Inhibition of acetylcholine synthesis and of carbohydrate utilization by maple-syrup-urine disease metabolites.

Abstract

AbstractThe branched‐chain 2‐oxo acids which accumulate in maple‐syrup‐urine disease inhibited the production of acetylcholine and of lipids, proteins, nucleic acids and of CO2. in sliced adult rat brains incubated with [U‐14C] glucose. Inhibition of the biosynthetic reactions was proportional to the inhibition of CO2 production, even though the flux of radioactivity into the biosynthetic products was less than 2% of that to CO2.The oxo acids reduced the production of 14CO2, from [U‐14C] glucose and from [2‐14C]pyruvic acid more than from [1‐14C]pyruvic acid in sliced brains. They inhibited the solubilized oxoglutarate dehydrogenase complex more than they did the solubilized pyruvate dehydrogenase complex. Valine and isoleucine, which also accumulate in maple‐syrup‐urine disease, inhibited pyruvate kinase from rat brain allosterically. Quantitative comparison of the effects of the disease metabolites on cell‐free systems with their effects on fluxes in intact cells indicated that the inhibition of oxoglutarate dehydrogenase appeared to be functionally significant. The residual activities of the other enzymes studied were adequate to support the normal flux of carbohydrates.The oxo acids were effective at concentrations within the range reported to occur in patients with maple‐syrup‐urine disease. The effects on biosyntheses including that of acetylcholine would be expected to impair brain development and function and could be important in the development of brain disease in the patients. In contrast to the results with metabolites from maple‐syrup‐urine disease, metabolites which accumulate in phenylketonuria (phenylalanine and 2‐oxo‐3‐phenylpropionic acid) did not inhibit carbohydrate utilization or the biosynthetic reactions studied, under the conditions of these experiments.