11 lipidmetabolism

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.)


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


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


Formation of Acetoacetyl ACP

CH3CO-S-ACP + -O2CCH2CO-S-ACP

CH3COCH2CO-S-ACP + CO2

Acetoacetyl ACP

-Ketoacyl ACP

Synthetase

38


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


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


Chain Elongation

CH3CH2CH2CO-S-ACP -O2CCH2CO-S-ACP+

CH3CH2CH2COCH2CO-S-ACP

CH2CH2CH2CHCH2CO-S-ACP CH3CH2CH2C=CCO-S-ACP

H

H

OH

41


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 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


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


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


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



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



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)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)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


(Cont’d)CO2H

Arachidonic acid

HOO

CO2H12-Lipoxygenase

12-Hydroperoxyeicosa-


(12-HPETE)

HO

CO2H

12-Hydroxyeicosa-


(12-HETE)

73


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


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


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


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

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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

11 lipidmetabolism

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