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At least 37 records · Page 2Linked to original sources
PubMed1988

Leucine kinetics at graded intakes in young men: quantitative fate of dietary leucine.

To explore leucine metabolism in relation to leucine intake, five young adult men received an L-amino acid diet that supplied 40, 30, 20, and 10 mg leucine.kg-1.d-1 for 6 d. A stable-isotope-tracer infusion study was then conducted for 5 h while subjects received an intragastric infusion of the test diet. Primed, constant infusions of L-[1-13C]leucine (intragastric) and L-[2H3]leucine (intravenous) were given simultaneously. A final infusion study was conducted in subjects in the postabsorptive state after an additional 2 d with the 10-mg diet. Estimates were made of leucine flux and oxidation, rates of uptake and release of absorbed leucine by the splanchnic region, and leucine balance. The rate of appearance of dietary leucine in the systemic circulation (Leud) decreased (p less than 0.01) between the 40- and 10-mg diets. At the latter intake, splanchnic uptake was approximately 37% of absorbed leucine. The correlation between Leud and plasma leucine concentration was highly positive. A leucine intake of approximately 40 mg. kg-1.d-1 was close to that required to maintain leucine balance under these conditions.

Adult↗
PubMed1992

Role of the conserved leucines in the leucine zipper dimerization motif of yeast GCN4.

Yeast GCN4 belongs to the class of eukaryotic transcription factors whose bZIP DNA-binding domains dimerize via a leucine zipper motif that structurally resembles a coiled coil. The leucine zipper contains 4-5 highly conserved leucine residues spaced exactly 7 residues apart that are located within the alpha-helical hydrophobic interface between protein monomers. Here, we investigate the role of the four canonical leucines in the GCN4 leucine zipper by analyzing a series of mutated derivatives for their ability to activate transcription in vivo and to bind DNA in vitro. The GCN4 leucine zipper is surprisingly tolerant of mutations, with a wide variety of single substitutions at any of the four leucines including basic and acidic amino acids behaving indistinguishably from wild-type GCN4. Moreover, some derivatives containing two leucine substitutions display detectable though reduced function. These results indicate that other residues within the coiled coil are crucial for efficient dimerization, and they suggest that some eukaryotic transcriptional regulatory proteins lacking the conserved leucine repeat will dimerize through a structurally homologous motif. Interestingly, our results differ in several respects from those obtained by analyzing mutations in the GCN4 leucine zipper in the context of a lambda repressor-GCN4 zipper hybrid protein. These apparent differences may reflect a functional interrelationship between the leucine zipper and basic region subdomains for DNA-binding by bZIP proteins.

Base Sequence↗
PubMed1992

Nitrogen absorption from isonitrogenous solutions of L-leucyl-L-leucine and L-leucine: a study in the isolated perfused rat small intestine.

1. We assessed the efficacy of nitrogen absorption from luminal L-leucine (1.2 and 12 mmol/l) and from isonitrogenous L-leucyl-L-leucine (0.6 and 6.0 mmol/l) in a preparation of vascularly and luminally perfused rat small intestine by measuring luminal leucyl-leucine disappearance and venous leucine appearance. 2. No intact dipeptide was found in the vascular perfusate. Leucine-nitrogen absorption, as judged by venous leucine appearance, was as efficient from free leucine (29 +/- 3 and 245 +/- 19 ng-atom min-1 g-1) as from leucyl-leucine (27 +/- 4 and 211 +/- 58 ng-atom min-1 g-1). It was not reduced in the presence of glycyl-L-proline or of the brush-border dipeptidase inhibitors alanine-beta-naphthylamide and cilastatin. 3. After one passage of the whole small intestine, only trace amounts of dipeptide, but large amounts of free leucine, were detected in the luminal effluent. Peptidase activity in the luminal effluent was demonstrated in 100,000 g supernatant and was inhibited by p-hydroxy-mercuribenzoate, but not by brush-border dipeptidase inhibitors. 4. We propose that nitrogen absorption from luminal leucyl-leucine may proceed predominantly via intraluminal peptide hydrolysis and subsequent transport of free leucine. Nevertheless, our findings and conclusions are at variance with previous observations and current opinion on intestinal handling of dipeptides, which may be due, in part, to the different methodological approach.

