Oxoglutarate Dehydrogenase and the y-Aminobutyric Acid GABA Shunt

Glutamate decarboxylase tmd GABA cuninotransferase are found in regions of the central nervous system other them those in which GABA has a 

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. 

Some patients with maple syrup urine disease respond to high doses (10 to 1,000 mg per day) of thiamin in some patients, the defect is clearly in the Ela subunit, which has a 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 Ela 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 liver content 

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