BIOCHEMISTRY - L. Stryer - 1984

VOLUME 2

PART II GENERATION AND STORAGE OF METABOLIC ENERGY

CHAPTER 17. FATTY ACID METABOLISM

17.10. Isomerase and Epimerase Are Required for the Oxidation of Unsaturated Fatty Acids

Let us now turn to the Oxidation of Unsaturated Fatty acids. Many of the reactions involved are identical to those of saturated fatty acids. Indeed, The breakdown of A wide variety of Unsaturated fatty acids requires only two accessory Enzymes: an isomerase and an epimerase.

Consider The oxidation of palmitoleate. This unsaturated C₁₆ fatty acid, containing a single double bond between C-9 and C-10, is activated and transported across The inner mitochondrial membrane in the same manner as palmitate. Palmitoleoyl-CoA then undergoes three cycles of degradation catalyzed by the same enzymes as the Oxidation of Saturated fatty acids. However, cis-∆³-enoyl-CoA, formed in the third cycle, is not a substrate for acyl-CoA dehydrogenase. The presence of a double bond between C-3 and C-4 prevents The formation of another double bond between C-2 and C-3. This obstacle is overcome by a novel reaction that shifts the position and configuration of the cis-∆³ double bond. Under the action of the isomerase, this double bond is converted into a trans-∆² double bond. Subsequent reactions are similar to those of the saturated Fatty acid oxidation pathway, with trans-∆²-enoyl-CoA serving as a normal substrate.

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A second accessory enzyme is required for the oxidation of polyunsaturated fatty acids. An activated unsaturated C₁₈ fatty acid with cis-∆¹² and cis-∆⁹ double bonds undergoes two cycles of degradation via the saturated fatty acid oxidation pathway. Then, cis-∆²,cis-∆⁵-dienoyl-CoA is hydrated by enoyl-CoA hydratase, the same enzyme that hydrates the trans-∆² double bond in the oxidation of saturated fatty acids. However, Hydration of the cis-∆² double bond yields the D-isomer of 3-hydroxyacyl-CoA, which cannot serve as a substrate for _L-3-hydroxyacyl-CoA dehydrogenase. This difficulty is resolved by an epimerase that inverts the configuration of the hydroxyl group at C-3.

17.11. Odd-Chain Fatty Acids Yield Propionyl-CoA Upon Terminal Thiolysis

Fatty acids with an odd number of carbon atoms are relatively uncommon. They are oxidized in the same manner as even-chain fatty acids, with the sole exception that the final Cleavage step yields one molecule of propionyl-CoA and one molecule of acetyl-CoA, rather than two molecules of acetyl-CoA. The activated three-carbon fragment, propionyl-CoA, enters The Tricarboxylic Acid Cycle after being converted into succinyl-CoA. The pathway from propionyl-CoA to succinyl-CoA is discussed in the next chapter (Section 18.11), since propionyl-CoA is also generated during the degradation of Certain Amino Acids.

17.12. Formation of Ketone Bodies from Acetyl-CoA When Fat Breakdown Predominates

Acetyl-CoA produced by fatty acid oxidation enters the tricarboxylic acid cycle when the breakdown of fats and CARBOHYDRATES is properly balanced. The Molecular Basis of the adage that "fats burn in the flame of carbohydrates" is now clear. The entry of acetyl-CoA into the cycle depends on the availability of oxaloacetate to form citrate. However, when fat degradation predominates, The Fate of acetyl-CoA changes. This is because in the absence of carbohydrates or when their utilization is impaired, the concentration of oxaloacetate drops. During starvation or diabetes, oxaloacetate is drained off to synthesize glucose and therefore cannot condense with acetyl-CoA. Under these conditions, the metabolic pathway of acetyl-CoA is diverted toward the formation of acetoacetate and _D-3-hydroxybutyrate. Acetoacetate, _D-3-hydroxybutyrate, and acetone are frequently referred to as Ketone Bodies.

Acetoacetate is formed from acetyl-CoA in three steps. Two molecules of acetyl-CoA condense to form acetoacetyl-CoA. This reaction, catalyzed by thiolase, represents the Reversal of the thiolysis step in fatty acid oxidation. Acetoacetyl-CoA then reacts with acetyl-CoA and H₂O to yield 3-hydroxy-3-methylglutaryl-CoA and CoA. The unfavorable equilibrium in the formation of acetoacetyl-CoA is driven by the favorable equilibrium of this final reaction, which is powered by the Hydrolysis of a thioester bond. 3-Hydroxy-3-methylglutaryl-CoA is subsequently cleaved into acetyl-CoA and acetoacetate. The overall reaction for these trans-

formations is as follows:

2 Acetyl-CoA + H₂O → Acetoacetate + 2CoA + H⁺.

Reduction of acetoacetate in the mitochondrial matrix yields 3-hydroxybutyrate. The ratio of 3-hydroxybutyrate to acetoacetate depends on the [NADH]/[NAD⁺] ratio in the Cell/35.html">Mitochondria. Acetoacetate also undergoes slow spontaneous decarboxylation to acetone. In individuals with high Blood levels of acetoacetate, the breath may carry the characteristic odor of acetone.

17.13. Acetoacetate Is a Major Fuel for Certain Tissues

The Liver is the primary site of acetoacetate and 3-hydroxybutyrate synthesis. These compounds diffuse out of liver mitochondria into the blood and are transported to peripheral Tissues. Until a few years ago, ketone bodies were considered to be mere degradation waste products of little physiological significance. However, studies by George Cahill and others have demonstrated that these derivatives of acetyl-CoA play a vital role in METABOLISM/26.html">Energy Metabolism. Acetoacetate and 3-hydroxybutyrate normally function as respiratory fuels and serve as quantitatively important sources of energy. In fact, cardiac Muscle and the renal cortex preferentially utilize acetoacetate rather than glucose. In contrast, glucose is the primary fuel for the Brain in well-fed individuals consuming A balanced diet. Nevertheless, during starvation and diabetes, the brain adapts to using acetoacetate. During prolonged fasting, up to 75% of the brain's Energy Requirements are met by acetoacetate.

Acetoacetate can be activated by The transfer of CoA from succinyl-CoA in a reaction catalyzed by a specific CoA transferase. Acetoacetyl-CoA is then cleaved by thiolase to yield two molecules of acetyl-CoA, which can subsequently enter the tricarboxylic acid cycle. The liver cannot supply acetoacetate to other Organs for energy because it lacks this specific CoA transferase.

Acetoacetate can be viewed as a Water-soluble, transportable form of acetyl units. Fatty acids are mobilized by adipose tissue and converted into acetyl units by the liver, which then exports them in the form of acetoacetate. As might be expected, acetoacetate also plays a regulatory role. A high blood level of acetoacetate signals an Abundance of acetyl units and leads to a decrease in The rate of lipolysis in adipose tissue.