Fatty acid breakdown is used to produce energy in cells and occurs through a process called beta-oxidation. Beta-oxidation produces acetyl-coenzyme A, which is further broken down to carbon dioxide and water or fed back into the citric acid cycle. Disturbances in fatty acid degradation can lead to serious diseases.
What is fatty acid breakdown?
Fatty acid breakdown is used to produce energy in cells and occurs through a process called beta-oxidation. Fatty acids are broken down in the mitochondria. Along with glucose breakdown in the organism, fatty acid breakdown is an important metabolic process for energy production in the cell. The fatty acids are broken down in the mitochondria. The degradation takes place via the so-called beta-oxidation. The name “beta” originated from the fact that oxidation takes place at the third carbon atom (beta carbon atom) of the fatty acid molecule. At the completion of each oxidation cycle, two carbon atoms are split off in the form of activated acetic acid (acetyl coenzyme A). Since the breakdown of a fatty acid requires several oxidation cycles, the process used to be called a fatty acid spiral. Acetyl-coenzyme is further broken down in the mitochondria to ketone bodies or carbon dioxide and water. If it re-enters the cytoplasm from the mitochondrion, it is fed back into the citric acid cycle. More energy is produced during fatty acid breakdown than during glucose burning.
Function and task
Fatty acid degradation occurs through several reaction steps and takes place within mitochondria. Initially, the fatty acid molecules are located in the cytosol of the cell. They are inert molecules that must first be activated and transported into the mitochondria for degradation to occur. To activate the fatty acid, coenzyme A is transferred to form acyl-CoA. In this process, ATP is first cleaved into pyrophosphate and AMP. AMP is then used to form acyl-AMP (acyl adenylate). After AMP has been cleaved, the fatty acid can be esterified with coenzyme A to form acyl-CoA. Then, with the help of the enzyme carnitine acyltransferase I, carnitine is transferred to the activated fatty acid. This complex is transported by the carnitine-acylcarnitine transporter (CACT) into a mitochondrion (mitochondrial matrix). There, in turn, carnitine is cleaved and coenzyme A is transferred again. The carnitine is shuttled out of the matrix and acyl-CoA is ready in the mitochondrion for the actual beta-oxidation. The actual beta-oxidation takes place in four reaction steps. The classical oxidation steps occur with even-numbered saturated fatty acids. When odd-numbered or unsaturated fatty acids are broken down, the starting molecule must first be prepared for beta-oxidation by further reactions. The acyl-CoA of even-numbered saturated fatty acids is oxidized in a first reaction step with the aid of the enzyme acyl-CoA dehydrogenase. In this process, a double bond is formed between the second and third carbon atoms in the trans position. In addition, FAD is converted into FADH2. Normally, the double bonds in unsaturated fatty acids are in the cis position, but only with a double bond in the trans position can the next reaction step of fatty acid degradation take place. In a second reaction step, the enzyme enoyl-CoA hydratase adds a water molecule to the beta-carbon atom to form a hydroxyl group. The so-called L-3-hydroxyacyl-CoA dehydrogenase then oxidizes the beta-C atom to a keto group. The result is 3-ketoacyl-CoA. In the final reaction step, additional coenzyme A binds to the beta-C atom. In the process, acetyl-CoA (activated acetic acid) splits off and an acyl-CoA shorter by two carbon atoms remains. This shorter residual molecule undergoes the next reaction cycle until further acetyl-CoA cleavage occurs. The process continues until the entire molecule is broken down into activated acetic acid. The reverse process to beta-oxidation would also be theoretically possible, but does not occur in nature. For fatty acid synthesis, there is a different reaction mechanism. In the mitochondrion, acetyl-CoA is further degraded to carbon dioxide and water or to ketone bodies with the release of energy. In the case of odd-numbered fatty acids, propionyl-CoA with three carbon atoms remains at the end. This molecule is degraded via a different pathway.During fatty acid degradation of unsaturated fatty acids, specific isomerases convert the double bonds from cis to trans configurations.
Diseases and disorders
Disorders of fatty acid degradation, although rare, can lead to serious health problems. Almost always, these are genetic disorders. Almost every relevant enzyme of fatty acid degradation has a corresponding gene mutation. For example, a deficiency of the enzyme MCAD is caused by a gene mutation that is inherited in an autosomal recessive manner. MCAD is responsible for the degradation of medium-chain fatty acids. Symptoms include hypoglycemia (low blood sugar), seizures, and frequent comatose states. Since the fatty acids cannot be used for energy production, glucose is burned to a greater extent. Therefore, hypoglycemia and the risk of coma occur. Since the body must always be supplied with glucose for energy production, there must be no long-term abstinence from food. If necessary, a high-dose glucose infusion must be applied in an acute crisis. Furthermore, all myopathies are characterized by mitochondrial fatty acid depletion disorders. This results in muscle weakness, disturbances in liver metabolism and hypoglycemic states. Up to 70 percent of sufferers go blind in the course of their lives. Serious diseases also occur when the breakdown of overlong fatty acids is disturbed. These very long-chain fatty acids are not broken down in the mitochondria, but in the peroxisomes. Here, the enzyme ALDP is responsible for the insertion into the peroxisomes. However, if ALDP is defective, the long fatty acid molecules accumulate in the cytoplasm, leading to severe metabolic disorders. This also attacks the nerve cells and the white matter of the brain. This form of fatty acid degradation disorder leads to neurological symptoms such as balance disorders, numbness, convulsions, and adrenal hypofunction.
