23-1 Principles and Applications of Inorganic, Organic, and Biological Chemistry Denniston,Topping, and Caret 4 th ed Chapter 23 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Power Point to Accompany
Jan 19, 2016
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
23-3
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
23-5
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.
23-6
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
23-18
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
23-22
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.
23-24
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