Fatty acids are an important source of energy for many organisms. Triglycerides yield more than twice as much energy for the same mass as do carbohydrates or proteins. All cell membranes are built up of phospholipids, each of which contains two fatty acids. Fatty acids are also commonly used for protein modification, and all steroid hormones are ultimately derived from fatty acids. The metabolism of fatty acids, therefore, consists of catabolic processes which generate energy and primary metabolites from fatty acids, and anabolic processes which create biologically important molecules from fatty acids and other dietary carbon sources.
Fatty acids, stored as triglycerides in an organism, are an important source of energy because they are both reduced and anhydrous. The energy yield from a gram of fatty acids is approximately 9 kcal (39 kJ), compared to 4 kcal/g (17 kJ/g) for proteins and carbohydrates. Since fatty acids are non-polar molecules, they can be stored in a relatively anhydrous (water free) environment. Carbohydrates, on the other hand, are more highly hydrated. For example, 1 g of glycogen can bind approximately 2 g of water, which translates to 1.33 kcal/g (4 kcal/3 g). This means that fatty acids can hold more than six times the amount of energy. Put another way, if the human body relied on carbohydrates to store energy, then a person would need to carry 67.5 lb (31 kg) of glycogen to have the equivalent energy of 10 lb (5 kg) of fat.
Fatty acids are usually ingested as triglycerides, which cannot be absorbed by the intestine. They are broken down into free fatty acids and monoglycerides by lipases with the help of bile salts. Once across the intestinal barrier, they are reformed into triglycerides and packaged into chylomicrons or liposomes, which are released in the lymph system and then into the blood. Eventually, they bind to the membranes of adipose cells or muscle, where they are either stored or oxidized for energy. The liver also acts as a major organ for fatty acid treatment, processing liposomes into the various lipoprotein forms, namely VLDL, LDL, IDL or HDL.
Three major steps are involved in the degradation of fatty acids.
The breakdown of fat stored in fat cells is known as lipolysis. During this process, free fatty acids are released into the bloodstream and circulate throughout the body. Ketones are produced, leading to the process of ketosis in the case where insufficient carbohydrates are present in the diet. Lipolysis testing strips are available which can sometimes measure whether or not this process is taking place.
The following hormones induce lipolysis: epinephrine, norepinephrine, glucagon and adrenocorticotropic hormone. These trigger 7TM receptors, which activate adenylate cyclase. This results in increased production of cAMP, which activates protein kinase A, which subsequently activate lipases found in adipose tissue.
Triglycerides undergo lipolysis (hydrolysis by lipases) and are broken down into glycerol and fatty acids. Once released into the blood, the free fatty acids bind to serum albumin for transport to tissues that require energy. The glycerol backbone is absorbed by the liver and eventually converted into glyceraldehyde 3-phosphate (G3P), which is an intermediate in both glycolysis and gluconeogenesis.
Fatty acids must be activated before they can be carried into the mitochondria, where fatty acid oxidation occurs. This process occurs in two steps:
The formula for the above is:
RCOO- + CoA + ATP + H2O --> RCO-CoA + AMP + Pi + 2H+
Once activated, the acyl CoA is transported into the mitochondrial matrix. This occurs via a series of similar steps:
1. Acyl CoA is conjugated to carnitine by carnitine plamitoyltransferase I
2. Acyl carnitine is shuttled inside by Carnitine acyltranslocase
3. Acyl carnitine is converted to acyl CoA by carnitine palmitoyltransferase II
Once inside the mitochondria, the β-oxidation of fatty acids occurs via four recurring steps:
1. Oxidation by FAD
3. Oxidation by NAD+
The first step is the oxidation of the fatty acid by FAD. The following reaction is catalyzed by acyl CoA dehydrogenase:
The enzyme catalyzes the formation of a double bond between the C-2 and C-3. The end product is trans-Δ2-enoyl-CoA.
