ß-oxidation

=ß-Oxidation =

Authors: Sanggitha Kusumo, Stacy Lee, and Kyli Putnam

ß-oxidation is the process by which fatty acids are catabolized in the mitochondria and/or in peroxisomes to produce Acetyl-CoA, the entry molecule for the Citric Acid Cycle.

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**Break down of fatty acids**
The process of ß-oxidation begins with the formation of a thiol ester bond between the fatty acid and the thiol group of coenzyme A, which is catalyzed by acyl-CoA synthetase. This condensation with CoA activates the fatty acid for reaction in the ß-oxidation pathway(1). The enzymes of the  ß-oxidation pathway are located in the mitochondrial matrix. Short-chain fatty acids are transported into the matrix as free acids and form the acyl-CoA derivatives there. For long- chain fatty acids, this reaction normally occurs at the outer mitochondrial membrane in higher eukaryotes before entry of the fatty acid into the mitochondrion, but it may also occu r at the surface of the endoplasmic reticulum. Long-chain fatty acyl-CoA derivatives must first be converted acylcarnitine derivatives, which are transported across the inner membrane by a translocase. On the matrix side of the inner membrane, a second acylcarnitine transferase reforms the fatty acyl-CoA. In all cases, the reaction is accompanied by the hydrolysis of ATP to form AMP and pyrophosphate. The pyrophosphate produced in this reaction is rapidly hydrolyzed by inorganic pyrophosphate to two molecules of phosphate. Thus pyrophosphate is maintained at a low concentration in the cell and the synthetase reaction is strongly promoted. The mechanism of the acyl-CoA synthetase reaction involves attack of the fatty acid carboxylate on ATP to form an acyladenylate intermediate, which is subsequently attacked by CoA, forming a fatty acyl-CoA thioester (2).



Four recurring steps
Inside the mitochondria, beta-oxidation of saturated fatty acids occurs in a sequence of four reactions:

 1.) Oxidation by FAD: The first step is the oxidation of the fatty acid by Acyl-CoA-Dehydrogenase. The enzyme catalyzes the formation of adouble bondbetween the C-2 and C-3.



2.) Hydration: The next step is the hydration of the bond between C-2 and C-3. The reaction is stereospecific, forming only the L isomer.



3.) Oxidation by NAD+: The third step is the oxidation of L-ß-hydroxyacyl-CoA by NAD+. This converts the hydroxyl group into a keto group.

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<span style="font-family: Georgia,serif;">4.) Thiolysis: The final step is the cleavage of ß-ketoacyl-CoA by the thiol group of another molecule of CoA. The thiol is inserted between C-2 and C-3.

<span style="font-family: Georgia,serif;"> <span style="font-family: Georgia,serif;">(1)

<span style="font-family: Georgia,serif;">ß-oxidation of unsaturated fatty acids
<span style="font-family: Georgia,serif;"> Unsaturated fatty acids are also catabolized by ß-oxidation, but two additional mitochondrial enzymes — an isomerase and a novel reductase — are required to handle the cis double bonds of naturally occurring fatty acids. The reactions of ß-oxidation proceed normally through three cycles, producing three molecules of acetyl-CoA and leaving a degradation product. This intermediate is not a substrate for acyl-CoA dehydrogenase. With a double bond at the 3,4 position, it is not possible to form another double bond at the ß position. Enoyl-CoA isomerase, an enzyme that rearranges this cis-Δ3﻿ double bond to a trans-Δ2﻿ double bond, solves this problem (2).

<span style="font-family: Georgia,serif;">ß-oxidation of odd-numbered chains
<span style="font-family: Georgia,serif;"> Human and animals metabolize odd-carbon fatty acids via the ß-oxidation pathway, with the final product being propionyl-CoA instead of acetyl-CoA. Three specialized enzymes carry out the reactions that convert propionyl-CoA to succinyl-CoA, a TCA cycle intermediate. Initially, carboxylation at the α-carbon of propionyl-CoA produces D-methylmalonyl-CoA, which is catalyzed by propionyl-CoA carboxylase. D-methylmalonyl-CoA is then converted to the L isomer by methylmalonyl-CoA epimerase. The epimerase reaction involves a carbanion at the α-position formed via a reversible dissociation of the acidic α-proton. The L-isomer is the substrate for methylmalonyl-CoA mutase, which catalyzes a migration of a carbonyl-CoA group from one carbon to its neighbor, yielding succinyl-CoA (2).

<span style="font-family: Georgia,serif;">ß-oxidation in peroxisomes and glyoxysomes
<span style="font-family: Georgia,serif;"> Although ß-oxidation in mitochondria is the principle pathway of fatty acid catabolism, organelles other than mitochondria, including peroxisomes and glyoxysomes, carry out ß-oxidation. Peroxisomal ß-oxidation is similar to mitochondrial ß-oxidation, except that the initial double bond formation is catalyzed by an FAD-dependent acyl-CoA oxidase. The action of this enzyme in the peroxisomes transfers the liberated electrons directly to oxygen instead of the electron transport chain. As a result, each two-carbon unit oxidized in peroxisomes produces fewer ATPs. The enzymes responsible for fatty acid oxidation in peroxisomes are inactive with acyl chains of eight carbons or fewer. Such short-chain products must be transferred to the mitochondria for further breakdown. Glyoxysomes are peroxisomes in plants that also carry out the reactions of the glyoxylate pathway and contain similar ß-oxidation enzymes (2).

<span style="font-family: Georgia,serif;">References
<span style="font-family: Georgia,serif;">1.Beta Oxidation. (2005). Statemaster encyclopedia. Retrieved December 5, 2010, from [] <span style="font-family: Georgia,serif;">2.Garrett, R.H., & Grisham, C.M. (2010). Biochemistry. Boston, MA: Brooks/Cole