Fatty acid degradation
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Fatty acid degradation is the process in which fatty acids are broken down into their metabolites, in the end generating acetyl-CoA, the entry molecule for the citric acid cycle, the main energy supply of animals. It includes three major steps:
- Lipolysis of and release from adipose tissue
- Activation and transport into mitochondria
Lipolysis and release
Initially in the process of degradation, fatty acids are stored in fat cells (adipocytes). The breakdown of this fat is known as lipolysis. The products of lipolysis, free fatty acids, are released into the bloodstream and circulate throughout the body.
Activation and transport into mitochondria
Formation of an activated thioester bond
The enzyme first catalyzes nucleophilic attack on the α-phosphate of ATP to form pyrophosphate and an acyl chain linked to AMP. The next step is formation of an activated thioester bond between the fatty acyl chain and Coenzyme A.
The balanced equation for the above is:
RCOO- + CoA + ATP + H2O → RCO-CoA + AMP + PPi + 2H+
This two-step reaction is freely reversible and its equilibrium lies near 1. To drive the reaction forward, the reaction is coupled to a strongly exergonic hydrolysis reaction: the enzyme inorganic pyrophosphatase cleaves the pyrophosphate liberated from ATP to two phosphate ions. Thus the net reaction becomes:
RCOO- + CoA + ATP + H2O → RCO-CoA + AMP + 2Pi + 2H+
Transport into the mitochondrial matrix
The inner mitochondrial membrane is impermeable to fatty acids and a specialized carnitine carrier system operates to transport activated fatty acids from cytosol to mitochondria.
- Acyl CoA is conjugated to carnitine by carnitine palmitoyltransferase I (palmitoyltransferase) I located on the outer mitochondrial membrane
- Acyl carnitine is shuttled inside by a translocase
- Acyl carnitine (such as Palmitoylcarnitine) is converted to acyl CoA by carnitine acyltransferase (palmitoyltransferase) II located on the inner mitochondrial membrane. The liberated carnitine returns to the cytosol.
It is important to note that carnitine acyltransferase I undergoes allosteric inhibition as a result of malonyl-CoA, an intermediate in fatty acid biosynthesis, in order to prevent futile cycling between beta-oxidation and fatty acid synthesis.
Once inside the mitochondria, the β-oxidation of fatty acids occurs via five recurring steps:
- Activation by ATP
- Oxidation by FAD,
- Oxidation by NAD+,
- The final product is acetyl-CoA, the entry molecule for the citric acid cycle.