Beta-oxidation of fatty acids

Preparation: activation and transport

Before entering chemical reactions, fatty acids (FAs) inside the cell must be activated. This process requires energy expenditure and is mediated by the enzyme acyl-CoA synthetase. This produces acyl-CoA, the active form of the fatty acid bound to coenzyme A.

Further oxidation takes place inside the mitochondria, but their inner membrane is completely impermeable to acyl-CoA. To deliver the fuel to the matrix, a specialized system is used — the carnitine shuttle:

1. At the outer membrane, the regulatory enzyme carnitine palmitoyltransferase I transfers the acyl group to carnitine.
2. A specialized translocase protein transports the resulting acylcarnitine across the membrane.
3. On the inner side, carnitine palmitoyltransferase II transfers the acyl group back to the intramitochondrial coenzyme A. The fuel is ready for oxidation.

$\beta$-oxidation cycle: 4 reactions

The process itself is named "$\beta$-oxidation" because the bond cleavage always occurs at the $\beta$-carbon atom of the fatty acid radical. In each cycle, the acid is shortened by two carbon atoms. One cycle includes four consecutive stages:

1. First dehydrogenation. The enzyme acyl-CoA dehydrogenase removes hydrogen, transferring it to the coenzyme FAD. A double bond is formed.
2. Hydration. The enzyme enoyl-CoA hydratase adds a water molecule across the double bond.
3. Second dehydrogenation. Oxidation continues involving $\beta$-hydroxyacyl-CoA dehydrogenase and the $NAD^+$ coenzyme.
4. Cleavage (thiolase reaction). With the participation of coenzyme A, a two-carbon fragment — acetyl-CoA — is cleaved off. The remaining shortened acyl-CoA proceeds to the next round.

The cycles repeat until the entire fatty acid chain is broken down into acetyl-CoA molecules.

Energy balance (ATP formula)

The amount of energy depends on the number of carbon atoms in the acid ($n$).

• The acid yields $\frac{n}{2}$ molecules of acetyl-CoA. Each molecule entering the tricarboxylic acid cycle (TCA cycle) yields 12 ATP.
• The number of $\beta$-oxidation cycles itself is always one less: $(\frac{n}{2} - 1)$. The last cycle enters with a four-carbon fragment, which immediately splits into two molecules of acetyl-CoA. Each $\beta$-oxidation cycle generates 5 ATP (due to the reduction of FAD and $NAD^+$ and their subsequent oxidation in the electron transport chain).
• From the final sum, it is necessary to subtract 2 ATP, which were consumed at the very first activation step.

Example: complete oxidation of stearic acid (18 carbon atoms) yields 120 ATP, making fats the most energy-dense fuel in the body.

Important: The process is impossible without oxygen. Under anaerobic conditions, the electron transport chain is blocked, coenzymes are not regenerated, and oxidation halts.

Regulation: fed vs. fasted state

The key regulatory enzyme of the pathway is carnitine palmitoyltransferase I, and its most potent inhibitor is malonyl-CoA.

• Postprandial state (insulin): fatty acid biosynthesis is activated in the body. Malonyl-CoA is one of the intermediates of this synthesis. It blocks the carnitine shuttle. Fatty acids cannot enter the mitochondria, so their oxidation stops (synthesis and breakdown do not occur simultaneously).
• During fasting or muscle exertion (glucagon, adrenaline): the concentration of malonyl-CoA drops sharply. The blockade on the transporter is removed, $\beta$-oxidation accelerates, and fatty acids become the primary source of energy for muscles, heart, and liver.

Brain metabolism and ketone bodies

Despite the high energy density of fats, the brain cannot use them. Fatty acids are hydrophobic and unable to cross the blood-brain barrier (BBB).

During prolonged starvation, the liver comes to the rescue. It redirects about 50% of the incoming fatty acids to an alternative pathway — ketogenesis. The synthesized ketone bodies easily penetrate the brain and serve as a reliable backup energy source, saving the organism from death during carbohydrate deficiency.

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• Features of unsaturated fatty acid oxidation using oleic acid as an example
• Hormonal profile and regulation of $\beta$-oxidation in skeletal muscles during exercise
• Comparative analysis of fatty acid biosynthesis and $\beta$-oxidation pathways
• Mechanism of AMP-activated protein kinase activation under ATP deficiency

Other topics in the «Lipid metabolism» section

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