Thiamine increases the specific activity of human liver branched chain α-ketoacid dehydrogenase

Abstract

THIAMINE pyrophosphate (TPP), the active derivative of vitamin B₁, functions as a coenzyme in dehydrogenase reactions such as the oxidative decarboxylation of α-ketoisovaleric (KIV), α-keto-β-methylvaleric (KMV) and α-ketoisocaproic (KIC) acids in humans¹. Impairment of these reactions produces the group of disorders known as maple syrup urine disease^2,3. In the classic form of the disease, the ketoacids and their amino acid precursors accumulate in homozygous affected individuals and depress the function of the central nervous system early in life. Therapy involves restriction of branched chain amino acids in the diet to decrease their concentrations in the body fluids⁴. Further reduction in plasma leucine, isoleucine and valine has been achieved by supplementing this diet with thiamine for patients with partial (60%) and severe (95%) reduction in enzyme activity^5,6. Other investigators found no effect in patients lacking all enzyme activity^7,8. We are seeking an explanation for the clinical response at the enzyme level and have already reported that branched chain α-ketoacid dehydrogenase activity was increased in peripheral white blood cells. This occurred after 3 weeks of oral thiamine treatment in patients with 5% activity and in normal controls⁵. In contrast, activity in mitochondrial inner membranes from cultured normal and mutant skin fibroblasts was not stimulated directly by TPP/Mg²⁺, but was prolonged by the presence of TPP/Mg²⁺, suggesting that the cofactor increases the half life of the dehydrogenase complex. We have now found that thiamine supplementation of normal diets increases normal human liver branched chain α-ketoacid dehydrogenase activity.