Adenosine triphosphate (ATP) is an important molecule that provides energy for many cellular processes. ATP is often referred to as the “energy currency” of the cell, as it can be rapidly turned over to release energy. While ATP can be generated through different metabolic pathways, one way ATP is synthesized is through the breakdown of lipids via beta oxidation. In this process, fatty acids from lipids are broken down to produce acetyl CoA, which can then enter the citric acid cycle to generate ATP.
Structure of Lipids
Lipids are a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins, monoglycerides, diglycerides, triglycerides, phospholipids, and others. The main structural feature of lipids is that they are generally hydrophobic, or insoluble in water. Lipids are made up of carbon, hydrogen, and oxygen and the ratio of hydrogen to oxygen is usually higher than in carbohydrates.
Structurally, lipids contain a glycerol backbone with fatty acids attached. Fatty acids are long hydrocarbon chains containing carboxyl groups. The number of carbons in fatty acids can range from 4 to 36, with most naturally occurring fatty acids having an even number of carbon atoms between 12-22.
Triglycerides, also known as triacylglycerols, are the most common type of lipid. Triglycerides consist of a glycerol molecule bound to three fatty acid chains via ester bonds. The fatty acids attached can be saturated, monounsaturated, or polyunsaturated. Phospholipids are another major category of lipids, consisting of two fatty acids, a phosphate group, and a glycerol backbone. The presence of the charged phosphate group makes phospholipids amphipathic, meaning they have both hydrophobic and hydrophilic regions.
Catabolism of Lipids – Beta Oxidation
In order to extract energy from lipids, the triglycerides need to be broken down through a catabolic process known as beta oxidation. This takes place in the mitochondria of the cell. Before beta oxidation can occur, triglycerides first need to be processed into fatty acids through the action of lipases.
The first step in beta oxidation involves the fatty acid molecule being activated by forming a thioester bond with a molecule of coenzyme A (CoA). This reaction is catalyzed by acyl CoA synthetase and requires ATP. The product formed is a fatty acyl CoA.
Beta Oxidation Cycle
Once the fatty acid has been activated to a fatty acyl CoA molecule, it can then enter the beta oxidation pathway. Beta oxidation is a 4 step cycle that results in the sequential removal of 2 carbon units from the fatty acyl CoA in the form of acetyl CoA molecules. The four reactions of beta oxidation are:
1. Dehydrogenation – Acyl CoA dehydrogenase removes 2 hydrogen atoms by oxidizing the fatty acyl CoA at the beta position forming a trans double bond. This forms an unsaturated fatty enoyl CoA.
2. Hydration – Enoyl CoA hydratase catalyzes the addition of water across the double bond to form L-3-hydroxyacyl CoA.
3. Oxidation – L-3-hydroxyacyl CoA dehydrogenase oxidizes the hydroxyl group to a keto group forming 3-ketoacyl CoA.
4. Thiolysis – Thiolase cleaves the 3-ketoacyl CoA to form acetyl CoA and a fatty acyl CoA that is shortened by 2 carbons.
The cycle then repeats itself until the entire fatty acid chain is broken down to acetyl CoA units. For each rotation of the beta oxidation cycle, 1 molecule of NADH, 1 molecule of FADH2, and 1 molecule of acetyl CoA is produced. The acetyl CoA generated can then enter the citric acid cycle for more energy generation.
Regulation of Beta Oxidation
Beta oxidation is carefully regulated in order to meet cellular energy demands. The entry of fatty acids into mitochondria for beta oxidation is controlled by carnitine palmitoyltransferase 1 (CPT1). This enzyme converts fatty acyl CoA into fatty acyl carnitine so that it can cross the mitochondrial membrane. CPT1 is inhibited by malonyl CoA, which prevents too much beta oxidation when cellular energy status is high.
The beta oxidation pathway is also regulated by the relative amounts of NAD+ and NADH. A high NADH/NAD+ ratio indicates that beta oxidation needs to be slowed down to allow the cell to catch up with oxidative metabolism. In contrast, a low NADH/NAD+ ratio signals that the rate of beta oxidation should be increased. The dehydrogenase enzymes in the beta oxidation pathway are inhibited by acetyl CoA and NADH buildup.
Oxidative Phosphorylation for ATP Generation
The end goal of beta oxidation is to produce acetyl CoA that can then enter the citric acid cycle for energy generation. In the citric acid cycle, the acetyl CoA is further oxidized, producing reduced electron carriers NADH and FADH2. These electron carriers bring the electrons to the electron transport chain, located in the inner mitochondrial membrane.