Animals↗
PubMed1968

Biosynthesis of branched-chain amino acids in yeast: regulation of leucine biosynthesis in prototrophic and leucine auxotrophic strains.

The first enzyme in the biosynthesis of leucine in yeast, alpha-isopropylmalate synthetase, is inhibited by l-leucine. In a mutant resistant to the analogue 5',5',5'-trifluoroleucine, the enzyme is markedly resistant to inhibition by l-leucine. Growth ing the presence of exogenous l-leucine results in repression of the second and third enzymes of the pathway. The first enzyme is not repressed unless both l-leucine and l-threonine are supplied in the medium. Comparison of levels of the remaining two enzymes in leucine auxotrophs grown under conditions of leucine excess and leucine limitation reveals deviations from the wild-type derepression pattern in some mutants. In some, repression of the synthetase by leucine alone was observed. In others, the repressibility of the dehydrogenase was lost. It is unlikely that these deviations were due to the same primary mutational event that caused leucine auxotrophy. No mutants were found in which an altered gene was recognized to be clearly responsible for the level of the leucine-forming enzymes.

Enzyme Repression↗
PubMed1987

Effects of leucine, isoleucine, or threonine infusion on leucine metabolism in humans.

Leucine and/or its alpha-keto acid, alpha-ketoisocaproate (KIC), have been reported to spare protein in humans. To determine whether specific amino acid infusions affect whole-body protein metabolism as estimated by changes in leucine flux and oxidation, five groups of normal subjects were infused with saline, leucine (0.47 and 0.94 mumol . kg-1 . min-1), isoleucine (0.47 mumol . kg-1 . min-1), or threonine (0.47 mumol . kg-1 . min-1). Independent estimates of leucine metabolism were obtained using simultaneous infusions of [3H]-leucine and alpha-[14C]ketoisocaproate. Nearly identical results were obtained using either tracer compared with the saline controls. Compared with the saline controls, leucine infusion 1) had no effect on estimated rates of appearance of endogenous leucine, 2) stimulated leucine oxidation, 3) decreased plasma concentrations of other amino acids, and 4) stimulated non-oxidized leucine disappearance in a dose-dependent fashion. In contrast, isoleucine and threonine infusions had no effect on leucine metabolism. Assuming the validity of the isotope model employed, these data suggest that the purported anabolic effect of leucine infusion on whole-body protein metabolism is mediated via stimulation of protein synthesis rather than decreased proteolysis.

Analysis of Variance↗
PubMed2000

Subclinical infection with the nematode Trichostrongylus colubriformis increases gastrointestinal tract leucine metabolism and reduces availability of leucine for other tissues.

Gastrointestinal (GI) tract leucine metabolism was measured in 6- to 9-mo-old lambs subjected to trickle infection with Trichostrongylus colubriformis larvae and in separate animals that were not infected. Animals prepared with a jejunal catheter and with indwelling catheters into the aorta and the portal- (PDV) and mesenteric- (MDV) drained viscera were infused simultaneously with [1-13C] and [5,5,5-2H3] leucine to determine GI tract sequestration of leucine from arterial and luminal amino acid pools by tracer and tracee arteriovenous concentration differences. Leucine oxidative losses and net fluxes were also determined across the GI tract. Infection had no detectable effect on whole-body leucine flux, but it increased total GI tract leucine sequestration by 24% (P<.05) and GI tract oxidative losses of leucine by 22 to 41% (P<.01). Net PDV fluxes of leucine were decreased by 20 to 32% during the infection. The infection did not alter either the proportion of precursor leucine used by GI tract metabolism that was derived from the arterial leucine pool (.84 to .88) or the proportional sequestration of digesta-derived leucine during "first pass" absorptive metabolism (.12 to .18). These findings help to elucidate the metabolic basis for the reduced growth rates and nitrogen retention observed when animals are subjected to subclinical nematode infection.

Animals↗
PubMed1983

Effect of abdominal irradiation on the kinetic parameters of intestinal uptake of glucose, galactose, leucine, and gly-leucine in the rat.

