11.10: Fatty Acid Catabolism

Learning Objectives

• To describe the reactions needed to completely oxidize a fatty acid to carbon dioxide and water.

Like glucose, the fatty acids released in the digestion of triglycerides and other lipids are broken down in a series of sequential reactions accompanied by the gradual release of usable energy. Some of these reactions are oxidative and require nicotinamide adenine dinucleotide (NAD⁺) and flavin adenine dinucleotide (FAD). The enzymes that participate in fatty acid catabolism are located in the mitochondria, along with the enzymes of the citric acid cycle, the electron transport chain, and oxidative phosphorylation. This localization of enzymes in the mitochondria is of the utmost importance because it facilitates efficient utilization of energy stored in fatty acids and other molecules.

Fatty acid catabolism is initiated in the cytoplasm. There the fatty acid is activated by conversion to an energy-rich fatty acid derivative of coenzyme A called fatty acyl-coenzyme A (CoA). The activation is catalyzed by acyl-CoA synthetase. For each molecule of fatty acid activated, one molecule of coenzyme A and one molecule of adenosine triphosphate (ATP) are used, equaling a net utilization of the two high-energy bonds in one ATP molecule (which is therefore converted to adenosine monophosphate [AMP] rather than adenosine diphosphate [ADP]). For this reason the activation of one fatty acid is considered to require the energy equivalent of 2 ATP's.

Figure \(\PageIndex{1}\): Activation of the fatty acid by CoA for catabolism.

The fatty acyl-CoA diffuses to the inner mitochondrial membrane for the catabolism.

Catabolism of Fatty Acids

Catabolism of the fatty acyl-CoA occurs in the mitochondrial matrix via a sequence of four reactions known collectively as β-oxidation because the β-carbon undergoes successive oxidations in the progressive removal of two carbon atoms (Figure \(\PageIndex{2}\)). The fatty acyl-CoA formed in the final step becomes the substrate for the first step in the next round of the spiral.

Figure \(\PageIndex{2}\): A spiral in fatty acid catabolism. Each spiral shortens the fatty acid chain by two carbons.

STEP 1: First oxidation of an alkane (dehydrogenation)

A fatty acyl-CoA is oxidized to yield a trans double bond between the α- and β- carbons (the second and third carbons). FAD is oxidizing agent and is converted to FADH₂, which moves into the electron transport chain.

STEP 2: Hydration (addition of water across the double bond)

The trans alkene is then hydrated to form a secondary alcohol. The hydroxyl group is placed on the β-carbon.

STEP 3: Second oxidation (oxidation of an alcohol)

The secondary alcohol is then oxidized to a ketone by NAD⁺ acting as the oxidizing agent.

STEP 4: Cleavage

Acetyl-CoA cleaves off to yield a fatty acid that is two carbons shorter than before. The chain shortened fatty acid will start back at step 1 and go through another spiral.

Note

In each spiral, 1 molecule of acetyl-CoA, 1 molecule of NADH, and 1 molecule of FADH₂ are produced. The final spiral yields two acetyl-CoA molecules.

Because each shortened fatty acyl-CoA cycles back to the beginning of the pathway, β-oxidation is referred to as the fatty acid spiral.

The fate of the acetyl-CoA obtained from fatty acid oxidation depends on the needs of an organism. It may enter the citric acid cycle and be oxidized to produce energy, it may be used for the formation of water-soluble derivatives known as ketone bodies, or it may serve as the starting material for the synthesis of fatty acids.

Looking Closer: Ketone Bodies

In the liver, most of the acetyl-CoA obtained from fatty acid oxidation is oxidized by the citric acid cycle. However, some of the acetyl-CoA is used to synthesize a group of compounds known as ketone bodies: acetoacetate, β-hydroxybutyrate, and acetone shown in figure 11.10.3.

Figure \(\PageIndex{3}\): Ketone bodies are produced from acetyl-CoA not consumed by the citric acid cycle.

The acetoacetate and β-hydroxybutyrate synthesized by the liver are released into the blood for use as a metabolic fuel (to be converted back to acetyl-CoA) by other tissues, particularly the kidney and the heart. Thus, during prolonged starvation, ketone bodies provide about 70% of the energy requirements of the brain. Under normal conditions, the kidneys excrete about 20 mg of ketone bodies each day, and the blood levels are maintained at about 1 mg of ketone bodies per 100 mL of blood.

