-OXIDATION

Fatty acid breakdown produces a lot of energy !

Complete Oxidation
Fatty Acids: 9 kcal/g

Carbohydrates: 4 kcal/g Protein: 4 kcal/g

²oxidation:
Is the breaking of a fatty acid into 2 carbon compounds (acetyl(acetylCoA).
produces acetyl CoA and NADH and FADH2, which are sources of energy(ATP). energy(ATP). It takes place in the mitochondrial matrix.

Sources of Fatty Acid Fuel
Diet Fat Storage Cells

Energy

Release of Fatty Acids from Triacylglycerols
H 2 OC-R CHOC-R
1

H 2 OH

Li ases
2

HOH

CH 2 OC-R

3

H 2 OH

Triacylglycerol

Glycerol
+

H

-R

1

H

-R

2

H

-R

3

1) Activation of fatty acids
Fatty acids must be activated before they can be catabolized. AcylAcyl-CoA is the active fatty acid. The enzyme used is called acylacylCoA synthetase. synthetase. Two ATPs are used for activation.

2) Transport of acyl-CoA into acylmitochondria
Short ( 2-6 carbon) and medium chain (82(812 carbon) fatty acids pass through the inner mitochondrial membrane unaided. Long chain acyl-CoAs (14-20 carbon) acyl(14need a special carrier (carnitine) to pass through inner mitochondrial membrane.

Formation of acyl carnitine
3 + 3 3
   

O O O

O

3 + 3 3
   

+

O O

o S

R

+

o S

carnitine

acyl o

O O R

acyl carnitine

an get transported across inner mitochondrial membrane

Membrane Transport of Fatty Acyl CoA Esters
FA with e 12 carbons enter mitochondrial matrix (MM) FA with u 14 carbons use CA NITINE SHUTTLE
H

Rate-limiting step of FA oxidation

N
-

carnitine

3) Reactions of -oxidation
Takes place inside the mitochondrial matrix using a group of enzymes known collectively as fatty acid oxidase. oxidase. These oxidize acyl-CoA acylto acetyl-CoA. acetyl-

Activated fatty acid

1/ Oxidation Acyl CoA oxidized by FAD

unsaturated Acyl CoA

2/ Hydration Acyl CoA hydrated

-hydroxyacyl CoA

3/ Oxidation -hydroxyacyl CoA -Ketoacyl CoA

oxidized by NAD

4/ Cleavage -Ketoacyl CoA cleaved by Thiolase (-2Cs)

acetyl CoA

acyl CoA

Beta Oxidation Reaction Sequence

Repeat Sequence

Occurs in Mitochondria

Reactions of betabetaoxidation
The cycle of reactions is repeated until the fatty acid is converted to acetyl CoA

AcylAcyl-CoA 1) dehydrogenase
FAD

EnoylEnoyl-CoA 2) hydratase
H2

3-hydroxyacyl-CoA hydroxyacyl3) dehydrogenase
NAD

3-ketoacyl-CoA ketoacyl4) thiolase

AcylAcyl-CoA -2C + acetyl-CoA acetyl-

Beta
1

xidation on 16 C fatty Acid
2
¡ ¡ ¡ ¡

3
¡ ¡ ¡

5
¡ ¡

6
¡ ¡ ¡

7
¡

8
¡

7 rounds of Beta oxidation (bottom numbers) Form 8 acetyl Co A (top numbers)

¢

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

7

3 6 5 2 1

Energy calculations
1 FADH2««««««««««2 ATP ««««««««««2 1 NADH««««««««««.3 ATP NADH««««««««««.3 Per cut 5 ATP 1 Acetyl CoA to Krebs
3 NADH X 3 ATP / NADH««« 9 ATP 1 FADH2 X 2«««««««««2 ATP «««««««««2 1 ATP««««««««««« 1 ATP

Total per acetyl CoA=12ATP 12ATP

Overall energy released from total oxidation of palmitic acid
7 cycles X 5 = 35 ATP 8 acetyl CoA X 12 = 96 ATP Total energy 131 ATP Activation energy - 2 ATP Net energy = 129 ATP Why do we subtract two ATPs?