A previously validated in vitro technique was used to determine the effect of abdominal irradiation on the intestinal uptake (Jd) of glucose, galactose, leucine, and gly-leucine in the rat. Three days after 600 rads from a cesium-137 source, there was a rise in the jejunal maximal transport rate (Jdm) and the apparent Michaelis constant (Km*) but a decline in the apparent passive permeability coefficient (Pd*) for glucose. Thereafter, there was a progressive decline in Km* and Jdm but a rise in Pd* for glucose uptake. In the ileum, irradiation was associated with an increased Km* and Jdm and a decreased Pd*. Fourteen days after 600 rads, Jd of leucine into the jejunum was unchanged but Jd of leucine into the ileum was increased because of a higher Pd*. The Jd of leucine from gly-leucine was greater than from leucine alone. The Jd of 0.5 to 10 mM gly-leucine into the jejunum was increased after 600 rads, whereas the greater Jd of gly-leucine into the ileum after irradiation was most marked at 40 mM. Fourteen days after 300 rads, the Jd of glucose and galactose was increased into the ileum, whereas the Jd of leucine was decreased and the Jd of these probes into the jejunum and colon was unchanged; 14 days after 900 rads, the Jd of glucose and galactose was unchanged in each site and the Jd of leucine was reduced in the ileum but not the jejunum or colon.(ABSTRACT TRUNCATED AT 250 WORDS)

Abdomen↗
PubMed1992

In vivo differences between the turnover rates of leucine and leucine's ketoacid in stable cirrhosis.

Based on urinary nitrogen excretion, previous studies have indicated increased protein breakdown rates in cirrhosis. However, studies using [1-13C]-leucine infusion methodology have found normal protein breakdown rates. Because abnormal partitioning between extracellular and intracellular leucine exists in cirrhosis, plasma enrichment of leucine's keto acid (KIC), a marker of intracellular leucine, may more accurately reflect protein metabolism than plasma [1-13C]leucine enrichment. Therefore, protein breakdown and oxidation were calculated using both [1-13C]leucine and [1-13C]KIC and compared with urinary nitrogen excretion in seven cirrhotics and seven matched controls after an overnight fast. The ratio of KIC and leucine plasma enrichment was decreased (P less than 0.001) in cirrhosis because of lower KIC enrichment (P less than 0.006). Cirrhotics had increased rates of protein breakdown (P less than 0.006) and protein oxidation (P less than 0.05) based on KIC (P less than 0.006) but not leucine enrichment. In controls, protein oxidation calculated from urinary nitrogen excretion did not differ from KIC results (0.88 +/- 0.08 vs. 0.83 +/- 0.06) but was higher than the leucine method (0.88 +/- 0.08 vs. 0.73 +/- 0.05; P less than 0.01). However, in cirrhotics protein oxidation based on urinary nitrogen was lower than the KIC methodology (P less than 0.01). Therefore, cirrhotics have accelerated rates of protein breakdown and oxidation associated with increased extrarenal nitrogen loss. Furthermore, these results suggest abnormal leucine transport across cell membranes.

Adult↗
PubMed1984

The measurement of whole body protein turnover in the preterm infant with intragastric infusion of L-[1-13C]leucine and sampling of the urinary leucine pool.

The measurement of whole body protein turnover in the preterm infant has been investigated with an intragastric infusion of L-[1-13C]-leucine and with sampling of the urinary leucine pool. Measurements have been made in seven preterm infants with body weights averaging 1733 g, fed with either human breast milk (n = 3) or proprietary formulae (n = 4), giving intakes of 541 (+/- 25) kJ/kg and 465 (+/- 42) mg of N day-1 kg-1 and growing satisfactorily (14.7 +/- 2.6 g day-1 kg-1). The measurement of the enrichment of urinary leucine was well within the capability of gas chromatography-spectrometry, and similar values for the enrichment of plasma and urinary leucine were observed (plasma/urinary ratio was 0.93 +/- 0.04, mean +/- 1 SEM, n = 13). Isotopic equilibrium, as indicated by a plateau in the urinary leucine and expired CO2 enrichment, was obtained within 8 h and was maintained for at least 48 h. Nitrogen retention, measured by nitrogen balance, was similar to that calculated from the leucine retention (determined as the leucine intake--oxidation), i.e. 310 +/- 45 and 301 +/- 38 mg of N day-1 kg-1 (means +/- 1 SEM). Because of this it is suggested that in this specific type of study the direct measurement of nitrogen retention dispenses with the need for measurement of leucine oxidation, thereby simplifying the measurements. From the leucine flux, leucine intake and nitrogen retention, rates of whole body protein synthesis and degradation were shown to be 11.32 (+/- 0.78) and 9.54 (+/- 0.55) g day-1 kg-1.