In starvation, diabetes mellitus, and certain other physiological conditions in which cells do not receive sufficient amounts of carbohydrate, the rate of fatty acid oxidation increases to provide energy. This leads to an increase in the concentration of acetyl-CoA. The increased acetyl-CoA cannot be oxidized by the citric acid cycle because of a decrease in the concentration of oxaloacetate, which is diverted to glucose synthesis. In response, the rate of ketone body formation in the liver increases further, to a level much higher than can be used by other tissues. The excess ketone bodies accumulate in the blood and the urine, a condition referred to as ketosis. When the acetone in the blood reaches the lungs, its volatility causes it to be expelled in the breath. The sweet smell of acetone, a characteristic of ketosis, is frequently noticed on the breath of severely diabetic patients.

Because two of the three kinds of ketone bodies are weak acids, their presence in the blood in excessive amounts overwhelms the blood buffers and causes a marked decrease in blood pH (to 6.9 from a normal value of 7.4). This decrease in pH leads to a serious condition known as acidosis. One of the effects of acidosis is a decrease in the ability of hemoglobin to transport oxygen in the blood. In moderate to severe acidosis, breathing becomes labored and very painful. The body also loses fluids and becomes dehydrated as the kidneys attempt to get rid of the acids by eliminating large quantities of water. The lowered oxygen supply and dehydration lead to depression; even mild acidosis leads to lethargy, loss of appetite, and a generally run-down feeling. Untreated patients may go into a coma. At that point, prompt treatment is necessary if the person’s life is to be saved.

Note

The number of times a spiral is repeated for a fatty acid containing n carbon atoms is (n/2 – 1) because the final spiral yields two acetyl-CoA molecules.

ATP Yield from Fatty Acid Oxidation

The amount of ATP obtained from fatty acid oxidation depends on the size of the fatty acid being oxidized. As an example, we’ll study octanoic acid, a saturated long chain carboxylic acid acid with 8 carbon atoms. Calculating its ATP yield provides a model for determining the ATP yield of all other fatty acids.

Figure \(\PageIndex{4}\): Catabolism of octanoic acid.

Activation and Spirals

The catabolism of 1 molecule of octanoic acid requires 2 molecules of ATP (for activation) and forms 4 molecules of acetyl-CoA, 3 molecules of NADH, and 3 molecules of FADH₂. This complete conversion requires 3 spirals to be repeated.

Citric Acid Cycle

The 4 molecules of acetyl-CoA are then processed by the citric acid cycle. Recall from earlier that each molecule of acetyl-CoA metabolized by the citric acid cycle yields 3 molecules of NADH, 1 molecule of FADH₂, and 1 molecule of GTP. The 4 molecules of acetyl-CoA require 4 citric acid cycles and produce 12 molecules of NADH, 4 molecules of FADH₂, and 4 molecules of GTP.

Electron Transport Chain

The reduced coenzymes NADH and FADH₂ from the spirals and the citric acid cycle then enter the electron transport chain and are converted to ATP. Each NADH molecule is responsible for the formation of 2.5 ATP and each FADH₂ forms 1.5 ATP. There are 12 + 3 = 15 NADH and 4 + 3 = 7 FADH₂ molecules from the 3 spirals and 4 Citric Acid Cycles that enter the ETC to produce 48 ATP (15 x 2.5 + 7 x 1.5).

Total ATP count

The 4 molecules of GTP from the citric acid cycle are equivalent in energy to ATP and so are added to 48 ATP from the ETC. Two ATP molecules are required for the activation step and hence subtracted. The total ATP yield from octanoic acid is 48+4-2= 50 ATP.

The oxidation of fatty acids produces large quantities of water. This water, sustains migratory birds and animals (such as the camel) for long periods of time.

Summary

• Fatty acids, obtained from the breakdown of triglycerides and other lipids, are oxidized through a series of four reactions known in a spiral.
• In each round of the spiral, 1 molecule of acetyl-CoA, 1 molecule of NADH, and 1 molecule of FADH₂ are produced.
• The acetyl-CoA, NADH, and FADH₂ are used in the citric acid cycle, the electron transport chain, and oxidative phosphorylation to produce ATP.