Lipid Catabolism - Biochemistry

Hydroxyacyl-CoA dehydrogenase oxidizes the beta hydroxyl group, forming a carbonyl.

Thiolase catalyzes the cleavage of the beta-ketoacyl-CoA.

NAD is required for the oxidation of beta-hydroxyacyl-CoA to beta-Ketoacyl-CoA by hydroxyacyl-CoA dehydrogenase.

The two major products of the thiolase-catalyzed reaction are acetyl-CoA and a fatty acyl-CoA shortened by two carbons.

To answer this question, we'll need to keep in mind some of the highlights of beta oxidation. When a fatty acid is broken down by this method, the hydrocarbon chain is broken down two carbons at a time through a series of repeating reactions. These two carbons come off in the form of acetyl-CoA, with an additional generation of one molecule each of NADH and . Since we know the original chain we're starting with contains twelve carbons, we know that there will be six molecules of acetyl-CoA produced. Furthermore, in order to generate these six molecules, beta-oxidation must proceed five times. Thus, we are going to have five molecules of NADH and five molecules of . The acetyl-CoA generated from beta oxidation is able to enter the citric acid cycle. For each molecule of acetyl-CoA that goes through the cycle, 1 molecule of ATP, 1 molecule of , and 3 molecules of NADH are generated. Therefore, since six molecules will be sent into the citric acid cycle, there will be a total generation of six molecules of ATP, six molecules of , and eighteen molecules of NADH. Now, we need to add everything up. So far, we have six molecules of ATP. We also have five molecules of NADH from beta-oxidation, and eighteen from the citric acid cycle, for a total of twenty-three. We've also obtained five molecules of from beta-oxidation, and another six from the citric acid cycle for a total of eleven. All of the NADH and that was generated from these reactions can donate their electrons into the electron transport chain to generate ATP. The rule of thumb is that for every NADH, molecules of ATP are produced. And for every molecules of , molecules of ATP is made. So, we have:

And if we add to this the six ATP that was generated directly by substrate-level phosphorylation in the citric acid cycle, that gives us a total of:

Palmitate is a sixteen-carbon chain and its beta-oxidation will produce 8 acetyl-CoA molecules, since each acetyl-CoA is two-carbons long. Glucose, on the other hand, will be broken down to form 2 acetyl-CoA molecules. Therefore, palmitate forms 4 times as many acetyl-CoA molecules.

This first step of beta oxidation is catalyzed by acyl-CoA dehydrogenase. One way to remember is that the enzyme is named for exactly what it does: remove a hydrogen (dehydrogenate) from acyl-CoA, which is the reactant. In order to be acetyl-CoA the R-group must specifically be a methyl group.

This second step of beta oxidation is catalyzed by enoyl-CoA hydratase. One way to remember is that the enzyme is named for exactly what it does: adding water (hydrate) across the double bond of enoyl-CoA, which is the reactant.

This third step in beta oxidation is catalyzed by L-hydroxacyl-CoA dehydrogenase. One way to remember is that the enzyme is named for exactly what it does: remove a hydrogen (dehydrogenate) L-hydroxyacyl-CoA (the reactant).

This fourth step in beta oxidation is catalyzed by thiolase. The reduced form of coenzyme-A is used as a cofactor to cleave the bond between the alpha and the beta carbon.

removes two hydrogens to form . These two electrons will be donated to the electron transport chain.

Enoyl-CoA hydratase catalyzes the the addition of water across the carbon-carbon double bond.

Three enzymes are ultimately involved in activating fatty acids as fatty acyl-CoA and transferring this molecule into the inner mitochondrial matrix to be broken down via the beta-oxidation pathway. The first enzyme is acyl-CoA synthetase. This enzyme is a type of ATPase, and it uses the thermodynamically favorable dephosphorylation of ATP to drive the synthesis of fatty acyl-CoA from a fatty acid and CoASH. Fatty acids alone cannot cross mitochondrial membranes, but fatty acyl-CoA can cross the outer membrane.

Carnitine palmitoyl transferase II also synthesizes fatty acyl-CoA but acyl-CoA synthetase is the first enzyme to do so, and its dephosphorylation of ATP is what initially activates a fatty acid.

The carnitine transport protein, known as the carnitine-acylcarnitine translocase, allows the facilitated diffusion of a fatty acid into the mitochondrial matrix. Fatty acids cannot be transported into the mitochondrial matrix alone.

Following this step, carnitine palmitoyl transferase II catalyzes the reaction that reforms fatty acyl-CoA from CoASH and the fatty acylcarnitine.

Acyl-CoA dehydrogenase converts fatty acyl-CoA to trans-Δ2-enoyl-CoA forming the high energy redox cofactor from .

Enoyl-CoA hydratase uses hydrates the double bond between the alpha and beta carbons of trans-Δ2-enoyl-CoA by adding a hydroxyl group to the beta carbon and a hydrogen to the alpha carbon.

3-L-hydroxyacyl-CoA dehydrogenase converts 3-L-Hydroxyacyl-CoA to beta-Ketoacyl-CoA, forming the high energy redox cofactor from . This reaction oxidizes the hydroxyl group on the beta carbon of 3-L-hydroxyacyl-CoA to a carbonyl group, and adds a hydrogen with 2 high energy electrons to .

Beta-Ketoacyl-CoA thiolase converts beta-Ketoacyl-CoA back to acetyl-CoA and a fatty acyl-CoA two carbons shorter than the original fatty acyl-CoA. The new cofactor of acyl-CoA bonds to the beta carbon of beta-Ketoacyl-CoA, and thus the beta carbon of beta-Ketoacyl-CoA becomes the new alpha carbon of the new fatty acyl-CoA. The new fatty acyl-CoA can then re-enter into beta oxidation pathway.

The beta-oxidation pathway is cyclic. Two carbons are removed from a fatty acid chain each time it goes around the pathway. If the initial fatty acid chain has an even number of carbons then the final round of beta oxidation yields two copies of acetyl-CoA.

In the last round of beta oxidation, fatty acids with odd numbers of carbons will yield acetyl-CoA and Coenzyme-A attached to a fatty acid with three carbons (propionyl-CoA)