Branched-Chain Oxo-acid Decarboxylase and Maple Syrup Urine Disease

4 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. 

Various mutations tiffecting either the El or the E2 suhunit of the dehydrogenase are involved in different forms of maple syrup 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 mtirgincdly adequate residual activity of the enzyme that is able to cope with the brcmched-chciin oxo-acids arising from the metabolism of modest cunounts of branched-chciin amino acids, but not relatively large cunounts. 

Some patients with maple syrup urine disease respond to high doses (10 to 

000 mg per day) of thicunin in some patients, the defect is clearly in the El a subunit, which has a. Km for thiamin diphosphate 16-fold higher than normal. But in other thiamin-responsive cases, the mutation is in the E2 subunit, suggesting that assembly of the active multienzyme complex affects the affinity of the thiamin diphosphate binding site of the El a subunit. 

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 fiver content 

But in other thitunin-responsive cases, the mutation is in the L2 subunit, suggesting that assembly of the active multienzyme complex eiffects the eiffinity of the thitunin diphosphate binding site of the LI a subunit. 

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