Body Weight↗
PubMed1995

The 24-h kinetics of leucine oxidation in healthy adults receiving a generous leucine intake via three discrete meals.

The significance of meal size and frequency for the 24-h leucine tracer-balance technique was examined. Continuous measurements of leucine oxidation throughout a 24-h d were performed in six healthy, young adults who were given a weight-maintaining diet (188 kJ.kg-1.d-1; 1 g protein.kg-1.d-1) for 6 d followed by primed, continuous intravenous infusions of L-[1-13C]leucine and [15N-15N]urea. The 24-h study was started at 1800 on day 6 and three equal discrete meals were given at 2000, 0600, and 1200. Leucine oxidation was assessed from plasma [13C]alpha-ketoisocaproate enrichment and 13CO2 excretion. The mean (+/- SD) leucine oxidation after each meal (over 6 h) was not significantly different (P > 0.5) among the three discrete meals: 20.0 +/- 3.9, 20.2 +/- 1.9, and 20.3 +/- 2.4 mg.kg-1.d-1 for the meals given at 2000, 0600, and 1200, respectively. Twenty-four-hour leucine oxidation was 75.0 +/- 7.8 mg.kg-1.d-1 for a leucine dietary intake of 80 mg.kg-1.d-1 (and approximately 9.7 mg tracer.kg-1.d-1). The 24-h pattern in leucine oxidation was paralleled by plasma leucine concentrations. Further, leucine oxidation and urea excretion predicted relatively similar values for 24-h protein oxidation. These data are compared with results from our similar previous studies using a multiple-small-meal feeding protocol.

Adult↗
PubMed1977

Pathway for isoleucine formation form pyruvate by leucine biosynthetic enzymes in leucine-accumulating isoleucine revertants of Serratia marcescens.

Leaky revertants isolated from isoleucine auxotrophs of Serratia marcescens mutant resistant to alpha-aminobutyric acid were previously reported to accumulate leucine in the medium, due to the absence of both feedback inhibition and repression of leucine biosynthesis. Growth of the revertant was accelerated by pyruvate, D(-)-citramalate, citraconate, and alpha-ketobutyrate, but not by threonine. Extracts of the revertant exhibited high activities of pyruvate-dependent coenzyme A liberation from acetyl-coenzyme A, hydration of citraconate, and conversion of citraconate to alpha-ketobutyrate, but showed no threonine-deaminating activity. In the leucine-accumulating revertants the above three activities were not affected by leucine, but in the wild strain and other revertants accumulating no leucine all or one of these activities was controlled by leucine. A leucine auxotroph isolated from the leucine-accumulating revertant showed isoleucine auxotrophy as well. From these data, it is concluded that, in leucine-accumulating revertants, of S. marcescent, isoleucine, is synthesized from alpha-ketobutyrate via citramalate formed from pyruvate annd acetyl-coenzyme A by leucine biosynthetic enzymes, as a result of desensitization of alpha-isopropylmalate synthetase to feedback inhibition.

Acetyl Coenzyme A↗
PubMed1986

Changes in leucine kinetics during meal absorption: effects of dietary leucine availability.

