Maple Isoleucine

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. 

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... 

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. 

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. 

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

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. 

These branched-chain aliphatic amino acids contain bulky nonpolar R-groups and participate in hydrophobic interactions. All three are essential amino acids. A defect in their catabolism leads to maple syrup urine disease (Chapter 17). Isoleucine has asymmetrical centers at both the a- and 8-carbons and four stereoisomers, only one of which occurs in protein. The bulky side chains tend to associate in the interior of water-soluble globular proteins. Thus, the hydrophobic amino acid residues stabilize the three-dimensional structure of the polymer. 

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... 

In maple syrup urine disease, also called branched chain ketoaciduria, the a-keto acids derived from leucine, isoleucine, and valine accumulate in large quantities in blood. Their presence in urine imparts a characteristic odor that gives the malady its name. All three a-keto acids accumulate because of a deficient branched chain a-keto acid dehydrogenase complex. (This enzymatic activity is responsible for the conversion of the a-keto acids to their acyl-CoA derivatives.) If left untreated, affected individuals experience vomiting, convulsions, severe brain damage, and mental retardation. They often die before 1 year of age. As with phenylketonuria, treatment consists of rigid dietary control. 

Maple syrup urine disease This defect in the decarboxylation of branched chain amino acids such as leucine, isoleucine and valine leads to severe brain damage and death during the first year of life... 

When transaminated, the three branched-chain amino acids (valine, leucine, and isoleucine) form compounds that have the characteristic odor of maple symp. An enzyme known as branched-chain a-keto acid dehydrogenase converts these compounds into CoA esters. People who do not have this enz3me have the genetic disease known as maple syrup urine disease—so-called because their urine smells like maple syrup. 

Table 41.6 Leucine-, Isoleucine- and vallne-free dietary preparations for the management of Maple syrup urine disease ...

Maple syrup urine disease is a rare genetic disorder affecting the metabohsm of leucine, isoleucine and valine. Accumulation of these branched-chain amino acids results in severe neurological damage and death. The aim of dietary management is to prevent the accumulation of these amino acids, by the use of a low-protein diet and leucine-, isoleucine-and vahne-free amino acid preparations. Natural protein supplies the necessary leucine, isoleucine and valine, based on a leucine exchange system with additional isoleucine and/ or valine available as single amino acid supplements. 

The leucine-, isoleucine- and vafrne-free drink mix MSUD Aid III is suitable for infants, children, adolescents and adults but, unlike other proprietary preparations suitable for the management of Maple syrup urine disease, it is carbohydrate, fat, vitamin and mineral free, which need to be added to the diet. This may allow more appropriate age-specific supplementation including iodine. 

Maple syrup urine disease (MSUD) is caused by a deficiency in the branched-chain keto acid dehydrogenase enzyme complex that metabolizes the keto acids of leucine, isoleucine, and valine. 

Maple syrap urine disease (MSUD) is an inborn error of the branched-chain keto acid dehydrogenase (BCKDH) enzyme complex required for the catabolism of the branched-chain amino adds (BCAA) leucine, valine, and isoleucine (Fig. 16.1). 

Maple syrup urine Branched-chain keto Elevated blood, urine, and Neonatal form poor feeding, Vahne, isoleucine, and Only in variant... 

Isoleucine, Leu, and Val are elevated in maple syrup unne disease and decreased in starvation (see above). 

MSUD is an autosomal recessive disorder caused by deficiency of branched-chain a-ketoacid dehydrogenase (Pig. 47.1). The a-ketoadds derived from isoleucine, valine and leucine (branched-chain amino adds) accumulate and are excreted in the urine, giving it the peculiar odour of maple syrup. The branched-chain amino acids and the branched-chain a-ketoacids that accumulate in the blood are neurotoxic, causing severe neurological symptoms, cerebral oedema and mental retardation. A diet low in branched-chain amino acids is an effective treafinenL... 

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