More Fun with Fat: Fatty Acid Oxidation

This week is about how fat is used to make energy.
Beta-oxidation is the process that fat undergoes which produces large amounts of energy. This process occurs within the mitochondrial matrix of the cells. Between meals, during fasting, or during prolonged exercise, fatty acids are released from the adipose tissue in response to a drop in insulin and an increase in glucagon. The main type of fats released are the long-chain fatty acids palmitate (C-16), oleate (C-18), and stearate (C-18:1), since these encompass the highest proportion of fats consumed in the diet and also synthesized in the body.
When these fatty acids enter the blood, they cannot travel far without assistance because they are extremely hydrophobic. Therefore, they bind to albumin, which is the major protein in the blood. Once they reach the cells, they still need a lot of help to get inside. They are able to enter the cell by binding to a fatty acid binding protein located at the plasma membrane, which facilitates their transport through. Once in the cytosol, the fatty acid becomes activated by reacting with ATP and coenzyme A (CoA), making it into a fatty acyl CoA.
At this point, fatty acyl CoA may take several paths:
1. It can go on into the mitochondrial matrix to undergo Beta-oxidation or ketogenesis and create energy.
2. It can go to storage in the form of triglyceride
3. It can become part of phospholipids or sphingolipids

If fatty acyl CoA goes toward energy formation, it can pass through into the outer mitochondrial membrane alone. However, it still needs help to cross the inner membrane, again due to being hydrophobic. It goes through the inner mitochondrial membrane by binding with carnitine and becoming fatty acyl carnitine. Carnitine is made from the essential amino acids lysine and methionine. Therefore, carnitine is not an essential amino acid because it is synthesized in the body. Carnitine contains nitrogen and oxygen, which gives it charges - allowing it to react with water. That is why it is needed to cross the membrane.
Once across the inner membrane, carnitine comes off and CoA attaches back, catalyzed by the enzyme carnitine palmitoyltransferase I (CPTI) to the fatty acyl, making it back into fatty acyl CoA. At this point, it is ready to undergo Beta-oxidation inside the mitochondrial matrix.

Beta-oxidation is a spiral-like pathway that continues to cleave the fatty acyl by two-carbon acetyl CoA units, beginning at the carboxyl end of the molecule, until only a 4 carbon fatty acyl CoA remains, which is broken into 2 acetyl CoA's.
Beta-oxidation consists of four different types of reactions.
1. the first reaction, catalyzed by acyl CoA dehydrogenase, results in a double bond with the trans configuration when hydrogen is transferred from between the alpha and beta carbons to FAD to make FAH(2H).
2. the second reaction, catalyzed by enoyl CoA hydratase, adds an OH group to the Beta carbon, and an H to the alpha carbon.
3. The third reaction, catalyzed by beta-hydroxyacyl CoA dehydrogenase, the OH group on the beta carbon is oxidized and forms a ketone. 2 hydrogen get transferred to NAD+, forming NADH+H+. This results in the beta-carbon becoming the carbonyl carbon.
4. The last step is catalyzed by Beta-ketothiolase, and in this step the bond between the alpha and beta carbons is broken, releasing acetyl CoA, and resulting in a new fatty acyl CoA that is 2 carbons shorter.

The new fatty acyl CoA will go through several more cycles of Beta-oxidation, losing 2 more carbons each time, until only a 4 carbon unit is left-which is broken to two molecules of acetyl CoA. These acetyl CoA's can then enter the TCA, or Kreb's, cycle.
This results in a very large amount of energy being produced, because each Acetyl CoA that enters the Kreb's cycle makes 10 ATP.
So, if a 16 carbon fatty acyl like palmytic acid goes through oxidation, it goes through 7 total cycles (number of cycles=number of carbon/2 - 1). This makes 8 acetyl CoA (number of acetyl CoA=number of carbon/2). So, 8 acetyl CoA's go through Kreb's and make 10 ATP each - that's 80 ATP so far.
Also, each cycle of Beta-oxidation produces 1 NADH2 and 1 FADH2. In this case, 7 cycles yields 7 of each. These also enter the Kreb's cycle. Each NADH2 can make 2.5 ATP - so there's another 17.5 ATP. FADH2 can each make 1.5 ATP - an additional 10.5.
All together, the complete oxidation of a 16 carbon fatty acid can make 108 ATP - but we have to subtract 2 of these, because 2 are used to initially make it into a fatty acyl CoA. A small price to pay - we still get a net gain of 106 ATP.
In comparison, the complete oxidation of one glucose molecule only generates 32 ATP. So, fat is a very important source of energy in our diet. It may cost us a lot of calories (9 calories per gram, compared to carbohydrates and protein, which are 4 calories per gram) but it gives a lot back!