Beta oxidation

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Schematic demonstrating mitochondrial fatty acid beta-oxidation and effects of LCHAD deficiency
Schematic demonstrating mitochondrial fatty acid beta-oxidation and effects of LCHAD deficiency

Beta oxidation is the process by which fatty acids, in the form of Acyl-CoA molecules, are broken down in mitochondria and/or in peroxisomes to generate Acetyl-CoA, the entry molecule for the Krebs Cycle.

Contents

[edit] Activation of fatty acids

Free fatty acids can penetrate the plasma membrane due to their poor water solubility and high fat solubility. Once in the cytosol, a fatty acid reacts with ATP to give a fatty acyl adenylate, plus inorganic pyrophosphate. This reactive acyl adenylate then reacts with free coenzyme A to give a fatty acyl-CoA ester plus AMP.

[edit] Four recurring steps

Once inside the mitochondria, the β-oxidation of fatty acids occurs via four recurring steps:

Description Diagram Enzyme End product
Oxidation by FAD: The first step is the oxidation of the fatty acid by Acyl-CoA-Dehydrogenase. The enzyme catalyzes the formation of a double bond between the C-2 and C-3.
acyl CoA dehydrogenase trans-Δ2-enoyl-CoA
Hydration: The next step is the hydration of the bond between C-2 and C-3. The reaction is stereospecific, forming only the L isomer.
enoyl CoA hydratase L-3-hydroxyacyl CoA
Oxidation by NAD+: The third step is the oxidation of L-3-hydroxyacyl CoA by NAD+. This converts the hydroxyl group into a keto group.
L-3-hydroxyacyl CoA dehydrogenase 3-ketoacyl CoA
Thiolysis: The final step is the cleavage of 3-ketoacyl CoA by the thiol group of another molecule of CoA. The thiol is inserted between C-2 and C-3.
β-ketothiolase An acetyl CoA molecule, and an acyl CoA molecule, which is two carbons shorter

This process continues until the entire chain is cleaved into acetyl CoA units. The final cycle produces two separate acetyl CoA's, instead of one acyl CoA and one acetyl CoA. For every cycle, the Acyl CoA unit is shortened by two carbon atoms. Concomitantly, one molecule of FADH2, NADH and acetyl CoA are formed.

[edit] β-oxidation of unsaturated fatty acids

β-oxidation of unsaturated fatty acids poses a problem since the location of a cis bond can prevent the formation of a trans-Δ2 bond. These situations are handled by an additional two enzymes.

Whatever the conformation of the hydrocarbon chain, β-oxidation occurs normally until the acyl CoA (because of the presence of a double bond) is not an appropriate substrate for acyl CoA dehydrogenase, or enoyl CoA hydratase:

  • If the acyl CoA contains a cis-Δ3 bond, then cis-Δ3-Enoyl CoA isomerase will convert the bond to a trans-Δ2 bond, which is a regular substrate.
  • If the acyl CoA contains a cis-Δ4 double bond, then its dehydrogenation yields a 2,4-dienoyl intermediate, which is not a substrate for enoyl CoA hydratase. However, the enzyme 2,4 Dienoyl CoA reductase reduces the intermediate, using NADPH, into trans-Δ3-enoyl CoA. As in the above case, this compound is converted into a suitable intermediate by cis-Δ3-Enoyl CoA isomerase.

To summarize:

  • odd numbered double bonds are handled by the isomerase.
  • even numbered bonds by the reductase (which creates an odd numbered double bond) and the isomerase.

[edit] β-oxidation of odd-numbered chains

Chains with an odd-number of carbons are oxidized in the same manner as even-numbered chains, but the final products are propionyl-CoA and acetyl-CoA.

Propionyl-CoA is carboxylated using a bicarbonate ion into succinyl-CoA (which is an intermediate in the citric acid cycle), in a reaction that involves a biotin co-factor, ATP, and the enzyme propionyl CoA carboxylase. The bicarbonate ion's carbon is added to the middle carbon of propionyl CoA, forming a D-methylmalonyl-CoA. However, the D conformation must converted into the L conformation by methylmalonyl CoA racemase, before methylmalonyl CoA mutase can convert the compound to succinyl-CoA. The succinyl-CoA formed can then enter the citric acid cycle.

