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Fatty acid metabolism
Fatty acids are an important source of energy for many organisms. Triglycerides can yield more than twice the amount of energy compared to carbohydrates or proteins. Fatty acids are also important building blocks (phospholipids in membranes), protein modifiers and their derivatives serve as hormone or other intracellular messengers.
Fatty acids as an energy source
Fatty acids, stored as triglycerides in an organism, is an important source of energy because it is both reduced and anhydrous. The energy yield from a gram of fatty acids is approximately 9 kcal (38 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, 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.
Three major steps are involved in the degradation of fatty acids.
Release from adipose
The following hormones induce lipolysis: epinephrine, norepinephrine, glucagon and adrenocorticotropic hormone. These trigger 7TM receptors, which activates adenylate cyclase. This results in an inflow 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.
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 + Pi + 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.
- Acyl CoA is conjugated to carnitine by carnitine acyltransferase I
- Acyl carnitine is shuttled inside by a translocase
- Acyl carnitine is converted to acyl CoA by carnitine acyltransferase II
Once inside the mitochondria, the β-oxidation of fatty acids occurs via four recurring steps:
Oxidation by FAD
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 end product is L-3-hydroxyacyl CoA.
Oxidation by NAD+
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 Β-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
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 converted into succinyl CoA (which is an intermediate in the citric acid cycle) in a reaction that involves Vitamin B12.
Oxidation in peroxisomes
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
- 106 ATP
- 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
Much like β-oxidation, elongation occurs via four recurring reactions:
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.
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.
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.
In this reaction, D-3-Hydroxybutyryl ACP is dehydrated to crotonyl ACP. This reaction is catalyzed by 3-Hydroxyacyl ACP dehydratase.
Reduction of crotonyl ACP
- Berg, J.M., et al., Biochemistry. 5th ed. 2002, New York: W.H. Freeman. 1 v. (various pagings).
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