Isoleucine oxidation

Fatty acids with odd numbers of carbon atoms are rare in mammals, but fairly common in plants and marine organisms. Humans and animals whose diets include these food sources metabolize odd-carbon fatty acids via the /3-oxida-tion pathway. The final product of /3-oxidation in this case is the 3-carbon pro-pionyl-CoA instead of acetyl-CoA. Three specialized enzymes then carry out the reactions that convert propionyl-CoA to succinyl-CoA, a TCA cycle intermediate. (Because propionyl-CoA is a degradation product of methionine, valine, and isoleucine, this sequence of reactions is also important in amino acid catabolism, as we shall see in Chapter 26.) The pathway involves an initial carboxylation at the a-carbon of propionyl-CoA to produce D-methylmalonyl-CoA (Figure 24.19). The reaction is catalyzed by a biotin-dependent enzyme, propionyl-CoA carboxylase. The mechanism involves ATP-driven carboxylation of biotin at Nj, followed by nucleophilic attack by the a-carbanion of propi-onyl-CoA in a stereo-specific manner. 

A concise and efficient asymmetric synthesis of L-( + )-carbafuranomycin 452, a novel analog of L-( + )-furanomycin, which is an unusual antibiotic amino acid of great interest, due to its activity as an isoleucine antagonist, has been reported (496). The synthesis starts with the 1,3-dipolar cycloaddition of a chiral nitrile oxide (obtained in situ from hydroximinoyl chloride 453 via slow addition of NEt3) with cyclopentadiene. Then methylation of cyclopentenyl acetate 454,... 

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 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). 

Natural sesquiterpene pyridine alkaloid formation needs two precursors, one for the pyridinium moiety and another for the sesquiterpene moiety. The a for formation of the pyridinium moiety is nicotinic acid, which reacts with isoleucine and, by oxidative reaction, produces evoninic acid, wilfordic acid or edulinic acids, a for the sesquiterpene moiety is still open to question, but E, E-famesyl cation has been suggested as one possibility and hedycarylol as a second. This moiety is dihydroagarofuran. Therefore, a for the sesquiterpene pyridine alkaloids is nicotinic acid and E, E-famesyl cation and, controversially, hedycaryol. The /3 is amacrocycling ring formation substance (two moieties), from which the alkaloid forms (Figure 62). 

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.

Table 3.1.3 Pathologic acylglycine species detected by organic acid analysis. CoA coenzyme A, FAO fatty acid oxidation, ILE isoleucine, LEU Leucine, MCAD medium-chain acyl-CoA dehydrogenase, MET methionine,...

Portions of the carbon skeletons of seven amino acids— tryptophan, lysine, phenylalanine, tyrosine, leucine, isoleucine, and threonine—yield acetyl-CoA and/or acetoacetyl-CoA, the latter being converted to acetyl-CoA (Fig. 18-21). Some of the final steps in the degrada-tive pathways for leucine, lysine, and tryptophan resemble steps in the oxidation of fatty acids. Threonine (not shown in Fig. 18-21) yields some acetyl-CoA via the minor pathway illustrated in Figure 18-19. 

NAD+ serves as the oxidant. The reaction is catalyzed by a complex of enzymes whose molecular mass varies from 4 to 10 x 106, depending on the species and exact substrate.297 Separate oxoacid dehydrogenase systems are known for pyruvate,298-300 2-oxoglut-arate,301 and the 2-oxoacids with branched side chains derived metabolically from leucine, isoleucine, and... 

Degradation of amino acids most often begins with conversion, either by transamination3563 or by NAD+-dependent dehydrogenation,357 to the corresponding 2-oxoacid and oxidative decarboxylation of the latter (Fig. 15-16). Alanine, valine, leucine, and isoleucine are all treated this way in the animal body. Alanine gives pyruvate and acetyl-CoA directly, but the others yield CoA derivatives that undergo... 

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... 

In the degradation of isoleucine, (3 oxidation proceeds to completion in the normal way with generation of acetyl-CoA and propionyl-CoA. However, in the catabolism of leucine after the initial dehydrogenation in the (3-oxidation sequence, carbon dioxide is added using a biotin enzyme (Chapter 14). The double bond conjugated with the carbonyl of the thioester makes this carboxylation analogous to a standard (3-carboxylation reaction. Why add the extra C02 ... 

Several deadly species of the genus Amanita produce colorless toxic octapeptides, the amani-tins.a b Two residues of glycine, one of L-isoleucine, one of the unusual L-dihydroxyisoleucine, one of L-asparagine, and one of L-hydroxyproline are present in a-amanitin. In the center a modified tryptophan residue has been combined oxidatively with an SH group of a cysteine residue. If the dihy-droxyisoleucine residue of a-amanitin is replaced with unhydroxylated leucine, the resulting compound, known as amanullin, is nontoxic. The LD50 for mice is 0.3 mg kg 1 and 50 g of fresh Amanita phalloides may be sufficient to kill a person. Arnan-itins act slowly, and it is impossible to kill mice in less than 15 h, no matter how high the dose. 

By this means, it has been found that the excess of L-isoleucine has two distinct effects—one that is relatively slow, and unothcr that is rapid. The slower effect is to repress production by the cell of all the enzymes required io catalyze the series of biochemical reactions in the metabolic pathway by which the cell synthesizes L-isoleucine. The Iasi effect is to inhibit production of the enzyme for the first reaction ill the series. This enzyme is L-thrconinc deaminase, which removes the amino group from L-threonine. as a preliminary step to iis oxidation and reimroduction of (he amino group, in order to produce L-isolcucine from it. 

The oxidation of L-norleucine, L-leucine, L-isoleucine, and r.-r-leucine with permanganate in strong acid medium showed an autocatalysis by Mn(II), except in the case of L-leucine. For the autocatalytic activity to initiate, a certain concentration of Mn(II) is required. Moreover, the autocatalytic phenomenon vanishes in concentrations of sulfuric acid that are greater than 4.3 mol dm-3. The oxidation showed a good correlation in a biparametric equation, with p = -4.57 and Sc = 2.23 at 318 K.43... 

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