Beta Oxidation of Fatty Acids

beta oxidation complete graphic

Core Concepts:

Beta oxidation is a metabolic process that involves the breakdown of fatty acids to generate cellular energy. In this article, you will learn the four reactions involved in beta oxidation, and how those reactions work.

Topics Covered in Other Articles:

What is Fatty Acid Beta-Oxidation?

Fatty acids are carboxylic acids with long-chain hydrocarbons. The function of fatty acids is to provide energy storage and are crucial for structural support of the cellular membrane. Beta-oxidation allows the cell to break down fatty acids into acetyl-CoA, which proceeds to the citric acid cycle to generate energy usable by the cell. Compared to glucose, the other main source of cellular energy, fatty acids are more energy-rich. This is because fatty acid structure is more reduced, meaning that when fatty acids are converted to carbon dioxide, more electrons are transferred to the electron transport chain to produce energy-rich ATP. Beta-oxidation is the first step in harvesting these valuable energy-rich electrons.

Overview of Beta Oxidation:

  1. Beta oxidation is a series of reactions that degrades fatty acids by removing a two-carbon unit.
  2. Before fatty acids enter the mitochondria for oxidation, they become activated via fatty acyl CoA synthetase
  3. Each round of beta oxidation produces 1 FADH2, 1 NADH2, and 1 acetyl-CoA.

The Preparation Step of Beta Oxidation:

Activation of Fatty Acids through coenzyme A:

Before fatty acids undergo beta oxidation, they are “prepped” through acylation to form fatty acyl-CoA. The “prep” or activation phase is catalyzed by fatty acyl CoA synthetase. This reaction involves the consumption of one ATP molecule. Because of this, some biochemists consider this “prep” step akin to the “energy investment” phase in glycolysis, which similarly requires consuming ATP.

fatty acyl coa synthetase reaction

How are fatty acids transported across the inner mitochondrial membrane?

While fatty acids activate in the cell’s cytosol, oxidation occurs in the mitochondria. Acyl-CoA and fatty acids cannot directly cross the inner mitochondrial membrane, so they must first be modified by the cofactor carnitine. Carnitine is an important cofactor used in metabolism energy production and is used to shuttle fatty acids in the mitochondria. This occurs by the following:

  1. The acyl group of acyl-CoA transfers to carnitine
  2. Carnitine carrier protein transports acyl-carnitine into the mitochondria.
  3. Next, the acyl group transfers to a CoA from the mitochondria.
  4. Finally, the carnitine transfers back to the cytosol.

Beta Oxidation Steps:

1: Dehydrogenation

fatty acyl coa dehydrogenation
Dehydrogenation. Alpha and beta carbons are indicated with α and ß.

The first step in the beta oxidation process is the formation of a double bond between the alpha (α) and beta (ß) carbons to the carbonyl by the enzyme Acyl-CoA dehydrogenase (AD).  Acyl-CoA dehydrogenase has a direct link to the electron transport chain. Many versions of acyl-CoA dehydrogenase exist in the mitochondria, and each has a specificity for certain-length fatty acyl-CoA substrates. In other words, acyl-CoA dehydrogenase targets fatty acids based on their chain length. Next, the fatty-acyl CoA substrate becomes oxidized, which is couped with the reduction of the cofactor FAD, producing FADH2. The FADH2 immediately enters the electron transport chain shortly. Biochemists call the resulting structure enoyl CoA.

2: Hydration Reaction

beta oxidation step 2

In step 2 of the reaction, the enzyme enoyl-CoA hydrase performs a hydration reaction across the newly formed double bond. This results in an alcohol on the beta carbon. Importantly, this reaction is chemoselective, meaning that the alcohol always forms on the double bond and never on the alpha carbon, due to the reaction’s mechanism within the active site of the hydrase. This contrasts with most other alkene addition reactions in organic chemistry, where the corresponding nucleophile has some probability of bonding with either carbon. The resulting alcohol has the name 3-L-hydroxyacyl-CoA.

3: Oxidation

beta oxidation step 3

 Step 3 of beta oxidation involves the oxidation of the beta alcohol to a ketone via the enzyme 3-L-hydroxyacyl-CoA dehydrogenase (HAD). This reaction couples this oxidation with the reduction of the cofactor NAD+ to NADH. The product NADH will later enter the electron transport chain, where ATP becomes generated for energy. This reaction also involves the release of H+ (not shown), which becomes pumped into the mitochondrial matrix through the electron transport chain. Biochemists call the resulting fatty acid derivative beta-ketoacyl CoA.

4: Thiolysis

beta oxidation step 4
Thiolysis. The resulting acyl-CoA is dehydrogenated by acyl-CoA dehydrogenase, commencing another round of beta oxidation.

In step 4 of beta oxidation, a second CoA performs a nucleophilic attack at the first ketone. Consequently, this allows the enzyme ketoacyl CoA thiolase to cleave the alpha and beta carbons, producing two molecules: an acetyl-CoA and an acyl-CoA. Biochemists use the term “thiolysis” to describe this reaction because it involves the nucleophilic thiol group of CoA initiating the breaking of the ketoacyl CoA. Importantly, the resulting acyl-CoA is two carbons shorter than the original acyl-CoA, which then reenters the beta oxidation cycle, which cleaves two more carbons. This cycle continues until all carbons in the original fatty acid become converted to acetyl CoA.

In the case of odd-chain fatty acids, beta oxidation removes two carbon units until the three-carbon propionyl CoA is produced. Rather than reenter beta oxidation, propionyl CoA converts to succinyl CoA, which serves as an important metabolite consumed in the citric acid cycle.