Isoleucine branched-chain amino acid

Methyl-2-oxopentanoate =iL-leucine 3-Methyl-2-oxobutanoate =iL-valine 3-Methyl-2-oxovalerate =iL-isoleucine ) Branched-chain-amino-acid aminotransferase L-Glutamate... 

Herbicides also inhibit 5- (9/-pymvylshikiniate synthase, a susceptible en2yme in the pathway to the aromatic amino acids, phenylalanine, tyrosine and tryptophan, and to the phenylpropanes. Acetolactate synthase, or acetohydroxy acid synthase, a key en2yme in the synthesis of the branched-chain amino acids isoleucine and valine, is also sensitive to some herbicides. Glyphosate (26), the sulfonylureas (136), and the imida2oles (137) all inhibit specific en2ymes in amino acid synthesis pathways. 

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. 

Similar to the work described by Spohn et al. [34], a trienzyme sensor was developed recently for the determination of branched-chain amino acids (L-valine, L-leucine, and L-isoleucine). Leucine dehydrogenase, NADH oxidase, and peroxidase were coimmobilized covalently on tresylate-hydrophylic vinyl polymer beads and packed into a transparent PILL tube (20 cm X 1.0 id), which was used as flow cell. The sensor was free of interferences from protein and NH4+ and it was stable for 2 weeks. The sensor system was applied to the determination of branched-chain amino acids in plasma with recoveries ranging from 98 to 100% [36],... 

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... 

Elimination reactions (Figure 5.7) often result in the formation of carbon-carbon double bonds, isomerizations involve intramolecular shifts of hydrogen atoms to change the position of a double bond, as in the aldose-ketose isomerization involving an enediolate anion intermediate, while rearrangements break and reform carbon-carbon bonds, as illustrated for the side-chain displacement involved in the biosynthesis of the branched chain amino acids valine and isoleucine. Finally, we have reactions that involve generation of resonance-stabilized nucleophilic carbanions (enolate anions), followed by their addition to an electrophilic carbon (such as the carbonyl carbon atoms... 

Transaminase enzymes (also called aminotransferases) specifically use 2-oxoglutarate as the amino group acceptor to generate glutamate but some have a wide specificity with respect to the amino donor. For example, the three branched-chain amino acids leucine, isoleucine and valine, all serve as substrates for the same enzyme, branched-chain amino acid transaminase, BCAAT ... 

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). 

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 aliphatic amino acids (class 1) include glycine, alanine, valine, leucine, and isoleucine. These amino acids do not contain heteroatoms (N, 0, or S) in their side chains and do not contain a ring system. Their side chains are markedly apolar. Together with threonine (see below), valine, leucine, and isoleucine form the group of branched-chain amino acids. The sulfurcontaining amino acids cysteine and methionine (class 11), are also apolar. However, in the case of cysteine, this only applies to the undissociated state. Due to its ability to form disulfide bonds, cysteine plays an important role in the stabilization of proteins (see p. 72). Two cysteine residues linked by a disulfide bridge are referred to as cystine (not shown). 

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.

Branched Chain Amino Acid Biosynthesis. The branched chain amino acids, leucine, isoleucine and valine, are produced by similar biosynthetic pathways (Figure 2.11). In one pathway, acetolactate is produced from pyruvate and in the other acetohydroxybutyrate is produced from threonine. Both reactions are catalysed by the same enzyme that is known as both acetolactate synthase (ALS) and acetohy-droxy acid synthase (AHAS). 

Additional or different labeled and unlabeled standards can be used. However, note that the incubation as described here includes isotopically labeled L-valine and L-isoleucine and that the metabolites of these branched chain amino acids can interfere with isotopically labeled internal standards for butyrylcarnitine or propi-onylcarnitine. 

FIGURE 18-28 Catabolic pathways for the three branched-chain amino acids valine, isoleucine, and leucine. The three pathways, which occur in extrahepatic tissues, share the first two enzymes, as shown here. The branched-chain -keto acid dehydrogenase complex... 

When Rinaldo analyzed Ryan s blood serum, he found high concentrations of methylmalonic acid, a breakdown product of the branched-chain amino acids isoleucine and valine, which accumulates in MMA patients because the enzyme that should convert it to the next product in the metabolic pathway is defective. And particularly telling, he says, the child s blood and urine contained massive amounts of ketones, another metabolic consequence of the disease. Like Shoemaker, he did not find any ethylene glycol in a sample of the baby s bodily fluids. The bottle couldn t be tested, since it had mysteriously disappeared. Ri-naldo s analyses convinced him that Ryan had died from MMA, but how to account for the results from two labs, indicating that the boy had ethylene glycol in his blood Could they both be wrong ... 

The branched-chain amino acids (isoleucine, leucine, and valine), unlike the other amino acids, are degraded only in extrahepatic tissues. 

Valine and isoleucine are branched-chain amino acids that yield succinyl CoA (Figure 20.10). 