As the electrons pass through the electron transport chain complexes, energy is released and used to pump protons (H+) across the membrane, generating an electrochemical gradient. The protons then flow back into the mitochondrial matrix through ATP synthase. This powers the phosphorylation of ADP to generate ATP.
The oxidative phosphorylation of ADP to ATP, fueled by NADH and FADH2 from beta oxidation, results in a large amount of energy being generated from the original lipid molecule. Each cycle of beta oxidation produces acetyl CoA containing 2 carbon units. For a 16 carbon fatty acid:
– 8 cycles of beta oxidation are required to break it down completely
– This yields 8 acetyl CoA molecules
– 8 NADH, 8 FADH2, and 8 ATP are directly generated from beta oxidation
– The 8 acetyl CoA produce ~24 ATP during oxidative phosphorylation
Therefore, a 16 carbon fatty acid yields approximately 56 ATP molecules (8 from beta oxidation directly + 24 from acetyl CoA oxidation). This demonstrates how energy-rich lipids are metabolized in a step-wise manner to generate large amounts of ATP for cellular processes.
Comparison to Glucose Catabolism
While lipids can produce substantially more ATP compared to carbohydrates, the beta oxidation pathway does have some disadvantages compared to glucose catabolism. Beta oxidation is more complex, requiring transport of lipids into the mitochondria and multiple steps to break them down. Glucose enters glycolysis more easily.
Beta oxidation also relies heavily on the availability of oxygen (O2) due to the requirements of the electron transport chain for oxidative phosphorylation. Glycolysis can produce some ATP without oxygen.
Finally, NADH generation from beta oxidation can sometimes exceed the capacity of the electron transport chain to oxidize it. This leads to a high NADH/NAD+ ratio that must be rebalanced before more beta oxidation can proceed. Glycolysis is better able to match NADH generation to mitochondrial oxidation.
Advantages of Lipid Catabolism
– Very energy rich, yielding more ATP per gram than carbohydrates
– Does not require carbohydrate intake, fasting individuals can rely on fat stores
– Fatty acids liberated from adipose tissue provide metabolic fuel
Disadvantages of Lipid Catabolism
– More complex multi-step process than glycolysis
– Requires mitochondrial import and several enzymes
– Dependent on oxygen availability
– Can produce sudden excess of reducing equivalents (NADH)
Clinical Significance
Defects in enzymes involved in beta oxidation or mitochondrial oxidative phosphorylation can severely impact a person’s health. Fatty acid oxidation disorders are a category of genetic diseases where the breakdown of fatty acids is impaired at some point. This can lead to a harmful buildup of fats. Some examples include:
– Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency – deficiency in MCAD enzyme causes backup of medium chain fatty acids. Can cause hypoglycemia and coma.
– Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency – VLCAD processes long chain fatty acids, its deficiency results in liver dysfunction and heart problems.
– Carnitine palmitoyltransferase II (CPT II) deficiency – mutation in CPT II enzyme prevents long chain fatty acids from entering mitochondria for beta oxidation. Causes myopathy and rhabdomyolysis.
– Multiple Acyl-CoA dehydrogenase deficiency – impairment in electron transfer flavoprotein impairs all beta oxidation steps.
Mitochondrial diseases that affect the electron transport chain or ATP synthase also impair ATP production from lipids. Some examples include Leigh syndrome, mitochondrial myopathy, and mitochondrial complex I-V deficiencies.
Dietary treatment for fatty acid oxidation disorders involves avoiding fasting and providing medium chain triglyceride supplementation. These medium chain fats can be metabolized independently of the defective enzymes. For mitochondrial disorders, providing anaplerotic substrates like glutamine may bypass the defects and improve ATP generation.
Conclusion
Beta oxidation is a catabolic process that allows cells to extract energy from lipids in the form of ATP. Triglycerides are broken down stepwise into two carbon acetyl CoA units that can enter the citric acid cycle. Reducing equivalents like NADH and FADH2 produced during beta oxidation allow for ATP generation during oxidative phosphorylation. Though more complex than glucose metabolism, beta oxidation yields significantly more energy per gram of lipid thanks to the long fatty acid chains and energy dense hydrocarbon bonds. Defects in beta oxidation enzymes or mitochondrial metabolism underlie many inherited fatty acid oxidation disorders that can be treated supportively with dietary approaches.