Dietary thiamin level influences levels of its diphosphate form and thiamin-dependent enzymic activities of rat liver

Paul V. Blair, Rumi Kobayashi, Hardy M. Edwards, Neil F. Shay, David H. Baker, Robert Harris

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

This study was prompted by our incomplete understanding of the mechanism responsible for the clinical benefits of pharmacological doses of thiamin in some patients with maple syrup urine disease (MSUD) and the question of whether thiamin diphosphate (TDP), a potent inhibitor of the activity of the protein kinase that phosphorylates and inactivates the isolated branched- chain α-ketoacid dehydrogenase (BCKDH) complex, affects the activity state of the complex. Rats were fed a chemically-defined diet containing graded levels of thiamin (0, 0.275, 0.55, 5.5, and 55 mg thiamin/kg diet). Maximal weight gain was attained over a 3-wk period only in rats fed diets with 5.5 and 55 mg thiamin/kg. Feeding rats the thiamin-free diet for just 2 d caused loss of nearly half of the TDP from liver mitochondria. Three more days caused over 70% loss, an additional 3 wk, over 90%. Starvation for 2 d had no effect, suggesting a mechanism for conservation of TDP in this nutritional state. Mitochondrial TDP was higher in rats fed pharmacological amounts of thiamin (55 mg thiamin/kg diet) than in rats fed adequate thiamin for maximal growth. Varying dietary thiamin had marked but opposite effects on the activities of α-ketoglutarate dehydrogenase (α-KGDH) and BCKDH. Thiamin deficiency decreased α-KGDH activity, increased BCKDH activity, and increased the proportion of BCKDH in the active, dephosphorylated, state. Excess dietary thiamin had the opposite effects. TDP appears to be more tightly associated with α-KGDH than BCKDH in thiamin-deficient rats, perhaps denoting retention of α-KGDH activity at the expense of BCKDH activity. Thus, thiamin deficiency and excess cause large changes in mitochondrial TDP levels that have a major influence on the activities of the keto acid dehydrogenase complexes.

Original languageEnglish
Pages (from-to)641-648
Number of pages8
JournalJournal of Nutrition
Volume129
Issue number3
StatePublished - 1999

Fingerprint

Thiamine Pyrophosphate
Thiamine
thiamin
3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)
enzyme activity
liver
Liver
3-methyl-2-oxobutanoate dehydrogenase (lipoamide)
rats
Thiamine Deficiency
Diet
Oxidoreductases
Maple Syrup Urine Disease
Pharmacology
diet
Keto Acids
Formulated Food
Liver Mitochondrion
Protein Kinase Inhibitors
Starvation

Keywords

  • Mitochondria
  • Rats
  • River
  • Thiamin
  • Thiamin-dependent enzymes

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Food Science

Cite this

Dietary thiamin level influences levels of its diphosphate form and thiamin-dependent enzymic activities of rat liver. / Blair, Paul V.; Kobayashi, Rumi; Edwards, Hardy M.; Shay, Neil F.; Baker, David H.; Harris, Robert.

In: Journal of Nutrition, Vol. 129, No. 3, 1999, p. 641-648.

Research output: Contribution to journalArticle

Blair, Paul V. ; Kobayashi, Rumi ; Edwards, Hardy M. ; Shay, Neil F. ; Baker, David H. ; Harris, Robert. / Dietary thiamin level influences levels of its diphosphate form and thiamin-dependent enzymic activities of rat liver. In: Journal of Nutrition. 1999 ; Vol. 129, No. 3. pp. 641-648.
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AU - Baker, David H.

AU - Harris, Robert

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AB - This study was prompted by our incomplete understanding of the mechanism responsible for the clinical benefits of pharmacological doses of thiamin in some patients with maple syrup urine disease (MSUD) and the question of whether thiamin diphosphate (TDP), a potent inhibitor of the activity of the protein kinase that phosphorylates and inactivates the isolated branched- chain α-ketoacid dehydrogenase (BCKDH) complex, affects the activity state of the complex. Rats were fed a chemically-defined diet containing graded levels of thiamin (0, 0.275, 0.55, 5.5, and 55 mg thiamin/kg diet). Maximal weight gain was attained over a 3-wk period only in rats fed diets with 5.5 and 55 mg thiamin/kg. Feeding rats the thiamin-free diet for just 2 d caused loss of nearly half of the TDP from liver mitochondria. Three more days caused over 70% loss, an additional 3 wk, over 90%. Starvation for 2 d had no effect, suggesting a mechanism for conservation of TDP in this nutritional state. Mitochondrial TDP was higher in rats fed pharmacological amounts of thiamin (55 mg thiamin/kg diet) than in rats fed adequate thiamin for maximal growth. Varying dietary thiamin had marked but opposite effects on the activities of α-ketoglutarate dehydrogenase (α-KGDH) and BCKDH. Thiamin deficiency decreased α-KGDH activity, increased BCKDH activity, and increased the proportion of BCKDH in the active, dephosphorylated, state. Excess dietary thiamin had the opposite effects. TDP appears to be more tightly associated with α-KGDH than BCKDH in thiamin-deficient rats, perhaps denoting retention of α-KGDH activity at the expense of BCKDH activity. Thus, thiamin deficiency and excess cause large changes in mitochondrial TDP levels that have a major influence on the activities of the keto acid dehydrogenase complexes.

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