Branched-chain oxo acids

In the case of hyperphenylalaninaemia, which occurs ia phenylketonuria because of a congenital absence of phenylalanine hydroxylase, the observed phenylalanine inhibition of proteia synthesis may result from competition between T.-phenylalanine and L-methionine for methionyl-/RNA. Patients sufferiag from maple symp urine disease, an inborn lack of branched chain oxo acid decarboxylase, are mentally retarded unless the condition is treated early enough. It is possible that the high level of branched-chain amino acids inhibits uptake of L-tryptophan and L-tyrosiae iato the brain. Brain iajury of mice within ten days after thek bkth was reported as a result of hypodermic kijections of monosodium glutamate (MSG) (0.5—4 g/kg). However, the FDA concluded that MSG is a safe kigredient, because mice are bom with underdeveloped brains regardless of MSG kijections (106). 

Additional information <2> (<2> kinase activity is an intrinsic activity of branched-chain oxo acid dehydrogenase complex [3]) [3]... 

Odessey, R. Purification of rat kidney branched-chain oxo acid dehydrogenase complex with endogenous kinase activity. Biochem. J., 204, 353-356 (1982)... 

The reaction of the pyruvate dehydrogenase complex is shown in Figure 6.2 the reactions of the 2-oxoglutarate and branched-chain oxo-acid dehydrogenase complexes follow the same sequence, and the multienzyme complexes are similar. 

Various mutations affecting either the El or the E2 subunit of the dehydrogenase are involved in different forms of maple symp urine disease. Acute infantile disease is caused by near complete lack of activity of the enzyme. The intermittent form of the disease is associated with marginally adequate residual activity of the enzyme that is able to cope with the branched-chain oxo-acids arising from the metabolism of modest amounts of branched-chain amino acids, but not relatively large amounts. 

In vitro, thiamin diphosphate inhibits the kinase that phosphorylates and inactivates branched-chain oxo-acid dehydrogenase, and might be expected to increase the activity of the enzyme in tissues, thus offering an alternative mechanism for thiamin-responsive maple syrup urine disease. However, this seems not to be relevant in vivo, possibly because tissue concentrations of thiamin diphosphate do not rise high enough to affect the activity of the kinase. In thiamin-deficient animals, there is an increase in the total liver content... 

Branched-Chain Oxo-acid Decarboxylase and Maple Syrup Urine Disease The third oxo-add dehydrogenase catalyzes the oxidative decarboxylation of the branched-chain oxo-acids that arise from the transamination of the branched-chain amino acids, leucine, isoleuctne, emd vtdine. It has a similEU subunit composition to pyruvate and 2-oxoglutarate dehydrogenases, and the E3 subunit (dihydrolipoyl dehydrogenase) is the stune protein as in the other two multienzyme complexes. Genetic lack of this enzyme causes maple syrup urine disease, so-called because the bremched-chain oxo-acids that are excreted in the urine have a smell reminiscent of maple syrup. 

The disease can be diagnosed biochemically by the reaction of the urinary branched-chain oxo acids with dinitrophenyl-hydrazine to form characteristic dinitrophenylhydrazone derivatives which can be identified chromatographically. 

Possible errors due to the methods used have been referred to in the sections of Part I and include the dehydration of hydroxy acids, for example 3-methyl-crotonic acid from 3-hydroxyisovaleric acid, crotonic acid from 3-hydroxy-butyric acid, either on acid steam distillation or alkaline treatment, decarboxylation of 2-oxo acids, for example phenylpyruvic acid to phenylacetic acid (Thompson et al., 1975b) and similar effects with branched-chain oxo acids, during sample preparation, particularly by solvent extraction. Derivatization artefacts produced during methylation have been detailed in Part I, and decarboxylation of free non-volatile acids during the analysis of volatile acids, for example, methylmalonic acid to propionic acid, are also detailed elsewhere. 

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