Whole-body leucine and alpha-ketoisocaproate (KIC) metabolism were estimated in mature dogs fed a complete meal, a meal devoid of branched-chain amino acids, and a meal devoid of all amino acids. Using a constant infusion of [4,5-3H]leucine and alpha-[1-14C]ketoisocaproate (KIC), combined with dietary [5,5,5-2H3]leucine, the rate of whole-body proteolysis, protein synthesis, leucine oxidation, and interconversion of leucine and KIC were estimated along with the rate of leucine absorption. Ingestion of the complete meal resulted in a decrease in the rate of endogenous proteolysis, a small increase in the estimated rate of leucine entering protein, and a twofold increase in the rate of leucine oxidation. Ingestion of either the meal devoid of branched-chain amino acids or devoid of all amino acids resulted in a decrease in estimates of whole-body rates of proteolysis and protein synthesis, decreased leucine oxidation, and a decrease in the interconversion of leucine and KIC. The decrease in whole-body proteolysis was closely associated with the rise in plasma insulin concentrations following meal ingestion. Together these data suggest that the transition from tissue catabolism to anabolism is the result, at least in part, of decreased whole-body proteolysis. This meal-related decrease in proteolysis is independent of the dietary amino acid composition or content. In contrast, the rate of protein synthesis was sustained only when the meal complete in all amino acids was provided, indicating an overriding control of protein synthesis by amino acid availability.

Absorption↗
PubMed1994

Validation of the tracer-balance concept with reference to leucine: 24-h intravenous tracer studies with L-[1-13C]leucine and [15N-15N]urea.

The validity of tracer-derived estimates of whole-body leucine balance was investigated. Seven healthy young adult subjects received an adequate protein diet for 6 d; at 1800 on the last day, L-[1-13C]leucine and [15N-15N]urea were given as primed, continuous intravenous infusions for 24 h. Subjects were in a fasting state for the first 12 h and at 0600 on day 7 they then received hourly 10 equal meals to achieve a fed state. Total leucine intake (diet plus tracer) was 89.4 mg.kg-1.d-1. Mean daily leucine oxidation was equivalent to 89.5 +/- 3.3 mg leucine/kg. The predicted daily oxidation rate, from measurements made during the last hour of the fast and the fifth hour of the fed period, was 91.2 +/- 5.8 mg/kg (P = 0.25 from measured). Measured and predicted whole-body leucine balances were 0.76 +/- 2.99 and -0.98 +/- 5.54 mg/kg, respectively (P = 0.25). Urea production exceeded urea excretion by 20%; daily protein oxidation was the same when estimated from leucine oxidation or nitrogen excretion. Thus, the tracer-balance concept is valid, and reliable predictions of total daily leucine oxidation and whole-body leucine balance can be obtained from short-term measurements of leucine oxidation during fasted and fed states.

Adult↗
PubMed1988

Relationships between plasma isotope enrichments of leucine and alpha-ketoisocaproic acid during continuous infusion of labelled leucine.

The ratio at steady-state of alpha-ketoisocaproic acid (KIC) to leucine 13C enrichments in plasma during continuous infusion of [13C]leucine was examined in 58 studies under a variety of conditions. The ratio was lower (P less than 0.001) in 'arterialized' venous plasma (mean +/- SD 0.85 +/- 0.09) than in deep venous plasma (0.95 +/- 0.08), the sampling site enrichment differences being greater for leucine than for KIC. Variation in the ratio between the various conditions studied was largely explained by analytical variation. Three normal subjects were given an intravenous bolus dose of L-[1-13C, 15N]leucine. Both [13C]KIC and [13C]leucine appeared quantitatively in plasma within 10 min, indicating that both transamination of leucine and KIC, and their equilibration between intracellular fluid and plasma, is rapid. This study suggests that changes in sampling site, rather than in study conditions, are more likely to lead to variation in the KIC:leucine enrichment ratio. The lesser variation for KIC, and the rapid equilibration of the [13C]leucine bolus, favour KIC as tracee for [13C]leucine protein turnover studies.

Adult↗
PubMed1985

Effects of [15N]leucine infused at low rates on leucine metabolism in humans.

