Fatty acid degradation
Encyclopedia
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:
. The products of lipolysis, free fatty acids, are released into the bloodstream and circulate throughout the body.
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 formula 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+
Once activated, the acyl
CoA
is transported into the mitochondrial matrix
. This occurs via a series of similar steps:
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
.
Acetyl-CoA
Acetyl coenzyme A or acetyl-CoA is an important molecule in metabolism, used in many biochemical reactions. Its main function is to convey the carbon atoms within the acetyl group to the citric acid cycle to be oxidized for energy production. In chemical structure, acetyl-CoA is the thioester...
, the entry molecule for the citric acid cycle
Citric acid cycle
The citric acid cycle — also known as the tricarboxylic acid cycle , the Krebs cycle, or the Szent-Györgyi-Krebs cycle — is a series of chemical reactions which is used by all aerobic living organisms to generate energy through the oxidization of acetate derived from carbohydrates, fats and...
, the main energy supply of animals. It includes three major steps:
- Lipolysis of and release from adipose tissue
- Activation and transport into mitochondria
- β-oxidation
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 lipolysisLipolysis
Lipolysis is the breakdown of lipids and involves the hydrolysis of triglycerides into free fatty acids followed by further degradation into acetyl units by beta oxidation. The process produces Ketones, which are found in large quantities in ketosis, a metabolic state that occurs when the liver...
. The products of lipolysis, free fatty acids, are released into the bloodstream and circulate throughout the body.
Activation and transport into mitochondria
Fatty acids must be activated before they can be carried into the mitochondria, where fatty acid oxidation occurs. This process occurs in two steps catalyzed by the enzyme fatty acyl-CoA synthetase.Formation of an activated thioester bond
The enzyme first catalyzes nucleophilic attack on the α-phosphate of ATPAdenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
to form pyrophosphate
Pyrophosphate
In chemistry, the anion, the salts, and the esters of pyrophosphoric acid are called pyrophosphates. Any salt or ester containing two phosphate groups is called a diphosphate. As a food additive, diphosphates are known as E450.- Chemistry :...
and an acyl
Acyl
An acyl group is a functional group derived by the removal of one or more hydroxyl groups from an oxoacid, including inorganic acids.In organic chemistry, the acyl group is usually derived from a carboxylic acid . Therefore, it has the formula RCO-, where R represents an alkyl group that is...
chain linked to AMP
Adenosine monophosphate
Adenosine monophosphate , also known as 5'-adenylic acid, is a nucleotide that is used as a monomer in RNA. It is an ester of phosphoric acid and the nucleoside adenosine. AMP consists of a phosphate group, the sugar ribose, and the nucleobase adenine...
. The next step is formation of an activated thioester
Thioester
Thioesters are compounds with the functional group C-S-CO-C. They are the product of esterification between a carboxylic acid and a thiol. Thioesters are widespread in biochemistry, the best-known derivative being acetyl-CoA.-Synthesis:...
bond between the fatty acyl chain and Coenzyme A
Coenzyme A
Coenzyme A is a coenzyme, notable for its role in the synthesis and oxidation of fatty acids, and the oxidation of pyruvate in the citric acid cycle. All sequenced genomes encode enzymes that use coenzyme A as a substrate, and around 4% of cellular enzymes use it as a substrate...
.
RCOO- + CoA + ATP + H2O → RCO-CoA + AMP + PPi + 2H+
This two-step reaction is freely reversible and its equilibrium
Chemical equilibrium
In a chemical reaction, chemical equilibrium is the state in which the concentrations of the reactants and products have not yet changed with time. It occurs only in reversible reactions, and not in irreversible reactions. Usually, this state results when the forward reaction proceeds at the same...
lies near 1. To drive the reaction forward, the reaction is coupled to a strongly exergonic hydrolysis reaction: the enzyme inorganic pyrophosphatase
Pyrophosphatase
Pyrophosphatase are acid anhydride hydrolases that act upon diphosphate bonds.Examples include:* Inorganic pyrophosphatase* Thiamine 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.Once activated, the acyl
Acyl
An acyl group is a functional group derived by the removal of one or more hydroxyl groups from an oxoacid, including inorganic acids.In organic chemistry, the acyl group is usually derived from a carboxylic acid . Therefore, it has the formula RCO-, where R represents an alkyl group that is...
