23-1

Principles and Applications ofInorganic, Organic, and Biological

Chemistry

Denniston,Topping, and Caret4th ed

Chapter 23

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

Power Point to Accompany

23-2

IntroductionAcetyl-CoA is a molecule preeminent in lipid

metabolism.

It is used in fatty acid synthesis, produced during fatty acid degradation, and used to build isoprenoid molecules.

Oadenine

OHPOO

O

CH2CH2NH

CO

CH2CH2NH

CO

CHOH

CCH3

CH3

O PO

OO CH2SH

acetyl here

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23.1 Lipid Metabolism in AnimalsTriglycerides (TAGs) are emulsified into fat

droplets in the intestine by bile salts from the gallbladder.

Bile: micelles of lecithin, cholesterol, protein, bile salts, inorganic ions, and bile pigments.

Pancreatic lipase catalyzes hydrolysis of TAGs to monoglycerides and fatty acids which are absorbed by intestinal epithelial cells, reassembled into TAGs and combined with protein to form chylomicrons which transmit TAGs to adipocytes.

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Stages of Digestion

Insert fig 23.3 and caption

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Lipid StorageFatty acids are stored in adipocytes as

triglycerides in the cells cytoplasm.

When energy is needed, hydrolysis converts TAGs to fatty acids which are transported to the matrix of abundant mitochondria where they are oxidized.

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23.2 Fatty Acid DegradationStep 1 of -oxidation : ActivationA fatty acyl CoA (thioester) is formed in two

steps. The process consumes the equivalent of two ATP because two high energy phosphoric anhydride bonds are cleaved.

High energy bonds cleaved

R1 COO-+ ATP

R1 CO

S-CoA

PPi 2 Pi

+ CoA

AMP +

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Crossing to the Matrix

The activated acyl group reacts with carnosine. The reaction is catalyzed by carnitine acyl transferase. The product crosses into the matrix. Acyl-CoA is regenerated in the matrix in another transesterification reaction.

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-oxidation-2

CH2 CO

SCoACH2R1

FAD

FADH2

CH CO

SCoACHR1trans

a -enoyl-CoA

Acyl-CoAdehydrogenase

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-oxidation-3

CH CO

SCoACHR1trans

H2O

CH2 CO

SCoACHR1OH

Enoyl-CoAhydrase

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-oxidation-4

CH2 CO

SCoACHR1OH NAD+

NADH + H+

CH2 CO

SCoACR1O

-hydroxyacyl-CoAdehydrogenase

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-oxidation-5

CH2 CO

SCoACR1O CoASH

acetyl-CoA

CR1O

SCoA CH3 CO

SCoA+

thiolase

Bond cleaves

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ATP from stearic acid ATP

acid to stearyl-CoA - 2

Steps 2-5

8 FADH2 + 2ATP/FADH2 16 ATP

8 NADH x 3 ATP/NADH 24 ATP

9 Ac-CoA (to TCA cycle)

9 x 1 GTP x 1 ATP/GTP 9 ATP

9 x 3 NADH x 3 ATP/NADH 81 ATP

9 x 1 FADH2 x 2 ATP/FADH2 18 ATP

NET-----------------------------> 146 ATP

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23.3 Ketone Bodies• A result of excess acetyl-CoA from -oxidation.

–High lipid intake and low carbohydrate intake

–(not enough oxaloacetate)

• Starvation (body consumes fats)

• Diabetes (problems with carbohydrate catabolism)

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Ketone Bodies-2

CH3 C

O

S CoA CH3 C

O

S CoA

CH3C O

CH2C

O

S CoA

CoASH

acetoacetyl-CoA

+

The enzyme catalyzes the substitution of the -carbonat the carbonyl carbon.

-C

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Ketone Bodies-3

H+ CO2

CH3

C O

CH3

acetoneCH3

CHOH

CH2

COO-

H+ +NADHNAD+

-hydroxybutyrate

CH3

C O

CH2

COO-

CH3C

O

CH2C

O

S CoA

CoASH

acetoacetate

H2O

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Ketone Bodies-4An excess of ketone bodies is called

ketosis. This condition overwhelms the buffering capacity of the blood. The body will excrete H+ (and K+ and Na+) in the urine. Dehydration and a mineral imbalance result. The condition can be fatal.

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23.4 Fatty Acid SynthesisIn the cytoplasm

Acyl group carrier is acyl carrier protein (ACP).

Synthesis by multienzyme complex known as fatty acid synthase.

NADPH is reducing agent

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Condensation

CH3CO

S-Synthase CH2CO

S-ACP-OOC

CH3CO

CH2CO

S-ACP ++ CO2 Synthase-SH

Acetoacetyl-ACP

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Step 4: First Reduction

CH3CO

CH2CO

S-ACP + NADPH + H+

CH3CHOH

CH2CO

S-ACP + NADP+

D--hydroxybutyryl-ACP

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Step 5: Dehydration

CH3CH CH2CO

S-ACPOH

CH3CH CH CO

S-ACPtrans

Crotonyl-ACP

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Step 6: Second Reduction

CH3CH CH CO

S-ACP + NADPH + H+

CH3CH2CH2CO

S-ACP+ NADP+

trans

Crotonyl--ACP is end of first cycleand beginning of second cycle

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32.5 Regulation of Carb/Lip Metab.Liver (Carb)Insulin causes glucogenesis to occur.Glucagon stimulates breakdown of glycogen

and release of glucose to bloodstream.Lactate from muscles is converted to glucose

(gluconeogenesis).

Liver (Lipid)Excess fuel results in fatty acids and TAGS

which are transported to adipose tissue by VLDL complexes.

During starvation or fasting, liver converts FAs to ketone bodies and exports them.

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Regulation of Carb/Lip Metab., cont.Adipose TissueMajor storage depot for fatty acids via

hydrolyzed TAGs.Limited glucose means limited glycerol-3-

phosphate which is essential for resynthesis of TAGs. Fatty acids and glycerol are consequently exported to the liver for further processing.

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Regulation of Carb/Lip Metab., cont.Muscle TissueResting muscle uses fatty acids for energy.Working muscle uses glycolysis. If there is a

lack of oxygen, lactate is produced. It is exported to the liver for gluconeogenesis.

The BrainUnder normal conditions the brain uses

glucose as it sole source of fuel. Under starvation conditions the brain will use acetoacetate and -hydroxybutyrate (ketone bodies).

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32.6 Glucagon and InsulinInsulin is secreted in response to high blood

glucose levels.Carbohydrate Metabolism

Stimulates glycogen synthesis while inhibiting glycogenolysis and gluconeogenesis.

Protein MetabolismStimulates incorporation of AA into

proteinsLipid Metabolism

Stimulates uptake of glucose by adipose cells and synthesis of triglycerides.

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Glucagon and Insulin, cont.Glucagon is secreted in response to low

blood glucose levels.Carbohydrate Metabolism

Inhibits glycogen synthesis while stimulating glycogenolysis and gluconeogenesis.

Lipid MetabolismStimulates the breakdown of fats and

ketogenesis.Protein Metabolism

No direct effect.

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The End

Fatty Acid Metabolism