Because it cannot be completely metabolized in the citric acid cycle, the products of its partial reaction must be removed in a process called cataplerosis. This allows regeneration of the citric acid cycle intermediates, possibly an important process in certain metabolic diseases.

[edit] Oxidation in peroxisomes

Fatty acid oxidation also occurs in peroxisomes, when the fatty acid chains are too long to be handled by the mitochondria. However, the oxidation ceases at octanyl CoA. It is believed that very long chain (greater than C-22) fatty acids undergo initial oxidation in peroxisomes which is followed by mitochondrial oxidation.

One significant difference is that oxidation in peroxisomes is not coupled to ATP synthesis. Instead, the high-potential electrons are transferred to O2, which yields H2O2. The enzyme catalase, found exclusively in peroxisomes, converts the hydrogen peroxide into water and oxygen.

Peroxisomal β-oxidation also requires enzymes specific to the peroxisome and to very long fatty acids. There are three key differences between the enzymes used for mitochondrial and peroxisomal β-oxidation:

  1. β-oxidation in the peroxisome requires the use of a peroxisomal carnitine acyltransferase (instead of carnitine acyltransferase I and II used by the mitochondria) for transport of the activated acyl group into the peroxisome.
  2. The first oxidation step in the peroxisome is catalyzed by the enzyme acyl CoA oxidase.
  3. The β-ketothiolase used in perixsomal β-oxidation has an altered substrate specificity, different from the mitochondrial β-ketothiolase.

Peroxisomal oxidation is induced by high fat diet and administration of hypolipidemic drugs like clofibrate.

[edit] Energy yield

The ATP yield for every oxidation cycle is 14 ATP (according to the P/O ratio), broken down as follows:

Source ATP Total
1 FADH2 x 1.5 ATP = 1.5 ATP (some sources say 2 ATP)
1 NADH x 2.5 ATP = 2.5 ATP (some sources say 3 ATP)
1 acetyl CoA x 10 ATP = 10 ATP (some sources say 12 ATP)
TOTAL = 14 ATP

For an even-numbered saturated fat (C2n), n - 1 oxidations are necessary and the final process yields an additional acetyl CoA. In addition, two equivalents of ATP are lost during the activation of the fatty acid. Therefore, the total ATP yield can be stated as:

(n - 1) * 14 + 10 - 2 = total ATP

For instance, the ATP yield of palmitate (C16, n = 8) is:

(8 - 1) * 14 + 10 - 2 = 106 ATP

Represented in table form:

Source ATP Total
7 FADH2 x 1.5 ATP = 10.5 ATP
7 NADH x 2.5 ATP = 17.5 ATP
8 acetyl CoA x 10 ATP = 80 ATP
Activation = -2 ATP
TOTAL = 106 ATP

For sources that use the larger ATP production numbers described above, the total would be 129 ATP equivalents per palmitate.

Beta-oxidation of unsaturated fatty acids changes the ATP yield due to the requirement of two possible additional enzymes. If a cis-Δ3 double bond is encountered, the action of enoyl-CoA isomerase replaces the action of acyl-CoA dehydrogenase, meaning no FADH2 will be generated. Thus, for each cis-Δ3 double bond enocountered, ATP yield is altered by -1.5 ATP. However, if a cis-Δ4 double bond is encountered, the action of 2,4-dienoyl-CoA reductase is required after the acyl-CoA dehydrogenase step (before the cycle can continue), which uses a molecule of NADPH, equivalent to 3.5 ATP (some sources say 4 ATP). Thus, each cis-Δ4 double bond encountered in a fatty acid molecule alters the ATP yield by -3.5 ATP.

[edit] Regulation of Beta Oxidation

Malonyl-CoA can act to prevent fatty acyl-CoA derivatives from entering the mitochondria by inhibiting the carnitine acyltranferase that is responsible for this transport. Thus, the beta oxidation pathway is inhibited. When fatty acyl-CoA levels rise, beta oxidation is stimulated. However, increased citrate levels inhibit beta oxidation.

[edit] See also

[edit] External links

v • d • e
Lipid metabolism: Lipid metabolism/Fatty acid metabolism
v • d • e
Metabolism: lipid metabolism - triglyceride and fatty acid enzymes
Lipid production
Lipid degradation
see also disorders