Jos tuo leusiinin KIC metaboliitti akkumuloituu sillä on estäviä vaikutuksia kloridijonissta riippuvien glutamaattirakkuloitten takaisin ottoon aivoissa.
Biochim Biophys Acta. 2000 Jul 3;1475(2):114-8. Chloride-dependent inhibition of vesicular glutamate uptake by alpha-keto acids accumulated in maple syrup urine disease.
Source
Departamento de Bioquímica Médica, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, RJ 21941-590, Cidade Universitária, Brazil.Abstract
Maple
syrup urine disease is a metabolic disorder caused by mutations of the
branched chain keto acid dehydrogenase complex, leading to accumulation
of alpha-keto acids and their amino acid precursors in the brain. We now
report that alpha-ketoisovaleric, alpha-keto-beta-methyl-n-valeric and
alpha-ketoisocaproic (KIC) acids accumulated in the disease inhibit glutamate
uptake into rat brain synaptic vesicles.
The alpha-keto acids did not affect the electrochemical proton gradient across the membrane, suggesting that they interact directly with the vesicular glutamate carrier.
Chloride anions have a biphasic effect on glutamate uptake.
Low concentrations activate the uptake (0.2 to 8 mM), while higher concentrations are inhibitory.
The alpha-keto acids inhibited glutamate uptake by a new mechanism, involving a change in the chloride dependence for the activation of glutamate uptake.
The activation of glutamate uptake by low chloride concentrations was shifted toward higher concentrations of the anion in the presence of alpha-keto acids.
Inhibition by alpha-keto acids was abolished at high chloride concentrations (20 to 80 mM), indicating that alpha-keto acids specifically change the stimulatory effect of low chloride concentrations.
High glutamate concentrations also reduced the inhibition by alpha-keto acids, an effect observed both in the absence and in the presence of low chloride concentrations.
The results suggest that in addition to their possible pathophysiological role in maple syrup urine disease, alpha-keto acids are valuable tools to study the mechanism of vesicular transport of glutamate.
The alpha-keto acids did not affect the electrochemical proton gradient across the membrane, suggesting that they interact directly with the vesicular glutamate carrier.
Chloride anions have a biphasic effect on glutamate uptake.
Low concentrations activate the uptake (0.2 to 8 mM), while higher concentrations are inhibitory.
The alpha-keto acids inhibited glutamate uptake by a new mechanism, involving a change in the chloride dependence for the activation of glutamate uptake.
The activation of glutamate uptake by low chloride concentrations was shifted toward higher concentrations of the anion in the presence of alpha-keto acids.
Inhibition by alpha-keto acids was abolished at high chloride concentrations (20 to 80 mM), indicating that alpha-keto acids specifically change the stimulatory effect of low chloride concentrations.
High glutamate concentrations also reduced the inhibition by alpha-keto acids, an effect observed both in the absence and in the presence of low chloride concentrations.
The results suggest that in addition to their possible pathophysiological role in maple syrup urine disease, alpha-keto acids are valuable tools to study the mechanism of vesicular transport of glutamate.