The next step is the hydration of the bond between C-2 and C-3. This reaction is catalyzed by enoyl CoA hydratase. The reaction is stereospecific, forming only the L isomer.
The end product is L-3-hydroxyacyl CoA.
The third step is the oxidation of L-3-hydroxyacyl CoA by NAD+, catalyzed by L-3-hydroxyacyl CoA dehydrogenase. This converts the hydroxyl group into a keto group.
The end product is 3-ketoacyl CoA.
The final step is the cleavage of 3-ketoacyl CoA by the thiol group of another molecule of CoA. This reaction is catalyzed by B-ketothiolase. The thiol is inserted between C-2 and C-3, which yields an acetyl CoA molecule and an acyl CoA molecule, which is two carbons shorter.
This process continues until the entire chain is cleaved into acetyl CoA units. For every cycle, one molecule of FADH2, NADH and acetyl CoA are formed.
β-oxidation of unsaturated fatty acids poses a problem since the location of a cis bond can prevent the formation of a trans-δ2 bond. These situations are handled by an additional two enzymes: cis-δ3-Enoyl CoA isomerase and 2,4 Dienoyl CoA reductase. Whatever the conformation of the hydrocarbon chain, β-oxidation occurs normally until the acyl CoA (because of the presence of a double bond) is not an appropriate substrate for acyl CoA dehydrogenase, or enoyl CoA hydratase.
If the acyl CoA contains a cis-Δ3 bond, then the isomerase will convert the bond to a trans-Δ2 bond, which is a regular substrate.
If the acyl CoA contains a cis-Δ4 double bond, then its dehydrogenation yields a 2,4-dienoyl intermediate, which is not a substrate for enoyl CoA hydratase. However, the enzyme 2,4-Dienoyl CoA reductase reduces the intermediate, using NADPH, into trans-Δ3-enoyl CoA. As in the above case, this compound is converted into a suitable intermediate by cis-Δ3-Enoyl CoA isomerase.
To summarize, odd numbered double bonds are handled by the isomerase, and even numbered bonds by the reductase (which creates an odd numbered double bond) and the isomerase.
Chains with an odd-number of carbons are oxidized in the same manner as even-numbered chains, but the final products are propionyl CoA and acetyl CoA. Propionyl CoA is converted into succinyl CoA (which is an intermediate in the citric acid cycle) in a reaction that involves Vitamin B12. Succinyl CoA can then enter the citric acid cycle. Because it cannot be completely metabolized in the citric acid cycle, the products of its partial reaction must be removed in a process called cataplerosis. This allows regeneration of the citric acid cycle intermediates, possibly an important process in certain metabolic diseases.
Fatty acid oxidation also occurs in peroxisomes. However, the oxidation ceases at octanyl CoA. One significant difference is that oxidation in peroxisomes is not coupled to ATP synthesis. Instead, the high-potential electrons are transferred to O2, which yields H2O2. The enzyme catalase, found exclusively in peroxisomes, converts the hydrogen peroxide into water and oxygen.
The ATP yield for every oxidation cycle is 14 ATP, broken down as follows:
1 FADH2 x 1.5 ATP = 1.5 ATP
1 NADH x 2.5 ATP = 2.5 ATP
1 acetyl CoA x 10 ATP = 10 ATP
For an even-numbered saturated fat (C2n), n - 1 oxidations are necessary and the final process yields an additional acetyl CoA. In addition, two equivalents of ATP are lost during the activation of the fatty acid. Therefore, the total ATP yield can be stated as: (n - 1) * 14 + 10 - 2.
For instance, the ATP yield of palmitate (C16, n = 8) is:
(8 - 1) * 14 + 10 - 2
7 FADH2 x 1.5 ATP = 10.5 ATP
7 NADH x 2.5 ATP = 17.5 ATP
8 acetyl CoA x 10 ATP = 80 ATP
ATP equivalent used during activation = -2
Total: 106 ATP
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