Fatty acid metabolism

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 used for protein modification. 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 as an energy source

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.

Digestion

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. Most are absorbed as free fatty acids and 2-monoglycerides, but a small fraction is absorbed as free glycerol and as diglycerides. 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.

Degradation

Three major steps are involved in the degradation of fatty acids.

Release from adipose tissue

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 such as Ketostix 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.

Activation and transport into mitochondria

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 + PP_i + 2H⁺
This reaction is reversible and its equilibrium lies near 1. However, pyrophosphate is hydrolized by a pyrophosphatase, which drives the reaction forward, and to completion.

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 palmitoyltransferase I
2. Acyl carnitine is shuttled inside by carnitine acyltranslocase
3. Acyl carnitine is converted to acyl CoA by carnitine palmitoyltransferase II

β-Oxidation

Once inside the mitochondria, the β-oxidation of fatty acids occurs via four recurring steps:

1. Oxidation by FAD
2. Hydration
3. Oxidation by NAD⁺
4. Thiolysis

Through β-oxidation , an acyl-CoA with n carbon atoms yields one NADH, one FADH₂, one acetyl-CoA and a shortened acyl-CoA with n-2 carbon atoms, which can be subjected to further rounds of degradation.

β-oxidation of unsaturated fatty acids

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.

β-oxidation of odd-numbered chains

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 carboxylated to methyl-malonyl-CoA, which is then converted into succinyl CoA (an intermediate in the citric acid cycle) in a reaction that involves Vitamin B12. Succinyl CoA can then be used in heme biossynthesis or enter the citric acid cycle.

Oxidation in peroxisomes

Fatty acid oxidation also occurs in peroxisomes. However, the oxidation ceases at octanyl CoA, which must then move to the mitochondria in order to be fullt oxidized. Another significant difference is that oxidation in peroxisomes does not use FAD as electron acceptor. 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. Acyl-CoA entry into the peroxissome does not require carnitine.

Energy yield

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 (C_2n), 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

106 ATP

or

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

Synthesis

Fatty acid synthesis occurs in the cytosol, in humans primarily in the liver, also adipose tissue and mammary gland during lactation. Precursors are acetyl-CoA and malonyl-CoA. Most of acetly-CoA is formed in the mitochondria and is transported into cytosol in the form of citrate.

Elongation

Much like β-oxidation, elongation occurs via four recurring reactions:

1. Condensation
2. Reduction
3. Dehydration
4. Reduction

In the second step of elongation, butyryl ACP condenses with malonyl ACP to form an acyl ACP compound. This continues until a C₁₆ acyl compound is formed, at which point it is hydrolyzed by a thioesterase into palmitate and ACP.

Condensation

The first step is condensation of acetyl ACP and malonyl ACP, catalyzed by acyl-malonyl ACP condensing enzyme. This results in the formation of acetoacetyl ACP.

Although this reaction is thermodynamically unfavourable, the evolution of CO₂ drives the reaction forward.

Reduction of acetoacetyl ACP

In this step, acetoacetyl ACP is reduced by NADPH into D-3-Hydroxybutyryl ACP. This reaction is catalyzed by β-Ketoacyl ACP reductase. The double bond is reduced to a hydroxyl group. Only the D isomer is formed.

Dehydration

In this reaction, D-3-Hydroxybutyryl ACP is dehydrated to crotonyl ACP. This reaction is catalyzed by 3-Hydroxyacyl ACP dehydrase.

Reduction of crotonyl ACP

During this final step, crotonyl ACP is reduced by NADPH into butyryl ACP. This reaction is catalyzed by enoyl ACP reductase.

See also

• List of fatty acid metabolism disorders

References

1. Berg, J.M., et al., Biochemistry. 5th ed. 2002, New York: W.H. Freeman. 1 v. (various pagings).

External links

• The chemical logic behind the metabolism of fatty acid