Lecture 19 Summary

Fatty acid metabolism - the essentials. Fatty acids: physiological roles, energy content. Franz Knoop's classic experiment. Acyl CoA synthetase - activation of fatty acids for degradation. Carnitine shuttle. The cycle of reactions in b-oxidation. Thiolase [EC 2.3.1.16 ].

Activation of fatty acids for degradation

In eukaryotic systems, free fatty acids are converted to their acyl CoA derivatives prior to transport into the mitochondrial matrix where the energy-yielding degradation of fatty acids - b-oxidation - occurs. A free fatty acid is converted to a adenylated intermediate theough a reaction with ATP catalyzed by acyl CoA synthetatse [Official name: Long-chain-fatty-acid--CoA ligase, EC 6.2.1.3]. The reaction takes place in two steps:

    Step 1:  RCOOH  +  ATP  =  RCOOAMP  +  PP_i

    Step 2:  RCOOAMP  +  CoASH  =  RCOSCoA  +  AMP

The concomittant hydrolysis of pyrophosphate (PP_i), catalyzed by inorganic diphosphatase [EC 3.6.1.1], provides an extra thermodynamic driving force for product formation.

Lipid transport

Forms of lipid transport and the role of the liver.

Transport of fatty acyl CoA molecules from cytosol to mitochondrial matrix via the carnitine shuttle.

A system consisting of two isozymes of carnitine O-palmitoyltransferase [CPT, EC 2.3.1.21] and a carnitine/acylcarnitine translocase in the inner mitochondrial membrane accomplishes the transport of the activated (acyl CoA) forms of long-chain fatty acids from the cytosol to the mitochondrial matrix where b-oxidation takes place. The CPT I isozymes are associated with the outer mitochondrial membrane, while CPT II is integral to the inner mitochondrial membrane.

CPT catalyzes the exchange of fatty acyl groups between coenzyme A and carnitine:

acyl CoA + carnitine = acyl carnitine + CoA

The reaction proceeds in the forward direction outside the mitochondrial matrix. Once an acyl carnitine has been transported into the matrix, the reverse reaction is favored.

Study questions

• Predict the effects of a mutation in carnitine acyltransferase I or II on the rate of b-oxidation.
• Propose a mechanism for thiolase based on a Claisen ester cleavage.

Page updated 01-15-07

References

1. Berg, Tymoczko, and Stryer. Biochemistry (BTS): 6th edition (2007, Freeman) Ch.21 (pp.604-612)
2. Bruice PY. Organic Chemistry 5th edition, p.876-877.