Leucine is exclusively ketogenic in its catabolism, forming acetyl CoA and acetoacetate (see Figure 20.10). The initial steps in the catabolism of leucine are similar to those of the other branched-chain amino acids, isoleucine and valine (see below). 

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). 

Treatment The disease is treated with a synthetic formula that contains limited amounts of leucine, isoleucine, and valine—sufficient to provide the branched-chain amino acids necessary for normal growth and development without producing toxic levels. Infants suspected of having any form of MSUD should be tested within 24 hours of birth. Early diagnosis and treatment is essential if the child with MSUD is to develop normally. 

As indicated in Fig. 24-17, pyruvate is the starting material for the formation of both l- and D-alanine and also the branched chain amino acids valine, leucine, and isoleucine.339,340 The chemistry of the reactions has been discussed in the sections indicated in the figure. The first step is catalyzed by the thiamin diphosphate-dependent acetohydroxyacid synthase (acetolactate synthase), which joins two molecules of pyruvate or one of pyruvate and one of 2-oxobutyrate (Fig. 24-17 Fig. 14-3).340a b In E. coli there are two isoenzymes encoded by genes ilv B and ilv HI. Both are regulated by feedback inhibition by valine, probably... 

In a rare autosomal recessive condition (discovered in 1954) the urine and perspiration has a maple syrup odor/ High concentrations of the branched-chain 2-oxoacids formed by transamination of valine, leucine, and isoleucine are present, and the odor arises from decomposition products of these acids. The branched-chain amino acids as well as the related alcohols also accumulate in the blood and are found in the urine. The biochemical defect lies in the enzyme catalyzing oxidative decarboxylation of the oxoacids, as is indicated in Fig. 24-18. Insertions, deletions, and substitutions may be present in any of the subunits (Figs. 15-14,15-15). The disease which may affect one person in 200,000, is usually fatal in early childhood if untreated. Children suffer seizures, mental retardation, and coma. They may survive on a low-protein (gelatin) diet supplemented with essential amino acids, but treatment is difficult and a sudden relapse is apt to prove fatal. Some patients respond to administration of thiamin at 20 times the normal daily requirement. The branched-chain oxoacid dehydrogenase from some of these children shows a reduced affinity for the essential coenzyme thiamin diphosphate.d... 

For example, alkaponuria is characterized by homogentisic acid in urine phenylketonuria, which results in mental retardation, is characterized by quantities of phenylpyruvic acid in the urine. It is diagnosed in a suspected patient by determining the amount of this acid in the urine and the increased levels of phenylalanine in the plasma. Maple sugar disease is diagnosed the presence of large amounts of the branched chain amino acids, such as valine, leucine, and isoleucine in the blood and urine. 

Free amino acids are further catabolized into several volatile flavor compounds. However, the pathways involved are not fully known. A detailed summary of the various studies on the role of the catabolism of amino acids in cheese flavor development was published by Curtin and McSweeney (2004). Two major pathways have been suggested (1) aminotransferase or lyase activity and (2) deamination or decarboxylation. Aminotransferase activity results in the formation of a-ketoacids and glutamic acid. The a-ketoacids are further degraded to flavor compounds such as hydroxy acids, aldehydes, and carboxylic acids. a-Ketoacids from methionine, branched-chain amino acids (leucine, isoleucine, and valine), or aromatic amino acids (phenylalanine, tyrosine, and tryptophan) serve as the precursors to volatile flavor compounds (Yvon and Rijnen, 2001). Volatile sulfur compounds are primarily formed from methionine. Methanethiol, which at low concentrations, contributes to the characteristic flavor of Cheddar cheese, is formed from the catabolism of methionine (Curtin and McSweeney, 2004 Weimer et al., 1999). Furthermore, bacterial lyases also metabolize methionine to a-ketobutyrate, methanethiol, and ammonia (Tanaka et al., 1985). On catabolism by aminotransferase, aromatic amino acids yield volatile flavor compounds such as benzalde-hyde, phenylacetate, phenylethanol, phenyllactate, etc. Deamination reactions also result in a-ketoacids and ammonia, which add to the flavor of... 

As discussed earlier, the avermectin polyketide backbone is derived from seven acetate and five propionate extender units added to an a branched-chain fatty acid starter, which is either (S( I )-a-mcthylbutyric acid or isobutyric acid. The C25 position of naturally occurring avermectins has two possible substituents a. sec-butyl residue derived from the incorporation of S(+)-a-methy lbutyry 1-CoA ( a avermectins), or an isopropyl residue derived from the incorporation of isobutyiyl-CoA ( b avermectins). These a branched-chain fatty acids, which act as starter units in the biosynthesis of the polyketide ring, are derived from the a branched-chain amino acids isoleucine and valine through a branched-chain amino acid transaminase reaction followed by a branched-chain a-keto acid dehydrogenase (BCDH) reaction (Fig. 5) [23]. 

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