Lipid Metabolism (III)

Fatty Acid Oxidation

Learning objectives:
 Describe the mechanism of acetyl-CoA formation
 Describe how fat oxidation occurs
 Contrast the oxidation process of even and odd-
numbered carbon-chain fatty acids
Metabolism of fatty acids

Acetyl-CoA (from carbohydrates)

β-Oxidation of fatty acids
 Pathway for catabolism of saturated fatty acids
 Site--- mitochondria

 Two-carbon fragments are removed from carboxyl end of

fatty acyl CoA producing

 acetyl CoA,
 NADH and
 FADH2.
1. Activation of fatty acids
 Fatty acids inside the cell must be activated before proceeding through
metabolism.
 Site: cytosol
 Activation consists of conversion of the nonesterified fatty acid to its
CoA derivative.
 Enzyme: acyl CoA synthetase (thiokinase)
2. Transport of acyl-CoA into mitochondria

 The fatty acyl CoA may then be transported into the

mitochondrion for energy production.

 Mitochondrial membrane is impermeable to CoA

 Transport across the mitochondrial membrane requires a

carrier CARNITINE.
1. Acyl portion is first transferred to carnitine
 Releasing the CoA to its cytosolic pool
2. The resulting acyl-carnitine is transported into the
mitochondrial matrix by the carrier protein.
3. The acyl group is transferred to a CoA molecule from the
mitochondrial pool.
4. The product carnitine is returned to the cytosol.
Regulation of carnitine acyltransferase I (CAT-I)

 CAT-I is associated with the outer mitochondrial

membrane.

 CAT-I reaction is rate-limiting;

 The enzyme is allosterically inhibited by malonyl CoA.

 Malonyl CoA concentration would be high during fatty acid

synthesis.
 Inhibition of CAT-I by malonyl CoA prevents simultaneous
synthesis and degradation of fatty acids.
Entry of short and medium chain F.A into
mitochondria
 Carnitine and CAT system not required for fatty acids
shorter than 12 carbon length.

 They are activated to their CoA form inside mitochondrial

matrix.

 Not inhibited by malonyl CoA.

Reactions of beta-oxidation
 Beta-oxidation is the process by which long chain

fatty acyl CoA is degraded.

 The products of beta-oxidation are:

 acetyl CoA

 FADH2,

 NADH and

 H+
Four steps- four enzymes
 There are four individual reactions of beta-oxidation, each
catalyzed by a separate enzyme.

1-Dehydrogenation between carbon 2 and 3 in a FAD-linked

reaction.
Enzyme - acyl CoA dehydrogenase.
2-Hydration of the double bond by enoyl CoA hydratase.
3-A second dehydrogenation in a NAD-linked reaction.
Enzyme - 3-hydroxyacyl CoA dehydrogenase.
4-Thiolytic cleavage of the thioester by beta-ketoacyl CoA
thiolase.

This sequence of four steps is repeated until the fatty

acyl chain is completely degraded to acetyl CoA
1. Formation of a trans-α,β double bond through
dehydrogenation by the flavoenzyme acyl-CoA dehydrogenase
(AD).
2. Hydration of the double bond by enoyl-CoA hydratase (EH)
to form a 3-L-hydroxyacyl-CoA.
3. NAD+-dependent dehydrogenation of the β-hydroxyacyl-
CoA by 3-L-hydroxyacyl-CoA dehydrogenase (HAD) to form
the corresponding β-ketoacyl-CoA.
4. Cα—Cβ cleavage in a thiolysis reaction with CoA as catalyzed by β-
ketoacyl-CoA thiolase (KT; also called just thiolase) to form acetyl-CoA
and a new acyl-CoA containing two fewer C atoms than the original
one.
Types of fatty acyl CoA dehydrogenases

 Long chain fatty acyl CoA dehydrogenase (LCAD) acts on

chains greater than C12.

 Medium chain fatty acyl CoA dehydrogenase (MCAD) acts

on chains of C6 to C12.

 Short chain fatty acyl CoA dehydrogenase (SCAD) acts on

chains of C4 to C6.

MCAD deficiency is thought to be one of the most common

inborn errors of metabolism.
Reaction products
 The products are acetyl CoA and a long chain fatty
acyl CoA that is two carbons shorter than the original
fatty acyl CoA.

 The shortened fatty acyl group is now ready for

another round of beta-oxidation. After the fatty acyl
CoA has been reduced to acetyl or propionyl CoA,
beta-oxidation is complete.
 Fate of acetyl CoA
- Oxidation by the citric acid cycle to CO2 and H2O.
-In liver only, acetyl CoA may be used for ketone body
synthesis.

 Fate of the FADH2 and NADH + H+

- FADH2 and NADH + H+ are oxidized by the
mitochondrial electron transport system, yielding ATP.
Regulation of beta oxidation
 Beta-oxidation is regulated as a whole primarily by

fatty acid availability; once fatty acids are in the

mitochondria they are oxidized as long as there is
adequate NAD+ and CoA.
Energy yield from beta oxidation of Palmitic
Acid
 Oxidation of one molecule of palmitoyl CoA to CO2
and water produces

- 8 acetyl CoA
- 7 NADH
- 7 FADH2
 7 FADH2 = 2X 7 = 14 ATP
 7 NADH =3X7 = 21 ATP
 8 Acetyl CoA = 12 x 8 = 96 ATP
Total ATP = 131 ATP

 2 ATP are utilized during the formation of acyl CoA

(from cytosol to mito) .
 Therefore net yield is 129 ATP.
Comparison of synthesis and degradation of long
chain even numbered F.A
 OXIDATION OF FATTY ACIDS WITH ODD NUMBER OF
CARBONS

 Oxidation of fatty acids with odd number of carbons yield

 acetyl CoA and
 one molecule of propionyl CoA (3 Carbon compound)

 Propionyl CoA is converted to Methylmalonyl CoA

(MMCoA) by carboxylase --- a biotin requiring enzyme.

 MMCoA is moved within the molecule by MMCoA mutase

(vit.B12 coenzyme) to form succinyl CoA… gluconeogenic.
Succinyl-CoA

 Succinyl-CoA Is Not Directly Consumed by the Citric Acid

Cycle.

 In order for succinyl-CoA to undergo net oxidation by the

citric acid cycle, it must first be converted to pyruvate and
then to acetyl-CoA.

 This is accomplished by converting succinyl-CoA to malate

followed by its transport to the cytosol and oxidative
decarboxylation to pyruvate and CO2 by malic enzyme

 Pyruvate is then completely oxidized via pyruvate

dehydrogenase and the citric acid cycle