Catabolism of Amino Acids The Carbon Chains

STEP 4 OF FIGURE 20.5 ARGININE HYDROLYSIS The final step to complete the urea cycle is hydrolysis of arginine to give ornithine and urea. The reaction is catalyzed by the Mn -containing enzyme arginase and occurs by addition of H2O to the C=N bond, followed by proton transfer and elimination of ornithine from the tetrahedral intermediate. 

FIGURE 20.7 Carbon chains of the 20 common amino acids are converted into one of seven intermediates for further breakdown in the citric acid cycle. Ketogenic amino acids (red) can also enter the pathway for fatty-acid biosynthesis glucogenic amino acids (blue) can also enter the gluconeogenesis pathway for glucose biosynthesis. 

A detailed coverage of the catabolic pathways for all 20 protein amino acids would take far too much space—tryptophan catabolism alone requires 

14 steps—and would be far too complex for this book. The mechanisms of these pathways are understandable, but we won t attempt to cover them. Instead, we ll just look at several fairly straightforward schemes to see the kinds of chemistry involved in amino acid catabolism. 

Alanine is one of the six amino acids that are catabolized to give pyruvate. The pathway is a straightforward PLP-dependent transamination reaction, as discussed in Section 20.2, with the PMP intermediate then converted back to PLP by reaction with a-ketoglutarate. 

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The carbon chain of cysteine and cystine is derived from serine by a mechanism discussed in the chapter, Metabolism of Sulfur-Containing Compounds. The sole source of tyrosine for the vertebrates is phenylalanine, as is explained in the chapter. Carbon Catabolism of Amino Acids. 

Some catabolic reactions of amino acid carbon chains are easy transformations to and from TCA cycle intermediates—for example, the transamination of alanine to pyruvate. Reactions involving 1-carbon units, branched-chain, and aromatic amino acids are more complicated. This chapter starts with 1-carbon metabolism and then considers the catabolic and biosynthetic reactions of a few of the longer side chains. Amino acid metabolic pathways can present a bewildering amount of material to memorize. Perhaps fortunately, most of the more complicated pathways lie beyond the scope of an introductory course or a review such as this. Instead of a detailed listing of pathways, this chapter concentrates on general principles of amino acid metabolism, especially those that occur in more than one pathway. 

Reviews by Ruderman (19) and Adibi (20,21) indicate that the branched-chain amino acids, particularly leucine, have an important role along with alanine in gluconeogenesis. Leucine and the other two branched-chain amino acids are catabolized in skeletal muscle. The nitrogen that is removed from the branched-chain amino acids in skeletal muscle is combined with pyruvate and returned to the liver as alanine. In the liver the nitrogen is removed for urea production and the carbon chain is utilized as substrate for synthesis of glucose. Adibi et al. (22) reported that during the catabolic conditions of starvation, oxidation of leucine and fatty acids increases in skeletal muscles. While glucose oxidation is reduced, the capacity for oxidation of the fatty acid palmltate more than doubled, and leucine oxidation increased by a factor of six. 

In considering amino acid catabolism, one must distinguish the catabolism of the carbon chain from that of the nitrogen moiety. The breakdown of the carbon chain of the amino acids yields carbon units that can be used in carbohydrate metabolism, acetate metabolism, or the metabolism of single carbon units. The fate of the carbon units of the individual amino acids has been discussed in other sections of this book, and only a synopsis of the results will be presented here. The carbon skeletons of isoleucine, phenylalanine, threonine, tryptophan, valine, histidine, alanine, arginine, aspartic acid, glycine, proline, glutamic acid, and hydroxyproline are ultimately converted to pyruvic acid. 

The catabolic pathways of the carbon chains of the amino acids, alanine, glutamic, and aspartic acids, appear to be readily apparent once these amino acids lose their amino groups. When this occurs, alanine is converted to pyruvic acid, glutamic acid to a-ketoglutaric acid, and aspartic acid to either oxalacetic or fumaric acid. All of the above acids are integral members of the citric acid cycle, and the subsequent degradation of each one has been adequately explained in terms of the operation of the citric acid cycle (see the chapter. The Tricarboxylic Acid Cycle). 

With the amino group removed by transamination and the resultant ammonia converted into urea, the third and final stage of amino acid catabolism is the degradation of the carbon chains. As indicated in Figure 20.7, the carbon... 

Some amino acids enter the pathway of fatty acid catabolism after transamination or oxidative deamination. Since they give rise to branched-chain fatty acids, they undergo several changes (cf. Chapt. XII-5, and the right side of the fold-out chart). Leucine is broken down via hydroxymethylglutarate. If the shortening of the carbon chain yields propionyl-CoA, as in the case of isoleucine, then succinate can be obtained by carboxylation. 

The first stage of catabolism, digestion, takes place in the stomach and small intestine when bulk food is broken down into small molecules such as simple sugars, long-chain carboxylic acids (called fatty acids), and amino acids. In stage 2, these small molecules are further degraded in cells to yield two-carbon acetyl... 

This mitochondrial reaction permits the final steps in the catabolism of the branched-chain amino acid leucine. The final products, acetoacetate and acetyl CoA, either are oxidative metabolized to carbon dioxide and water or enter other reactions in lipid metabolism. 

These branched-chain aliphatic amino acids contain bulky nonpolar R-groups and participate in hydrophobic interactions. All three are essential amino acids. A defect in their catabolism leads to maple syrup urine disease (Chapter 17). Isoleucine has asymmetrical centers at both the a- and 8-carbons and four stereoisomers, only one of which occurs in protein. The bulky side chains tend to associate in the interior of water-soluble globular proteins. Thus, the hydrophobic amino acid residues stabilize the three-dimensional structure of the polymer. 

Propionic acid fermentation is not limited to propionibacteria it functions in vertebrates, in many species of arthropods, in some invertebrates imder anaerobic conditions (Halanker and Blomquist, 1989). In eukaryotes the propionic acid fermentation operates in reverse, providing a pathway for the catabolism of propionate formed via p-oxidation of odd-numbered fatty acids, by degradation of branched-chain amino acids (valine, isoleucine) and also produced from the carbon backbones of methionine, threonine, thymine and cholesterol (Rosenberg, 1983). The key reaction of propionic acid fermentation is the transformation of L-methylmalonyl-CoA(b) to succinyl-CoA, which requires coenzyme B12 (AdoCbl). In humans vitamin B deficit provokes a disease called pernicious anemia. 

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