Biochemistry I Fall Term, 2000

 December 8, 2000

Lecture 34: Catabolism of Fatty Acids

Assigned reading in Campbell: Chapter 17.1-17.5

Key Terms:
Acyl-carnitine
Acyl-CoA
b-oxidation 		Lipases
Phospholipases
Ketone bodies

Take the Review Quiz on Lecture 34 concepts.

Formation of Acyl-CoA

The fatty acids in the cytosol are coupled to Coenzyme A to form acyl-CoA.
The activation reaction is catalyzed by acyl-CoA synthetase and involves the following steps (Fig. 17.3):

  1. Nucleophilic attack of carboxyl group of fatty acid towards phosphate of ATP
  2. Formation of an acyl-AMP intermediate with release of PPi.
    This reaction is slightly endergonic; however, it is driven by the subsequent hydrolysis of PPi. This is another example of:
        The hydrolysis of a high energy compound to make a reaction irreversible; and
        Irreversibility in the first step of a pathway.
  3. Nucleophilic attack of the sulfur group of CoA on the carbonyl carbon of the fatty acyl-AMP intermediate.
The resulting high energy thioester bond (DG = -31.5 kJ/mol for hydrolysis) preserves the high energy of the ATP used to form the acyl-CoA.
Note that it is only necessary to utilize ATP in the formation of the first thioester bond.

Formation and Transport of Acyl-carnitine

The acyl-CoA is transported into the mitochondrial matrix for oxidation by transferring the acyl group on CoA to carnitine. The acyl-carnitine is transported into the mitochondria.

  1. DG = 0, therefore the free energy of the initial ATP hydrolysis is still preserved.
  2. Transport into mitochondria is a coordinated exchange: acyl-carnitine goes in, carnitine comes out.


The acyl group is moved from carnitine to CoA in the matrix space.
This is an another example of a cytosol-mitochondria shuttle. There is no net transfer of CoA or carnitine between these two cellular compartments. Many other types of shuttle exist, e.g. those for ATP and NADH.

b-Oxidation

In the mitochondrial matix space, the acyl-CoA is oxidized in 2-carbon units to acetyl-CoA.

  1. Formation of trans a-b double bond by dehyrogenation by acyl-CoA dehydrogenase, an FAD enzyme.


The FADH2 product is used in oxidative phosphorylation. This results in the regeneration of two ATP molecules, and recovers the energy spent to form the first acyl-CoA intermediate.

  1. Addition of water to the newly formed double bond to generate the alcohol by enoyl-CoA hydratase


  2. Oxidation of the alcohol by NAD+ to give the ketone; catalyzed by b-hydroxyacyl-CoA dehydrogenase. The reduced NADH is reoxidized by molecular oxygen in oxidative phosphorylation to yield 3 ATP molecules.
  3. Cleavage reaction by b-ketoacyl-CoA thiolase (Thiolysis)

Summary of the thiolase steps:
  1. Nucleophilic attack of Cys residue onto ketone carbon (b-carbon) to form an acyl-enzyme intermediate.
  2. Breakage of a-b bond to produce anionic acetyl-Co A group
  3. Anionic acetyl-Co A group abstracts proton from general base on the enzyme to form acetyl-Co A
  4. Nucleophilic attack of CoASH on to keto group of enzyme-acyl intermediate
  5. Breakage of acyl-enzyme bond to release acyl (n-2) Co A.

Similarities of thiolase to serine proteases:

Functionality Serine Protease Thiolase
Nucleophile Ser Cys
Acyl-enzyme formed yes yes
Proton provided by: His (base) unknown base
Acyl-enzyme hydrolyzed by: Water CoA

Energy Yield from Fatty Acid Oxidation

See Campbell, 17.3, for the detailed balance sheet (Table17.1)

  • ATP is derived from FADH2, NADH, and acetyl-CoA.
  • ATP's produced per six-carbon unit.
        Glucose: 32.
        Fatty acids: 40.
  • Acyl chains of fatty acids are hydrocarbon whereas carbohydrates are partially oxidized.

Additional Topics

  • Odd-numbered fatty acids and the catabolic products of some amino acids result in propionyl-CoA after b-oxidation.
  • Ketone bodies (acetoacetate and acetone) result from the condensation of two acetyl-CoA molecules.
        Synthesis occurs in the liver.
        Oxidation occurs normally in other organs.


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