Branched chain, metabolism

METABOLIC DISORDERS OF BRANCHED-CHAIN AMINO ACID CATABOLISM... 

The catabolism of leucine, valine, and isoleucine presents many analogies to fatty acid catabolism. Metabolic disorders of branched-chain amino acid catabolism include hypervalinemia, maple syrup urine disease, intermittent branched-chain ketonuria, isovaleric acidemia, and methylmalonic aciduria. 

Skeletal muscle is the principal site of metabolism of branched-chain amino acids, which are used as an energy source. 

Liver metabolism is affected by methylxanthines. In high doses, theophylline and caffeine increase the level of cyclic AMP. Very high levels of methylxanthines decrease the level of branched chain and aromatic amino acids in plasma. Coffee appears to have little effect on ethanol metabolism. 

Many organic acidurias originate in the breakdown of the three branched-chain amino acids, leucine, isoleucine and valine (Fig. 40-1). Metabolism of the organic acids requires the presence of specific enzymes, congenital... 

Effective treatment of maple syrup urine disease involves the restriction of dietary branched-chain amino acids. Long-term treatment entails the dietary restriction of the BCAAs. This is accomplished by administration of a special formula from which these amino acids are removed. The outlook for intellectual development is favorable in youngsters in whom diagnosis is made early and who do not suffer recurrent, severe episodes of metabolic decompensation [17]. 

Gene therapy for this metabolic defect may become available within the next few years. In vitro studies have demonstrated the feasibility of retroviral-mediated gene transfer of both the El-a and E2 subunits of the branched-chain decarboxylase complex [16,18],... 

One could plunge into the steric problems posed by the mechanism of protein synthesis on the ribosome 25 26)> or consider the steric fit of the hormone insulin to its acceptor in the cell membrane 27>. Or one could delve into the beautiful intricacy of terpenoid, squalene and steroid metabolism, or get lost in double bond formation, or in the steric problems posed by the branched chain fatty acids and their derivatives 28-34). 

Valine (Val or V) ((5)-2-amino-3-methyl-butanoic acid) is a nonpolar, neutral, aliphatic amino acid with the formula HOOCCH(NH2)CH(CH3)2. Along with Leu and He, Val is a branched-chain amino acid and is found in high concentrations in the muscles. Val is needed for muscle metabolism and coordination, tissue repair, and for the maintenance of proper nitrogen balance in the body. ° The steric hindrance present in Val and He (caused by branching) lowers the rate of coupling reactions, resulting in an increase in side reactions. ... 

Valine, leucine, and isoleucine are branched-chain amino adds whose metabolism is abnormal in maple syrup urine disease (discussed in Chapter 17). 

Liver Liver is the major organ for metabolism of almost all amino acids the exception is the branched-chain amino acids which are metabolised in muscle and adipose tissue (see Chapter 8). Of the amino acids absorbed from the lumen of the intestine in the adult, at least 70% are metabolised in the liver. Transporters for almost all amino acids are, therefore, very active in the membranes of hepatocytes. 

The major role of skeletal muscle is movement, which is described and discussed in Chapter 13). Nevertheless, since muscle comprises 40% of the body it is large enough to play a part in control of the blood concentrations of the major fuels glucose, fatty acids, triacylglycerol and some amino acids. Skeletal muscle contains the largest quantity of protein in the body, which is used as a source of amino acids under various conditions (e.g. starvation, trauma, cancer see above). It plays an important part in the metabolism, in particular, of branched-chain amino acids, glutamine and alanine, which are important in the overall metabolism of amino acids in the body (discussed below). 

Branched-chain amino acid metabolism in muscle and liver... 

Figure 8.17 The metabolism of branched-chain amino acids in muscle and the fate of the nitrogen and oxoacids. The a-NH2 group is transferred to form glutamate which is then aminated to form glutamine. The ammonia required for aminab on arises from glutamate via glutamate dehydrogenase, but originally from the transamination of the branded chain amino acids. Hence, they provide both nitrogen atoms for glutamine formation.

Patients snffering from metabolic disorders such as phenylketonuria (PKU), branched-chain ketoaciduria (maple syrup urine disease, MSUD), nrea and ammonia disorders or glycogen storage disease reqnire formulations manufactured specifically for each disease (Elsas Acosta, 2006). (Appendix 15.1). 

The intermediary metabolism has multienzyme complexes which, in a complex reaction, catalyze the oxidative decarboxylation of 2-oxoacids and the transfer to coenzyme A of the acyl residue produced. NAD" acts as the electron acceptor. In addition, thiamine diphosphate, lipoamide, and FAD are also involved in the reaction. The oxoacid dehydrogenases include a) the pyruvate dehydrogenase complex (PDH, pyruvate acetyl CoA), b) the 2-oxoglutarate dehydrogenase complex of the tricarboxylic acid cycle (ODH, 2-oxoglutarate succinyl CoA), and c) the branched chain dehydrogenase complex, which is involved in the catabolism of valine, leucine, and isoleucine (see p. 414). 

The acyl-Co A dehydrogenases are a family of mitochondrial flavoenzymes involved in fatty acid and branched chain amino-acid metabolism. In addition to long chain acyl-Co A dehydrogenases (LCADs), there are short/ branched chain acyl-CoA dehydrogenase (SBCAD) that act on 2-methyl branched chain acyl-CoA substrates of varying chain lengths. 

C. The branched-chain amino acids Leu, He, and Val share a common pathway for metabolism, which occurs in the peripheral tissues, such as muscle, rather than in the liver (Figure 9-4). 

At this point, the pathways for branched-chain amino acid metabolism diverge. 

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.

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