Amino acid degradation acetoacetate

Figure 9-4. Metabolism of the branched-chain amino acids. The first two reactions, transamination and oxidative decarboxylation, are catalyzed by the same enzyme in all cases. Details are provided only for isoleucine. Further metabolism of isoleucine and valine follows a common pathway to propionyl CoA. Subsequent steps in the leucine degradative pathway diverge to yield acetoacetate. An intermediate in the pathway is 3-hydroxy-3-methylglutaryl CoA (HMG-CoA), which is a precursor for cytosolic cholesterol biosynthesis.

The degradation of the aromatic amino acids is not as straightforward as that of the amino acids previously discussed, although the final products—acetoacetate, fumarate, and pyruvate—are common intermediates. For the aromatic amino acids, molecular oxygen is used to break an aromatic ring. 

How does the liver meet its ovm energy needs a-Ketoacids derived from the degradation of amino acids are the liver s own fuel. In fact, the main role of glycolysis in the liver is to form building blocks for biosyntheses. Furthermore, the liver cannot use acetoacetate as a fuel, because it has little of the transferase needed for acetoacetate s activation to acetyl CoA. Thus, the liver eschews the fuels that it exports to muscle and the brain. 

The major products obtained by degradation of the carbon skeletons of the amino acids are pyruvate, intermediates of the TCA cycle, acetyl CoA, and acetoacetate (Figure 7-7). 

Figure 7-11. Degradation of the branched-chain amino acids. Valine forms propionyl CoA. Isoleucine forms pro-pionyl CoA and acetyl CoA. Leucine forms acetoacetate and acetyl CoA.

Four amino acids (lysine, threonine, isoleucine, and tryptophan) can form acetyl CoA, and phenylalanine and tyrosine form acetoacetate. Leucine is degraded to form both acetyl CoA and acetoacetate. 

Although diverse in structure, most amino acids lead to a few central compounds that flow into the major metabolic pathways. All of them effectively produce pyruvate, a-ketoglutarate, oxaloacetate, succinate, fumarate, acetoacetate, or acetyl CoA (Fig. 19.6). Therefore, a large number of unusual compounds are not formed, which would require a new set of enzymatic machinery for metabolism. This is also advantageous because the carbons from degraded amino acids can be funneled into the major pathways of metabolism with normal metabolic controls. 

Acetyl CoA serves as a common point of convergence for the major pathways of fuel oxidation. It is generated directly from the (3-oxidation of fatty acids and degradation of the ketone bodies (3-hydroxybutyrate and acetoacetate (Fig. 20.14). It is also formed from acetate, which can arise from the diet or from ethanol oxidation. Glucose and other carbohydrates enter glycolysis, a pathway common to all cells, and are oxidized to pyruvate. The amino acids alanine and serine are also converted to pyruvate. Pyruvate is oxidized to acetyl CoA by the pyruvate dehydrogenase complex. A number of amino acids, such as leucine and isoleucine are also oxidized to acetyl CoA. Thus, the final oxidation of acetyl CoA to CO2 in the TCA cycle is the last step in all the major pathways of fuel oxidation. 

The pathways involved in the catabolism of the individual amino acids range from one-step reactions, such as with aspartate, glutamate, and alanine, which use the appropriate amino transferases, to multistep pathways of the aromatic amino acids and lysine (e.g., tyrosine is degraded in four steps to acetoacetate and fumarate). 

P-Hydroxybutyrate dehydrogenase (located in mitochondria) catalyses the conversion of acetoacetate to P-hydroxybutyrate. Acetone is formed by the spontaneous decarboxylation of acetoacetate (Fig. 1). Acetoacetate is also produced by degradation of the keto-plastic amino acids, leucine, isoleucine, phenylalanine and tyrosine. 

Nutritional Significance of the Amino Acids.— By means of feeding experiments on normal and diabetic animals it is possible to determine which amino acids are essential for life, and also which are capable of being converted into glucose or into acetoacetic acid. Experiments on the degradation of amino acids by surviving tissues afiord information as to the course of their metabolism, and this is supplemented by a study of the inborn metabolic diseases in which the subject is unable to metabolise one or more of the natural amino acids. 

Valine, isoleucine, and leucine are degraded in a quite analogous manner. Acti-yated fatty acids shortened by one C atom are treated in metabolism in essentially the same way as ordinary fatty acids. The only problem is raised by amino acids with a methyl group as a side chain of the carbon skeleton. We will discuss their degradation in connection with j3-oxidation of fatty acids (Chapt. XII-5). As mentioned already, leucine is converted to acetoacetate, isoleucine partially so. Valine, however, becomes methylmalonate, and is changed further by a rearrangement of the carboxyl group to succinate the way to the carbohydrates is thereby opened. 

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