolase
CH3COSCoA
Acetoacetyl CoA
HO2C-CH2-C-CH2COSCoA
OH
CH3
-Hydroxy--methyl-glutaryl CoA (HMG CoA)
HMG CoASynthase
HO2C-CH2-C-CH2CH2OH
OH
CH3
3R-Mevalonic acid
HMGCoAreductase
CoASH NADP + NADPH + H+
Key control stepin cholesterolbiosynthesis
Liver is primary site of cholesterol biosynthesis
80
Cholesterol Biosynthesis: Processing of Mevalonate
-O2C-CH2-C-CH2CH2OH
OH
CH3
Mevalonate
-O2C-CH2-C-CH2CH2OPOPCH3
OH
2 Steps
ATP5-Pyrophospho-mevalonate
CH2=C-CH2CH2OPOP
CH3
- CO2
- H2O
Isopentenylpyrophosphate
CH3-C=CH2CH2OPOPCH3
Dimethylallylpyrophosphate
Isomerase
81
Cholesterol Biosynthesis:Isoprenoid Condensation
H
OPOP
OPOP
Head
TailHead
Tail
IsopentenylPyrophosphate (IPP)
Dimethylallylpyrophosphate Head to tail
CondensationOPOP
Geranyl Pyrophosphate (GPP)
OPOP
Farnesyl Pyrophosphate (FPP)
Head to tailcondensationof IPP and GPP
Tail to tailcondensationof 2 FPPs
Squalene
Head Tail
Head Tail
Isoprenes
Geranyl transferase
Geranyl transferase
Squalene synthase
82
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
83
Conversion of Squalene to Cholesterol
OH +
CH3H3C
CH3
HO
CH3
CH3
CH3
HO
CH3
CH3
RCO2
Squalene
Squalenemonooxygenase
2,3-Oxidosqualenecyclase
Lanosterol
20 Steps
Cholesterol
Acyl-CoA:cholesterolacyltransferase Cholesterol esters
(principal transport form in blood)
O2
Squalene-2,3-epoxide
84
Inhibition of Cholesterol Biosynthesis
COSCoA
HOCO2
-CH3
C -S -CoA
HOCO2
-CH3
H
OH
][ HOCO2
-CH3
OH
HOCO2
-H
OH
CH2CH2
NF
C6H5NHCO
Atorvastatin (Lipitor):resembles intermediate
HMG CoA MevalonateIntermediate
HMGCoAreductase
85
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
86
Transformations of Cholesterol: Steroid Hormones
O
O
O
OH
OHHO
O
CH3
HO
CH3
Cholesterol
Estradiol
ProgesteroneCortisol
O
OH
TestosteroneHO
OH
CH2
HO
OH
OH Vitamin D