A Screen of Cell-Surface Molecules Identifies Leucine-Rich Repeat Proteins as Key Mediators of Synaptic Target Selection
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Use of an ion-exchange resin assay has shown that leucine is bound to a component of a dialyzed extract of yeast. Leucine binding may be related to in vivo uptake of the amino acid. A yeast strain with a 30-fold lower affinity for leucine uptake in vivo has a parallel reduction in affinity for in vitro leucine binding; the rate of leucine uptake in wild-type yeast can be increased four- to fivefold by growth on leucine as a sole nitrogen source. Under these conditions, the specific activity of the leucine-binding component also increases over threefold. Regulation of leucine uptake was studied by using wild-type strain 60615 and a mutant 60615/fl 2 with a constitutively elevated leucine uptake system. Leucine pool formation in the mutant was accompanied by an overshoot, leading to a loss of leucine from the pool. The phenomenon could be observed in the wild type under certain conditions. The mechanism of this process was examined. The leucine uptake system was found to be stable in the absence of protein synthesis. The rate of leucine uptake increased on reduction of the pool of amino acids, and in strain 60615/fl 2 the ability to overshoot was rapidly recovered on depletion of the leucine pool. The results suggest a control of leucine uptake by feedback inhibition, in which leucine or other amino acids, e.g., isoleucine, inhibit leucine uptake. The results do not exclude control by a rapidly activated-inactivated system.
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We have used the primed constant infusion of di-[15N]urea and [1–13C]leucine to determine the effects of mild exercise (approx 30% Vo2max for 105 min) on urea production and leucine metabolism in human subjects. The oxidation of plasma leucine was distinguished from the oxidation of leucine that never entered the plasma pool (“intracellular” leucine) by means of determining the enrichment of alpha-ketoisocaproic acid (alpha-KICA). Total leucine oxidation increased from 0.38 +/0 0.05 to 1.41 +/- 0.14 micromol . kg-1 . min-1 during exercise due to increases in the oxidation of plasma leucine (150%) and intracellular leucine (600%). Plasma leucine flux decreased slightly, but not significantly (0.1 greater than P greater than 0.05), and the percent of alpha-KICA derived from plasma leucine dropped significantly (P less than 0.05) from 79.5 +/- 4.3 at rest to 62.0 +/- 5.3% over the last 30 min of exercise. Despite the increase in leucine oxidation during exercise, urea concentration and production did not change. Thus in exercise urea production does not accurately reflect all aspects of amino acid metabolism.
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We examined the effect of insulin and plasma amino acid concentrations on leucine kinetics in 15 healthy volunteers (age 22 +/- 2 yr) using the euglycemic insulin clamp technique and an infusion of [1-14C]leucine. Four different experimental conditions were examined: (a) study one, high insulin with reduced plasma amino acid concentrations; (b) study two, high insulin with maintenance of basal plasma amino acid concentrations; (c) study three, high insulin with elevated plasma amino acid concentrations; and (d) study four, basal insulin with elevated plasma amino acid concentrations. Data were analyzed using both the plasma leucine and alpha-ketoisocaproate (the alpha-ketoacid of leucine) specific activities. In study one total leucine flux, leucine oxidation, and nonoxidative leucine disposal (an index of whole body protein synthesis) all decreased (P less than 0.01) regardless of the isotope model utilized. In study two leucine flux did not change, while leucine oxidation increased (P less than 0.01) and nonoxidative leucine disposal was maintained at the basal rate; endogenous leucine flux (an index of whole body protein degradation) decreased (P less than 0.01). In study three total leucine flux, leucine oxidation, and nonoxidative leucine disposal all increased significantly (P less than 0.01). In study four total leucine flux, leucine oxidation, and nonoxidative leucine disposal all increased (P less than 0.001), while endogenous leucine flux decreased (P less than 0.001). We conclude that: (a) hyperinsulinemia alone decreases plasma leucine concentration and inhibits endogenous leucine flux (protein breakdown), leucine oxidation, and nonoxidative leucine disposal (protein synthesis); (b) hyperaminoacidemia, whether in combination with hyperinsulinemia or with maintained basal insulin levels decreases endogenous leucine flux and stimulates both leucine oxidation and nonoxidative leucine disposal.
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Maple syrup urine disease (MSUD) is an inborn metabolic disease. The nutritional treatment with restricted intake of branched chain amino acids and prevention of leucine toxicity are crucially important for a favorable outcome. The aim of this study is to analyze the relation of blood leucine levels at diagnosis with future leucine tolerances, to determine whether any prediction about the future leucine tolerances or plasma leucine levels is possible by evaluating blood leucine levels at diagnosis.The study group consisted of 45 MSUD patients. Leucine levels at diagnosis were compared with age at diagnosis, leucine tolerances, maximum leucine levels/ages, and average blood leucine levels.The mean plasma leucine level at diagnosis was 2,355.47 ± 1,251.7 μmol/L (ref: 55-164 μmol/L). The median age at diagnosis was 17 days. Leucine tolerances per kg body weight declined until the age of 8 years and stabilized subsequently. The average age of maximum leucine level during follow-up was 3.14 ± 1.92 years, and the mean maximum lifetime plasma leucine level on follow-up was 1,452.13 ± 621.38 μmol/L. The leucine levels at diagnosis did not have any significant relationship with lifetime leucine tolerances, maximum plasma leucine levels or mean plasma leucine levels.The plasma leucine levels at diagnosis did not have a predictive value for later leucine tolerances or plasma leucine levels. The maximum lifetime leucine level is likely to happen within the first 3 years of life, underlining the importance of good metabolic control and compliance to dietary treatment at early ages.
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To investigate in humans whether interconversion of leucine and its alpha-keto acid, alpha-ketoisocaproate (KIC), is rate limiting for leucine metabolism, normal volunteers were infused with independent 3H and 14C labels of leucine and KIC. Total leucine carbon (leucine + KIC) entry into the plasma space determined by using both plasma specific activities (SA) of the infused isotopes or by using either plasma SA of the leucine moieties reciprocal to those being infused (e.g., [3H]KIC and [14C]leucine during [3H]leucine and [14C]KIC infusion) were nearly identical. When [3H]leucine and [14C]KIC were infused, the ratio of 3H/14C radioactivity of leucine in plasma proteins was similar both to the ratio of plasma [3H]KIC SA/[14C]leucine SA and to the ratio of the rate of [3H]leucine/[14C]KIC infused. Estimates of leucine oxidation using expired 14CO2 and the plasma SA of the 14C moiety reciprocal to infused [14C]leucine or [14C]KIC were similar. We conclude that the plasma SA of the leucine moiety reciprocal to infused labeled leucine or KIC may reflect more accurately whole-body leucine metabolism in postabsorptive humans.
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