oxidation of fatty acids with odd-numbered carbon chains
most of the fatty acids in natural lipids contain even-numbered carbon chains BUT: a small portion have odd-numbered carbon chains this is solved in the following way: ‡the substrate for the last cycle of F-oxidation is the five-carbon homolog of acetoacetyl-CoA

21:1

‡this five carbon compound is cleaved to yield acetyl-CoA and proprionyl-CoA ‡proprionyl-CoA must be further metabolized before its carbon atoms can enter the citric acid cycle for complete oxidation to CO2 ‡this involves a biotin-dependent carboxylation and a coenzyme B12 dependent rearrangement to yield succinyl-CoA which can enter the citric acid cycle

Beta Oxidation of Odd Carbon Fatty Acids
C
3C 2C 2 --C 2C 2 --C 2C 2 --C 2C 2 --C 2C 2 --C 2 CO
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CoA

5 Cycles 5 C 3CO CoA
TCA Cycle
Mutase

C 3C 2CO CoA
Propionyl CoA

Propionyl CoA Carboxylase ATP/CO2

CO 2 H
HO 2 CCH 2 CH 2 CO CoA

Epimerase

CO 2 H H-C-CH
3

CH 3 -C-H
Vit. B12

uccinyl CoA

CO CoA
-Methylmalonyl CoA

CO CoA

D-Methylmalonyl CoA

Unsaturated Fat Metabolism
special enzymes needed to convert cis bonds in fatty acids to trans bonds

Beta Oxidation of Unsaturated Fatty Acids
H H H 3 ( H 2 )7 - = - H
Beta Oxidation (3 ycles)
2(

H 2 )6 O

oA

Oleoyl oA

H H H 3 ( H 2 )7 - = - H

H

Isomerase
2

O

oA

H 3( H 2)7- H 2- = - O

oA

cis-(3

trans-(2 ontinuation of Beta Oxidation

H

BetaBeta-oxidation of unsaturated fatty acids

Unsaturated FA yield a bit less energy than saturated FA because they are already partially oxidized Less FADH2 is produced

Alternate Routes of FA Oxidation
Peroxisomal: AlphaAlpha-oxidation Omega oxidation

AlphaAlpha-oxidation

only after C-1 removal

plus more steps to give product on next slide

Oxidation of Phytanic Acid

Product of alpha-hydroxylation followed by decarboxylation of alphaC-1 and oxidation of C-2 to COOH: C-

decarboxylate

CO2
COOH

This product can undergo beta oxidation

Alpha Oxidation of Branched Chain Fatty Acids
C C
3 (C 3

C
2C 2C 2 )3 C

3

C

C

2 CO 2

Phytanic Acid (from breakdown of chlorophyll) E ydroxylase
C C
3 (C 3

C
2C 2C 2 )3 C

3

C

C CO O

2

CO2

C
3 (C

3

C
2C 2C 2 )3 C

3

E Oxidation

C

C

CO

2

(in peroxisomes)

Pristanic Acid

Omega oxidation of fatty acids A minor pathway that occurs in the endoplasmic reticulumn of liver and kidney A hydroxyl is introduced onto the omega carbon by a mixed ± function oxidase Two more enzymes act on the omega carbon alchohol dehydrogenase oxidizes the hydroxyl group to an aldehyde

aldehyde dehydrogenase oxidizes the aldehyde group to a carboxylic acid the product is a fatty acid with a carboxyl group at each end

Either end can be attached to Co-A and as the molecule undergoes beta oxidation Dicarboxylic acids are produced

21:5

MFO

MFOs

Associated diseases
Carnitine deficiency; results from deficiency; inadequate synthesis or renal leakage. Symptoms include hypoglycemia. Treated by oral supplementing of carnitine. MediumMedium-chain acyl-CoA dehydrogenase acyldeficiency (MCAD); genetic disease. Symptoms include hypoglycemia. Diagnosed by high concentrations of MediumMedium-chain carboxylic acids in plasma and urine. Treated by avoiding fasting.

