Muscle isoleucine

In a muscle at rest, most of the 2-oxo acids produced from transamination of branched chain amino acids are transported to the liver and become subject to oxidation in reactions catalysed by branched-chain 2-oxo acid dehydrogenase complex. During periods of exercise, however, the skeletal muscle itself is able to utilize the oxo-acids by conversion into either acetyl-CoA (leucine and isoleucine) or succinyl-CoA (valine and isoleucine). 

The long tail of myosin contains a high proportion of the amino acids leucine, isoleucine, aspartate and glutamate. These are released upon the degradation of myosin by intracellular proteases and peptidases and they provide nitrogen for the synthesis of glutamine. It is then stored in muscle and is a very important fuel for immune cells (Chapter 17). 

Branched-chain amino acids are leucine, isoleucine and valine the increased concentrations are also consistent with an increased rate of degradation, as muscle protein contains a high proportion of these amino acids. The extent of the decrease in ATP concentration is even greater than in exaustive physical activity. Note the very large fall is glutamine concentration. 

The branched-chain amino acids, isoleucine, leucine, and valine, are essential amino acids. In contrast to other amino acids, they are metabolized primarily by the peripheral tissues (particularly muscle), rather than by the liver. Because these three amino acids have a similar route of catabolism, it is convenient to describe them as a group (see Figure 20.10). 

Phospholamban is a homopentameric membrane protein involved in muscle contraction through regulation of the calcium pump in cardiac muscle cells. The stmcture of the unphospho-rylated protein solved in DPC micelles reveals a symmetric pentamer of phospholamban monomers (Fig. 2g) stabilized by leucine/isoleucine zipper motifs along the transmembrane domains (51). Notably, another stmcture was produced for phospholamban (Fig. 2h) that used a variant of the traditional simulated annealing and molecular dynamics protocol that reduced the chances of entrapment in local minima (52). 

The liver also plays an essential role in dietary amino acid metabolism. The liver absorbs the majority of amino acids, leaving some in the blood for peripheral tissues. The priority use of amino acids is for protein synthesis rather than catabolism. By what means are amino acids directed to protein synthesis in preference to use as a fuel The K jyj value for the aminoacyl-tRNA synthetases is lower than that of the enzymes taking part in amino acid catabolism. Thus, amino acids are used to synthesize aminoacyl-tRNAs before they are catabolized. When catabolism does take place, the first step is the removal of nitrogen, which is subsequently processed to urea. The liver secretes from 20 to 30 g of urea a day. The a-ketoacids are then used for gluconeogenesis or fatty acid synthesis. Interestingly, the liver cannot remove nitrogen from the branch-chain amino acids (leucine, isoleucine, and valine). Transamination takes place in the muscle. 

Isoleucine is required for muscle strength and stamina, is used as an energy source for muscle tissue, and is needed to produce hemoglobin. 

Because the hver metabohzes the aromatic amino acids (i.e., phenylalanine, tyrosine, and tryptophan), methionine, and glutamine, the plasma concentrations of these amino acids are elevated in cirrhotic patients. Plasma concentrations of the branched-chain amino acids (BCAAs) (i.e., valine, leucine, and isoleucine) often are depressed because these amino acids are metabohzed by skeletal muscle. This altered plasma aminogram contributes to the development of hepatic encephalopathy. 

C. Leucine but none of the other amino acids listed is a branched-chain amino acid. The muscle has a very active branched-chain amino acid metabolic pathway and uses that pathway to provide energy for its own use. The products of leucine metabolism are acetyl-CoA and acetoacetate, which are used in the tricarboxylic acid cycle. Acetoacetate is activated by succinyl-CoA and cleaved to two molecules of acetyl-CoA in the P-ketothiolase reaction. The other branched-chain amino acids, valine, and isoleucine, yield succinyl-CoA and acetyl-CoA as products of their catabolism. 

Certain amino acids are preferentially used in a tissue-specific manner. For example, skeletal muscle has a relatively high capacity for branched-chain amino acid (leucine, isoleucine, and valine) utilization. Following... 

Leucine is an essential, branched-chain amino acid that does not compete with tryptophan for nuclear tryptophan receptor binding in vitro.196 However, the addition of L-leucine to unlabeled L-tryptophan caused significantly less inhibition of 3H-tryptophan binding in vitro to hepatic nuclei than did unlabeled L-tryptophan alone.186 Also, L-isoleucine and L-valine revealed binding effects similar to that with L-leucine. In regard to hepatic protein synthesis, L-leucine alone has no effect, yet when added with L-tryp-tophan, it inhibits the increase of protein synthesis due to L-tryptophan alone. The mechanisms by which L-leucine acts are not yet clear. It does not appear to be related to altered transport of L-tryptophan, as can occur with branched-chain amino acids. Although L-leucine does not stimulate hepatic protein synthesis, it has been reported to stimulate muscle protein synthesis.188 Whether this effect of L-leucine on muscle may influence the liver response is not clear. 

