Maple Leucine

As the name implies, the odor of urine in maple syrup urine disease (brancbed-chain ketonuria) suggests maple symp or burnt sugar. The biochemical defect involves the a-keto acid decarboxylase complex (reaction 2, Figure 30-19). Plasma and urinary levels of leucine, isoleucine, valine, a-keto acids, and a-hydroxy acids (reduced a-keto acids) are elevated. The mechanism of toxicity is unknown. Early diagnosis, especially prior to 1 week of age, employs enzymatic analysis. Prompt replacement of dietary protein by an amino acid mixture that lacks leucine, isoleucine, and valine averts brain damage and early mortality. 

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. 

Mueller, G. M., McKenzie, L. R., Homanics, G. E., Watkins, S. C., Robbins, P. D. and Paul, H. S. Complementation of defective leucine decarboxylation in fibroblasts from a maple syrup urine disease patient by retrovirus-mediated gene transfer. Gene Ther. 2 461-468,1995. 

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

Maple syrup urine disease (branched-chain ketoaciduria) <0.4 Isoleucine, leucine, and valine degradation Branched-chain a-keto acid dehydrogenase complex Vomiting convulsions mental retardation early death... 

T There is a relatively rare genetic disease in which the three branched-chain a-lceto acids (as well as their precursor amino acids, especially leucine) accumulate in the blood and spill over into the urine. This condition, called maple syrup urine disease because of the characteristic odor imparted to the urine by the a-lceto acids, results from a defective branched-chain a-lceto acid dehydrogenase complex. Untreated, the disease results in abnormal development of the brain, mental retardation, and death in early infancy. Treatment entails rigid control of the diet, limiting the intake of valine, isoleucine, and leucine to the minimum required to permit normal growth. ... 

Maple syrup urine disease (MSUD) is a recessive disorder in which there is a partial or complete deficiency in branched-chain o-ketoacid dehydrogenase, an enzyme that decarboxylates leucine, isoleucine, and valine (see Figure 20.10). These amino acids and their corre sponding a-keto acids accumulate in the blood, causing a toxic effect that interferes with brain functions. The disease is characterized by feeding problems, vomiting, dehydration, severe metabolic acidosis, and a characteristic maple syrup odor to the urine. If untreated, the disease leads to mental retardation, physical disabilities, and death. 

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. 

People can suffer from a variety of inborn metabolic errors that can result in various amino acids exhibiting toxic effects if ingested above certain threshold levels. Specialty products, intended to be absent these amino acids, must be rigorously tested for verification that threshold levels are not exceeded. Examples of this situation include phenylketoneuria (intolerance of phenylalanine) and maple syrup urine disease (intolerance for leucine, isoleucine, and valine). 

A wide range of free amino acids are found in sterile maple sap (Heiligmann et al., 2006), including glycine, alanine, asparagines, threonine, leucine, isoleucine, valine, and methionine. Morselli and Whalen (1986) examined the change in the distribution of various amino acids over two maple sap seasons. Their results indicated that initially, only a small number (6-7) of amino acids were found in sap, all in relatively low concentration. As the season progressed, the diversity of amino acids increased to 12-15. In addition, the concentration of amino acids present... 

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. 

C-11) (1-9) Maple Syrup Urine Disease. There is a block in the degradation of the branched chain amino acids. Leucine, isoleucine, valine, and their ketoic acids are elevated in the blood and urine. Assays for these chemicals can be done in the laboratory. The urine acquires a maple syrup aroma. Infants with the condition have a variety of neurologic problems, including mental retardation. The condition is treated by dietary restriction of the affected amino acids. 

Isovaleric acidemia. This is believed to be a defect in the step from isovaleryl Co A to beta-methyl cro-tonyl Co A, in the metabolism of leucine. Rather than a maple syrup odor, there is an odor of sweaty feet . The patient has various neurologic disturbances and mental retardation. Isovaleric acid is elevated in the plasma. It is treated by restricting dietary intake of leucine. 

Although alcaptonuria is a relatively harmless condition, such is not the case with other errors in amino acid metabolism. In maple syrup urine disease, the oxidative decarboxylation of a-ketoacids derived from valine, isoleucine, and leucine is blocked because the branched-chain dehydrogenase is missing or defective. Hence, the levels of these a-ketoacids and the branched-chain amino acids that give rise to them are markedly elevated in both blood and urine. Indeed, the urine of patients has the odor of maple syrup—hence the name of the disease (also called branched-chain ketoaciduria). Maple syrup urine disease usually leads to mental and physical retardation unless the patient is placed on a diet low in valine. 

Branched-chain ketoaciduria (commonly known as Maple Syrup Urine Disease MSUD) is another ailment that may be caused by thiamine deficiency. In MSUD, the oxidative decarboxylation of alpha-keto acids derived from, i.e. valine, isoleucine, and leucine, is blocked due to an inadequate supply of the coenzyme thiamine pyrophosphate (TPP). Clinical symptoms of MSUD include mental and physical retardation. Describe briefly the structure of Riboflavin (Vitamin B-2) and its biochemical role. 

In maple syrup urine disease, the enzyme complex that decarboxy-lates the transamination products of the branched-chain amino acids is defective (see Figure 7-11). Valine, isoleucine, and leucine accumulate. Urine has the odor of maple syrup. Mental retardation occurs. 

C. In maple syrup urine disease, the branched-chain amino acids (valine, leucine, and isoleucine) can be transaminated but not oxidatively decarboxylated because the a-keto acid dehydrogenase is defective. 

A similar success was observed for studies of branched-chain ketoaciduria in which the second stage of the catabolism of leucine, valine and isoleucine involves an oxidative decarboxylation. In patients with branched-chain ketoaciduria, this step is blocked for all three of these amino acids. The urine of these patients takes on the odour of maple syrup and hence this condition... 

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