This study was prompted by our incomplete understanding of the mechanism responsible for the clinical benefits of pharmacological doses of thiamin (T) in .-iomr patients with maple syrup urine, disease and the question of whether thiamin diphosphate (TDP), potent inhibitor of the activity of the protein kinase that phosphorylates and inactivates the branrhed-chain a-ketoacid dehydrogeriH.se (BCKDH) complex, affects the activity state of this complex. Feeding rats a chemically defined. T-deficient diet for ju.st 2 days caused loss of nearly half of the TDP from liver mitochondria. Three more days caused over 70% loss; 3 weeks ovf-r W°/<. Starvation for 1? days had no effect, suggesting a mechanism for conservation of TDP in this nutritional stale. Mitochondria! TDP was higher in rats fed pharmacological -4mounts of T than in rats fed adequate T for maximum growth. Varying dietary T had marked but opposite effects on the activities of a-ketoglutarate dehydrogena.se (KGDH) and BCKDH. T deficiency decreased KGDH activity, increased BCKDH total activity, and increased the proportion of BCKDH in the active, dephosphorylated state. Excess dietary T had ihe opposite effects. More TDP is associated with KGDH than BCKDH in T-deficient rats, suggesting retention of KGDH activity at the expense of BCKDH activity. Thus. T deficiency and excess cause large changes in mitochondrial TDP levels that have rn<ijor effects on the activities of the keto acid dehydrogenasr- complexes. [Supported by the Grace M. Showalter Trust and PUS DK 19-4't (rah p.
|Original language||English (US)|
|State||Published - Dec 1 1998|
ASJC Scopus subject areas
- Molecular Biology