CoA
COA
COA can refer to:*Codename Amscray*Cash on Arrival*Cause of action*CedarOpenAccounts*Center of Attention*Certificate of Appealability*Certificate of Approval for marriage or civil partnership in the United Kingdom*Certificate of Authenticity...
is transported into the mitochondrial matrix
Mitochondrial matrix
In the mitochondrion, the matrix contains soluble enzymes that catalyze the oxidation of pyruvate and other small organic molecules.The mitochondrial matrix also contains the mitochondria's DNA and ribosomes. The word "matrix" stems from the fact that this space is viscous, compared to the...
. This occurs via a series of similar steps:
- Acyl CoA is conjugated to carnitineCarnitineCarnitine is a quaternary ammonium compound biosynthesized from the amino acids lysine and methionine. In living cells, it is required for the transport of fatty acids from the cytosol into the mitochondria during the breakdown of lipids for the generation of metabolic energy. It is widely...
by carnitine acyltransferase (palmitoyltransferase) I located on the outer mitochondrial membrane - Acyl carnitine is shuttled inside by a translocaseTranslocaseTranslocase is a general term for an enzyme that assists in moving another molecule, usually across a membrane.Translocases are most common secretion system in Gram positive bacteria.Examples include:...
- Acyl carnitine (such as PalmitoylcarnitinePalmitoylcarnitinePalmitoylcarnitine is an ester derivative of carnitine involved in the metabolism of fatty acids.Carnitine O-palmitoyltransferase breaks it down into palmitoyl CoA....
) 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
Malonyl-CoA
Malonyl-CoA is a coenzyme A derivative.-Functions:It plays a key role in chain elongation in fatty acid biosynthesis and polyketide biosynthesis....
, an intermediate in fatty acid biosynthesis, in order to prevent futile cycling between beta-oxidation and fatty acid synthesis
Fatty acid synthesis
Fatty acid synthesis is the creation of fatty acids from acetyl-CoA and malonyl-CoA precursors through action of enzymes called fatty acid synthases...
.
β-oxidation
Once inside the mitochondria, the β-oxidation of fatty acids occurs via four recurring steps:- Oxidation by FADFADIn biochemistry, flavin adenine dinucleotide is a redox cofactor involved in several important reactions in metabolism. FAD can exist in two different redox states, which it converts between by accepting or donating electrons. The molecule consists of a riboflavin moiety bound to the phosphate...
, - HydrationHydration reactionIn organic chemistry, a hydration reaction is a chemical reaction in which a hydroxyl group and a hydrogen cation are added to the two carbon atoms bonded together in the carbon-carbon double bond which makes up an alkene functional group. The reaction usually runs in a strong acidic, aqueous...
, - Oxidation by NAD+,
- ThiolysisThiolysisThiolysis is a reaction with a thiol that cleaves one compound into two. This reaction is similar to hydrolysis, which involves water instead of a thiol. This reaction is seen in β-oxidation of fatty acids. The depolymerisation of condensed tannins with the use of benzyl mercaptan as...
, - The final product is acetyl-CoAAcetyl-CoAAcetyl coenzyme A or acetyl-CoA is an important molecule in metabolism, used in many biochemical reactions. Its main function is to convey the carbon atoms within the acetyl group to the citric acid cycle to be oxidized for energy production. In chemical structure, acetyl-CoA is the thioester...
, the entry molecule for the citric acid cycleCitric acid cycleThe citric acid cycle — also known as the tricarboxylic acid cycle , the Krebs cycle, or the Szent-Györgyi-Krebs cycle — is a series of chemical reactions which is used by all aerobic living organisms to generate energy through the oxidization of acetate derived from carbohydrates, fats and...
.