Alanine metabolic fate

Pyruvate has several metabolic fates. It can be reduced to lactate, converted to oxaloacetate in a reaction important in gluconeogenesis (Chapter 15) and in an anaplerotic reaction of the TC A cycle (see below), transminated to alanine (Chapter 17), or converted to acetyl-CoA and CO2. Acetyl-CoA is utilized in fatty acid synthesis, cholesterol (and steroid) synthesis, acetylcholine synthesis, and the TCA cycle (Figure 13-6). 

In tissues other than the RBC, pyruvate has alternative metabolic fates that, depending on the tissue, include gluconeogenesis, conversion to acetyl-CoA by pyruvate dehydrogenase for further metabolism to CO in the tricarboxylic acid (TCA) cycle, transamination to alanine or carboxylation to oxaloacetate by pyruvate carboxylase (Table 23-1). In the RBC, however, the restricted enzymatic endowment precludes all but the conversion to lactate. The pyruvate and lactate produced are end products of RBC glycolysis that are transported out of the RBC to the liver where they can undergo the alternative metabolic conversions described above. 

Figure 4. Schematic representation of the metabolic fate of alanine in hepatocytes. Note that striking differences may exist between mammalian cell types on the one hand and individual amino acids on the other (see text). Solid and broken arrow lines refer to metabolic conversions and transport routes, respectively, and circles in membranes refer to specific transporters. Numbers refer to enzymes involved in alanine metabolism 1, alanine transaminase 2, pyruvate carboxylase 3, malate dehydrogenase 4, glutamate dehydrogenase 5, glutamine synthetase.

Alanine is the simplest L-amino acid found in protein. It has a simple metabolism, but complex physiological roles and functions. Alanine can transaminate reversibly with a-ketoglutarate, forming pyruvate and glutamate. This transamination occurs in many tissues, including liver and muscle. This is the only metabolic fate of pyruvate, other than protein synthesis. Therefore, alanine is glucogenic and is not required in the diet. 

Figure 9-3. Fates of the carbon skeletons upon metabolism of the amino acids. Points of entry at various steps of the tricarboxylic acid (TCA) cycle, glycolysis and gluconeogenesis are shown for the carbons skeletons of the amino acids. Note the multiple fates of the glucogenic amino acids glycine (Gly), serine (Ser), and threonine (Thr) as well as the combined glucogenic and ketogenic amino acids phenylalanine (Phe), tryptophan (Trp), and tyrosine (Tyr). Ala, alanine Cys, cysteine lie, isoleucine Leu, leucine Lys, lysine Asn, asparagine Asp, aspartate Arg, arginine His, histidine Glu, glutamate Gin, glutamine Pro, proline Val, valine Met, methionine.

In mammals, muscle breakdown or excess protein intake results in an imbalance between the fates of the carbon chains and the amino nitrogen. Unlike fat (lipid storage) or glycogen (carbohydrate storage), excess amino acids are not stored in polymeric form for later utilization. The carbon chains of amino acids are generally metabolized into tricarboxylic acid (TCA) cycle intermediates, although it is also possible to make ketone bodies such as acetoacetate from some. Conversion to TCA intermediates is easy to see in some instances. For example, alanine is directly transaminated to pyruvate. 

Apart from glutamate, asdocytes also uptake neurodans-mitters like gamma amino butyric acid (GABA), aspartate, taurine, [3-alanine, serotonin, and catecholamines. The fate of all these neurodansmitters is to be metabolized within asdocytes. 

Joy and his colleagues have also monitored the fate of the asparagine carbon skeleton. Almost 75% of the [ CJasparagine supplied was metabolized in 210 min in the light but only 45% in the dark. Over 50% of the metabolized asparagine accumulated in a novel compound 2-hydroxysuccinamate (see Section III,C,2). 2-Oxosuccinamic acid was shown to be a precursor of 2-hydroxysuccinamic acid. Other amino acids were also labeled particularly aspartate, with lesser amounts in glutamate, homoserine, and alanine. 2-Hydroxysuccinamate was only slowly metabolized (approximately 20% in 210 min) although there was evidence of more rapid breakdown in the dark (Lloyd and Joy, 1978). 

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. 

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