Refsum ·s disease; defect that causes disease; accumulation of phytanic acid which blocks oxidation. Zellweger ·s syndrome; absence of syndrome; peroxisomes in all tissues. Long-chain fatty Longacids accumulate in brain tissue. Jamaican vomiting sickness; caused by sickness; eating the unripe fruit of akee tree, which contains hypoglycin that inactivates medium and short chain acyl-CoA dehydrogenase acylcausing hypoglycemia.

Ketogenesis: Formation of Ketone Bodies
Thiolase

2 C 3COSCoA

C 3COC 2COSCoA Acetoacetyl CoA

C 3COSCoA MG CoA Synthase

Cholesterol (in cytosol)
See Slide 78

Several steps O2C C
2

O

C C 2COSCoA
C
3

(in liver: mitochon drial matrix)

Ketogenesis

F ydroxy F methylglutaryl CoA ( MG CoA)

Ketogenesis: Formation of Ketone Bodies (Cont¶d.)
O

O2C C

2

C C 2COSCoA
C
3

MG CoA lyase C 3COSCoA NAD Dehydrogenase NAD
¥

C 3COC 2CO2 Acetoacetate CO2

MG CoA

O C 3C C 2CO2
F ydroxybutyrate

Ketone bodies are important sources of energy, especially in starvation

¥

C 3COC Acetone (volatile)

3

Ketone Bodies As Energy Sources
In liver
F-Hydroxybutyrate

Acetoacetate

Succinyl CoA

Acetoacetate is major energy source in cardiac muscle and renal cortex; also in brain in starvation and diabetes

F-Ketoacyl CoA transferase

Not found in liver

Thiolase

2 Acetyl CoA Combines with oxaloacetate TCA Cycle

Acetoacetyl CoA

Succinate

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

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

Metabolic Acidosis in Untreated Diabetes Mellitus
CH3COCH2CO2H pKa 3.6
Acetoacetic Acid

OH CH3CHCH2CO2H pKa 4.7
F-Hydroxybutyric acid

Concentration of acetoacetic acid can result in metabolic acidosis (pH 7.1) affinity of Hb for O2.

Ketone Bodies
Starvation causes accumulation of acetyl CoA
not enough carbohydrates to keep Kreb¶s Cycle going acetyl CoA forms acetoacetate, bbhydroxybutyrate, and acetone.

Ketone bodies
‡ Excess acetyl CoA (from FA or carbohydrate degradation) is converted in liver to ketone bodies: acetoacetate, acetone, and acetoacetate, acetone, hydroxybutyrate ‡ Ketone bodies are soluble in blood and can be taken up and used by various tissues (muscle, heart, renal cortex) to regenerate acetyl CoA for energy production via the TCA cycle ‡ Even brain can use ketone bodies as their concentrations in blood rise enough

Regulation of Beta Oxidation
Largely by concentration of free fatty acids available Malonyl CoAinhibits carnitine transferase which will inhibit entry of acyl CoA into mitochondria

Ketone bodies
Acetoacetyl CoA is formed by incomplete FA degradation or by condensation of two acetyl CoAs by thiolase Acetoacetyl CoA condenses with a third acetyl CoA to form hydroxymethylglutaryl CoA (HMG(HMGCoA) CoA) HMGHMG-CoA is cleaved to produce acetoacetate acetyl CoA Reduction of acetoacetate to hydroxybutyrate, or spontaneous decarboxylation to acetone, produces the other two ketone bodies

KETONE BODIES
Are an easy way of transporting the energy stored in fat from the liver to other tissues because they are soluble in the blood.

In tissues that use ketone bodies, acetoacetate is condensed with CoA by transfer from succinyl CoA acetoacetyl CoA can then be converted to two acetyl CoAs

Ketone bodies
Excessive ketone bodies can be produced in diabetes mellitus or starvation (a lot of acetyl CoA in liver) When rate of production exceeds utilization, ketonemia, ketonuria, and acidemia can result

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