Bioc 460 Spring 1999
Lecture 34 - Chapter 24

- Overview of lipid metabolism
- Reactions of fatty acid oxidation
- Energy yield from fatty acid oxidation
- Formation of ketone bodies

Carbohydrate metabolism is but one component of energy production and storage. In fact, a much larger percentage of the total energy reserves in animals is lipids in the form of fat deposits. The central intermediate in fat metabolism is acetyl CoA.

Figure 17.15

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Fatty acids consist of a long hydrocarbon chain (mostly saturated carbons) with a terminal carboxylate group. Fatty acids have four major physiologic roles:

1. Building blocks of membrane phospholipids.

2. Can be covalently attached to proteins and serve as targeting signals.

3. They are the major fuel molecules in most animals.

4. Fatty acids derivatives serve as hormones and intracellular messengers.

Fatty acids vary in chain length and degree of unsaturation (C=C bonds).

Table 24.1

Triacylglycerols are very anhydrous and can therefore store much more energy with less mass. For example, one gram of anhydrous fat stores SIX TIMES more energy than a gram of hydrated glycogen. Put another [weigh], a man weighing 155 pounds with a normal amount of stored fat, would have to weigh 240 pounds if that same amount of energy were stored as glycogen. Where is the "extra" 95 pounds coming from?

Stored triacylglycerols are first hydrolyzed by lipases to release glycerol and free fatty acids. The fatty acids are activated by acetyl CoA to form fatty acyl CoA, and then these compounds are transported through the mitochondrial membrane by the carnitine carrier system. Once inside the mitochondrial matrix, fatty acids are oxidized 2 carbons at a time, releasing acetyl CoA, NADH and FADH2, which are then utilized by the citric acid cycle and oxidative phosphorylation to produce ATP.

cAMP-regulated lipases are activated in response to epinephrine hormone signaling. The fatty acids are oxidized and the glycerol is converted to DHAP which is further metabolized by glycolysis.

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Fatty acids are linked to CoA through an activation process on the outer mitochondrial membrane requiring the enzyme acyl CoA synthase. This reaction is driven by the hydrolysis of inorganic pyrophosphate.

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Fatty acyl CoA derivatives are carried across the inner mitochondrial membrane by conjugating them to carnitine. The carrier process requires carnitine acyltransferase I (outside) and carnitine acyltransferase II (inside). Defects in these enzymes have been found in humans resulting in metabolic diseases characterized by the inability to utilize stored fats.

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Figure 24.4

Once inside the mitochondrial matrix, the fatty acyl CoA derivative is degraded by a series of reactions that releases acetyl CoA and leads to the production of NADH and FADH2. There are four steps in fatty acid oxidation pathway; oxidation, hydration, oxidation, and thiolysis. It requires 7 rounds of this pathway to degrade palmitate, a C16 fatty acid.

Figure 24.5

Figure 24.6

Table 24.2

The complete oxidation of palmitate (C16 fatty acid) yields 106 ATP (see RLM 34.2).

Palmitoyl CoA + 7 FAD + 7 NAD + 7 CoA + 7 H2O --->

8 acetyl CoA + 7 FADH2 + 7NADH + 7H

8 acetyl CoA = 24 NADH + 8 FADH2 + 8 ATP[GTP]

31 NADH = 31 x 2.5 ATP = 77.5 ATP
15 FADH2 = 15 x 1.5 ATP = 22.5 ATP

8 ATP + 77.5 ATP + 22.5 ATP = 108 ATP - 2 ATP (palmitate activation) = 106 ATP

Note that the oxidation of NADH and FADH2, plus ATP synthesis, yields a large amount of H20 (subtracting the investment of H2O in beta oxidation). In fact, desert animals derive much of their water from fuel metabolism; oxidation of palmitate generates 169 H2O - 24 H2O = 145 moles of H2O, which works out to be:
~10 mls of H2O per gram of palmitate. WOW!
(see how this calculation was actually made; RLM 34.1)

FAT is the fuel of the carbohydrate furnace - if the furnace is broken, ketone bodies are formed!

In fasting or diabetes, oxaloacetate (OAA) is consumed to form glucose by gluconeogenesis, therefore, the citric acid cycle is no longer able to function at full capacity. The acetyl CoA that is accumulating from fatty acid oxidation is used instead to make acetoacetate and hydroxybutyrate. Acetone is formed from acetoacetate which is why it can be detected on the breath of someone with high levels of ketone bodies (e.g., diabetics). In what tissue do you think ketone bodies are made? (hint: ketone bodies are made when gluconeogenesis is very active and pyruvate is limiting).

Figure 24.8

Acetoacetate is a major fuel for some tissues. While the brain under NORMAL conditions prefers glucose, the heart muscle can metabolize acetoacetate which is present in the blood at low levels most of time. Acetoacetate metabolism yields 2 moles of acetyl CoA . Note that the brain under conditions of extreme STARVATION can shift to the use of acetoacetate (stay alive you may find food - tomorrow).

Figure 24.9

Can't acetyl CoA be used to make OAA, which is converted to pyruvate?
OF COURSE NOT (acetyl CoA is metabolized to two moles of CO2, duh).

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Department of Biochemistry The University of Arizona Spring 1999  RLM@u.arizona.edu cusanovi@u.arizona.edu http://www.biochem.arizona.edu/classes/bioc460/spring/springindex.html All contents copyright © 1999. All rights reserved.