The branched-chain amino acids, leucine, isoleucine, and valine, are metabolized similarly. They are transaminated, primarily in the muscle, then oxidatively decarboxylated to a branched-chain fatty-acyl CoA in... 

The branched-chain amino acids, or BCAA (valine, isoleucine, and leucine) are oxidized principally in skeletal muscle and other tissues and not in the liver. In skeletal muscle, the carbon skeletons and some of the nitrogen are converted to glutamine, which is released into the blood. The remainder of the nitrogen is incorporated into alanine, which is taken up by the liver and convened to urea and glucose. 

The efflux of amino acids from skeletal muscle supports the essential amino acid pool in the blood (see Fig. 42.3). Skeletal muscle oxidizes the BCAA (valine, leucine, isoleucine) to produce energy and glutamine. The amino groups of the BCAA, and of aspartate and glutamate, are transferred out of skeletal muscle in alanine and glutamine. Alanine and glutamine account for approximately 50% of the total a-amino nitrogen released by skeletal muscle (Fig. 42.4). 

The oxidative pathways of the BCAA convert the carbon skeleton to either suc-cinyl CoA or acetyl CoA (see Chapter 39 and Fig. 42.9). The pathways generate NADH and FAD(2H) for ATP synthesis before the conversion of carbon into intermediates of the TCA cycle, thus providing the muscle with euergy without loss of carbou as CO2. Leucine is ketogenic in that it is converted to acetyl CoA and ace-toacetate. Skeletal muscle, adipocytes, and most other tissues are able to use these products aud, therefore, directly oxidize leuciue to CO2. The portiou of isoleucine converted to acetyl CoA is also oxidized directly to CO2. For the portion of valine and isoleucine that enters the TCA cycle as succinyl CoA to be completely oxidized to CO2, it must first be converted to acetyl CoA. To form acetyl CoA, succinyl CoA is oxidized to malate in the TCA cycle, and malate is then converted to pyruvate by malic enzyme (malate + NADP pyruvate + NADPH + H ) (see Fig. 42.9). Pyruvate can then be oxidized to acetyl CoA. Alternatively, pyruvate can form alanine or lactate. 

The major route of valine and isoleucine catabolism in skeletal muscle is to enter the TCA cycle as succinyl CoA and exit as a-ketoglutarate to provide the carbon skeleton for glutamine formation (see Fig. 42.9). Some of the glutamine and CO2 that is formed from net protein degradation in skeletal muscle may also arise from... 

Fig. 42.9. Metabolism of the carbon skeletons of BCAA in skeletal muscle. 1. The first step in the metabolism of BCAA is transamination (TA). 2. Carbon from valine and isoleucine enters the TCA cycle as succinyl CoA and is converted to pyruvate by decarboxylating malate dehydrogenase (malic enzyme). 3. The oxidative pathways generate NADH and FAD(2H) even before the carbon skeleton enters the TCA cycle. The rate-limiting enzyme in the oxidative pathways is the a-keto acid dehydrogenase complex. The carbon skeleton also can be converted to glutamate and alanine, shown in blue.

Some of the alanine released from skeletal muscle is derived directly from protein degradation. The carbon skeletons of valine, isoleucine, aspartate, and glutamate, which are converted to malate and oxaloacetate in the TCA cycle, can be converted to pyruvate and subsequently transaminated to alanine. The extent to which these amino acids contribute carbon to alanine efflux differs between different types of muscles in the human. These amino acids also may contribute to alanine efflux from the gut. 

The branched-chain amino acids (valine, leucine, and isoleucine) can be used by most cell types as a fuel, including cells of the gut and skeletal muscle. After a... 

Skeletal muscles use many fuels to generate ATP. The most abundant immediate source of ATP is creatine phosphate. ATP also can be generated from glycogen stores either anaerobically (generating lactate) or aerobically, in which case pyruvate is converted to acetyl CoA for oxidation via the TCA cycle. All human skeletal muscles have some mitochondria and thus are capable of fatty acid and ketone body oxidation. Skeletal muscles are also capable of completely oxidizing the carbon skeletons of alanine, aspartate, glutamate, valine, leucine, and isoleucine, but not other amino acids. Each of these fuel oxidation pathways plays a somewhat unique role in skeletal muscle metabolism. 

Some products sold in health food stores feature the presence of the branched-chain amino acids isoleucine, leucine, and valine. These are essential amino acids in the sense that the body cannot synthesize them. Under normal circumstances, a diet with adequate protein intake provides enough of all the essential amino acids. Athletes involved in intensive training want to prevent muscle loss and to increase muscle mass. As a result, they take protein supplements and pay particular attention to branched-chain amino acids. (These three amino acids are by no means the only essential ones, but they are mentioned specifically here.)... 

Oxytocin has an isoleucine at position 3 and a leucine at position 8 it stimulates smooth muscle contraction in the uterus during labor and in the mammary glands during lactation. Vasopressin has a phenylalanine at position 3... 

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