Beta Oxidation of Fatty Acids

Beta oxidation is a fundamental metabolic process occurring within the cells of organisms (including humans) that converts fatty acids into energy (ATPs). This intricate biochemical pathway is crucial for utilizing stored fats as a source of fuel, especially during prolonged physical exertion or periods of low carbohydrate intake.

The process of β-oxidation is the key component in maintaining energy homeostasis and plays a pivotal role in sustaining life. Any kind of interruptions or dysfunctioning of this oxidation may result in fatty acid oxidation disorders (FAODs) or non-alcoholic fatty liver disease (NAFLD).

Beta Oxidation

Beta oxidation primarily takes place in the mitochondria of eukaryotes, the energy-producing organelles within cells. For prokaryotes, it occurs in the cytosol.

It is a cyclic process that breaks down long-chain fatty acids into smaller units called acetyl-CoA, which can then enter the citric acid cycle (Krebs cycle) to produce adenosine triphosphate (ATP), the universal energy currency of cells.

The acetyl-CoA molecules derived from beta oxidation play a crucial role in generating ATP through oxidative phosphorylation, a process that occurs in the mitochondria.

Mechanism of Beta Oxidation

The process of beta-oxidation involves four essential steps, each repeating until the entire fatty acid chain is completely broken down. It mainly consists of five essential steps; activation, first-oxidation, hydration, second-oxidation, and cleavage/thiolysis. (Some biochemists however do not consider ‘activation’ as a part of the beta-oxidation process).

Activation

The first step is the activation of the fatty acid molecule in a cell’s cytoplasm. The fatty acid combines with a Coenzyme A (CoA) molecule to form acyl-CoA. This reaction requires an initial input of energy in the form of ATP (2 ATPs in this case).

Fatty Acid + CoA + 2ATP → Acyl-CoA + 2AMP + 2Pi

After activation, the acyl-CoA is transported into the mitochondria, where it undergoes further (oxidation) reactions.

First Oxidation

In the first oxidation step, the dehydrogenation of fatty acyl-CoA produces a double bond between C_α and C_β of acyl-CoA and produces trans-Δ²-Enoyl-CoA along with an FADH₂ from an FAD molecule. This step occurs in the presence of acyl-dehydrogenase-CoA enzyme.

Acyl-CoA + FAD → FADH₂ + Trans-Δ²-Enoyl-CoA

Hydration

In this step, a water molecule is added to the ‘Enoyl-CoA’ molecule resulting from the first-oxidation step. This addition creates a hydroxyl group on the beta-carbon of the fatty acid, producing a β-Hydroxyacyl-CoA (3-hydroxyacyl-CoA). This step is catalyzed by the Enoyl-CoA-hydratase enzyme.

Enoyl-CoA + H₂O → β-Hydroxyacyl-CoA

Second Oxidation

During this step, the β-Hydroxyacyl-CoA is converted to β-Ketoacyl-CoA along with the production of NADH from NAD⁺. This step is catalyzed by β-Hydroxyacyl-CoA dehydrogenase.

This part of the oxidation reaction is therefore also referred to as the dehydrogenation step.

β-Hydroxyacyl-CoA + NAD⁺→ NADH + β-Ketoacyl-CoA + H⁺

Cleavage/Thiolysis

The last step in this oxidation process involves the cleavage of β-Ketoacyl-CoA by a thiol group (-SH) of another coenzyme-A. Since the cleavage takes place between C_α and C_β, the end products are therefore an acetyl-CoA molecule and an acyl-CoA chain.

The acyl-CoA chain produces here is 2 carbon atoms shorter than the original one. Whereas, the acetyl-CoA contains those 2 carbon atoms (C=O and C_α).

This step is catalyzed by β-keto thiolase (acyl-CoA-acetyl-transferase).

β-Ketoacyl-CoA + CoA-SH → Acetyl-CoA + Acyl-CoA

This Acyl-CoA chain is now ready to undergo the entire beta-oxidation cycle again until it is completely broken down into acetyl-CoA units.

Energy Yield

The energy yield here refers to the amount of energy produced through the breakdown of fatty acids during the beta oxidation process. Specifically, beta-oxidation generates energy in the form of ATPs.

To understand the energy yield of beta-oxidation, let’s consider the breakdown of a common long-chain fatty acid, e.g. palmitic acid, which has 16 carbon atoms. The complete beta-oxidation of palmitic acid involves seven rounds of the beta-oxidation cycle, resulting in the production of eight molecules of acetyl-CoA.

Energy Yield from β-oxidation of Palmitic acid

The energy yield of this beta oxidation can be summarized as follows:

1. Activation of palmitic acid (requires 2 ATP molecules).
2. Seven rounds (each round generates 1 FADH₂ and 1 NADH molecule).
3. Production of eight molecules of acetyl-CoA. [1 acetyl-CoA = 3NADH + 1FADH₂ + 1GTP]

The total ATP yield from the complete beta oxidation of palmitic acid can be calculated as follows:

1. Activation step (2 ATP molecules consumed).
2. Seven rounds (7 FADH2 x 2 ATP per FADH2) = 14 ATP.
3. Seven rounds (7 NADH x 3 ATP per NADH) = 21 ATP.
4. Eight molecules of acetyl-CoA (8 x 12 ATP per acetyl-CoA) = 96 ATP.

Total ATP yield = [(14+21+96) – 2] = 129 ATP molecules.

Therefore, the energy yield of beta-oxidation from the complete breakdown of one molecule of palmitic acid (16-carbon fatty acid) is approximately 129 ATP molecules.

This is a significant amount of energy that can be utilized by the body to support various cellular functions, especially during times of fasting or prolonged physical activity when fatty acids serve as a major source of energy.

Significance of Beta Oxidation

Beta oxidation plays a vital role in maintaining energy balance within the body. While carbohydrates are the primary source of energy for most cells, the body stores excess energy in the form of fats.

When glucose levels are low or during prolonged physical activity, the stored fats are mobilized, and beta oxidation ensures that these fats are efficiently broken down to provide a continuous supply of energy to meet the body’s energy demands.

This process is particularly critical during endurance activities, such as long-distance running or fasting, where the body heavily relies on fat metabolism to sustain energy levels. Additionally, individuals following low-carbohydrate diets may experience an upregulation of beta oxidation to meet the body’s energy needs.

Health Implications

A well-functioning beta oxidation process is crucial for overall health. Defects or disruptions in this pathway can lead to serious metabolic disorders. For instance, conditions like fatty acid oxidation disorders (FAODs) are genetic disorders where the body is unable to effectively utilize fatty acids for energy. This results in an accumulation of toxic fatty acid intermediates, leading to potentially life-threatening complications.

Moreover, beta oxidation plays a pivotal role in maintaining lipid homeostasis, preventing fat accumulation in non-adipose tissues, such as the liver and muscles. Dysregulation of this process may contribute to metabolic disorders like non-alcoholic fatty liver disease (NAFLD) and insulin resistance, which are associated with obesity and diabetes.

An overview of the consequences of dysfunctional beta-oxidation is that it can cause; energy depletion (FAODs), hypoglycemia, accumulation of toxic intermediates in the body, cardiac dysfunction, muscular weakness and pain, rhabdomyolysis (breakdown of muscles), kidney damage, neurological impairment, and metabolic crisis such as coma.

Key Takeaway(s)

Concepts Berg

References

• Article (biologydictionary.net)
• Fatty Acid Oxidation (Bio Libretexts)
• Oxidation of Fatty Acids (Chem LibreTexts)