Question

1. Starting with the fatty acid 18:0, write all of the steps of one round of the process of beta oxidation. How many rounds of beta oxidation are required to completely break down an 18C saturated fatty acids. How many molecules of acetyl-coA would this produce? What step of this process resembles a step in the citric acid cycle? How do electrons in this step enter into the ETC? Why is it necessary that the thiol group of the coA is the nucleophile in this reaction?

Answer 1

The first reaction is catalyzed by acyl-CoA dehydrogenase, a flavoprotein that is present as a family of three enzymes that differ in their specificity for the length of acyl-CoAs. Their mechanism involves the oxidation of Cα–Cβ bound to form a trans double bond. During the oxidation of the fatty acid, the FAD is reduced to FADH2, and the electrons are transfered to an electron transfer flavoprotein (ETF). Reduced ETF is reoxidized by a specific oxidoreductase that donates electrons to the electron transport chain at the level of coenzyme Q. The next past is a hydrogenation reaction, catalyzed by the ligase enoyl-CoA hydratase that saturates the new double bond by the addition of a hydroxyl group in the beta position. At least three enoyl-CoA hydratase activities are known. These enzymes present stereospecific and specifically converted trans-enoyl-CoA derivates to l-β-hydroxyacyl-CoA. The fourth reaction cleaves the β-keto ester, yielding one molecule of acetyl-CoA and a fatty acyl-CoA shortened in two carbons. The repetitions of this cycle with the shortened fatty acyl-CoA achieve the complete β-oxidation of fatty acid. At the final step of this cycle, a fatty acid with an even number of carbons yields two molecules of acetyl-CoA.
Fatty acids with an odd number of carbon atoms are rare in mammals but are common in plants and marine organisms. Humans and animals, whose diets include these food sources, metabolize odd-carbon fatty acids via the β-oxidation pathway. The final product of β-oxidation in this case is the 3-carbon propionyl-CoA instead of acetyl-CoA. Three specialized enzymes then carry out the reaction that converts propionyl-CoA to succinyl-CoA, a TCA cycle intermediate that may be oxidized to CO2.

Thiolysis: The final step is the cleavage of β-ketoacyl CoA by the thiol group of another molecule of Coenzyme A. The thiol is inserted between C-2 and C-3. The carbon-carbon single bond that connects methylene (-CH2-) groups in fatty acids is relatively stable. The β-oxidation sequence represents an elegant solution to the problem of breaking these bonds. The first three reactions of β oxidation have the effect of creating a much less stable C-C bond, in which one of the carbon atoms (the a carbon, C-2) is bonded to two carbonyl carbons. The ketone function on the β carbon (C-3) makes it a good point for nucleophilic attack by -SH of coenzyme A, catalyzed by thiolase. The acidity of the a carbon makes the terminal -CH2-CO-S-CoA a good leaving group, facilitating breakage of the α-β bond.