The present studies were carried out to determine whether infusions of [15N]leucine at low rates affect estimates of leucine oxidation and of proteolysis and protein synthesis in humans. Three groups of normal subjects were infused for 3 h with either [15N]leucine at a rate of 0.16 or 0.26 mumol X kg-1 X min-1 or saline using [2H3]leucine and alpha-[14C]ketoisocaproate as isotopic tracers of leucine metabolism. Data were analyzed at steady state using both single- and dual-isotope models. Preliminary studies were carried out to characterize the dual-isotope model in humans using infusions of [3H]leucine and alpha-[14C]ketoisocaproate. In the postabsorptive state estimates of leucine appearance, disappearance, and oxidation derived from the two isotope models were in good agreement. Infusion of stable isotope up to approximately 10% of the leucine carbon flux do not have a significant effect on leucine metabolism, but the data derived from such studies must be properly controlled and interpreted with care because these tracers are not massless.

Breath Tests↗
PubMedDate not supplied

Comparative evaluation of the quantitative utilization of parenterally and enterally administered leucine and L-[1-13C,15N]leucine within the whole body and the splanchnic region.

BACKGROUND: The purpose of this study was to quantify the kinetic aspects of leucine metabolism in the whole body and within the splanchnic region when an amino acid mixture is administered by the enteral route as compared with administration by the parenteral route. METHODS: Seven chronically catheterized dogs were studied during an intragastric infusion of L-[1-13C,15N]leucine with 0.24 g of complete amino acid mixture (kg-1.h-1) for 6 hours. The results are compared with those previously reported for nine dogs studied under essentially identical experimental conditions except that the tracer and amino acid mixtures were given by vein. RESULTS: At the whole body level, the various parameters of leucine metabolism (flux, oxidation, and disappearance into and release from proteins) were not significantly different among animals that were infused enterally and those that were infused parenterally. Leucine metabolism within the splanchnic region and gut was more extensive for enteral administration than for parenteral administration. For the splanchnic region, 31.4%, 27.9%, and 6.0% of enterally administered leucine was used for protein synthesis, deamination, and oxidization, respectively, compared with respective mean values of 19.5% (p < .001), 13.4% (p < .001), and 4.1% (p < .05) for parenterally administered leucine. For liver, 4.8% of enterally administered leucine was oxidized compared with 2.3% (p < .001) of parenterally administered leucine. These findings are qualitatively similar to those reported previously by us when comparing enteral and parenteral amino acid intakes but with an IV tracer infusion. CONCLUSION: Enteral administration seems to be more effective than an acute parenteral feeding regimen, at least in maintaining leucine (protein) balance in gut tissues.

Amino Acids↗
PubMed1987

Leucine kinetics during three weeks at submaintenance-to-maintenance intakes of leucine in men: adaptation and accommodation.

Previous results of short-term diet studies of leucine kinetics have suggested that the currently accepted requirement value for the amino acid in adults is too low. In the present study the effects of a more prolonged diet period at low leucine intakes on leucine kinetics and nitrogen balance (NB) were explored in healthy young men. They (4 or 5 subjects per group) received an adequate leucine intake (80 mg/kg/d) for 1 or 2 weeks (Period 1) followed by either 7, 14 or 30 mg/kg/d for 3 weeks (Period 2) with a return to 80 mg/kg/d for 1 week (Period 3). Estimates of leucine fluxes (LF), oxidation (LO) and balance (LB) were based on a constant intravenous infusion of L-[1-13C]leucine, at end of Period 1, at 1 and 3 weeks of Period 2 and on days 1 and 3 of Period 3. At all three intakes LF and LO, during the fed state, fell between 1 and 3 weeks of Period 2. LB was negative at 1 week of Period 2 for all groups but had approached equilibrium by 3 weeks. N balance at 3 weeks was similar for all groups but during Period 3 was significantly higher (P less than 0.05) and markedly positive (+18 mgN/kg/d) for the 7 and 14 mg groups, compared with the 30 mg group (+4 mgN/kg/d), indicating that 'depletion' had occurred at the lower leucine intakes during Period 2. Our interpretation is that LB was approached by an adaptation in the 30 mg group whereas it was achieved in the 7 and 14 mg groups by an accommodation, associated with a reduced and low rate of leucine uptake into protein (LF minus LO). Thus, the leucine requirement was judged to be greater than 14 mg/kg/d, a level currently accepted as the upper range of the requirement for healthy adults. The significance of these findings for assessment of nutrient requirements is discussed, with emphasis on the limitation of NB measurements for evaluation of human amino acid requirements.

Adaptation, Biological↗