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PubMed1964

ISOLEUCINE AND VALINE METABOLISM IN ESCHERICHIA COLI. XII. CHARACTERIZATION OF A FACTOR INVOLVED IN ACETOLACTATE FORMATION.

Leavitt, Richard I. (Long Island Biological Association, Cold Spring Harbor, N.Y.). Isoleucine and valine metabolism in Escherichia coli. XII. Characterization of a factor involved in acetolactate formation. J. Bacteriol. 88:172-178. 1964.-An unknown factor required for the formation of acetolactate, the first five-carbon precursor of valine, is described. The presence of this factor eliminates the dilution effect encountered when studying the effect of increasing enzyme concentration on the formation of acetolactate. It is suggested that this factor functions by increasing the enzyme affinities of both pyruvate and thiamine pyrophosphate.

Acetaldehyde↗
PubMed2000

Distinction and quantitation of leucine-isoleucine isomers and lysine-glutamine isobars by electrospray ionization tandem mass spectrometry (MS(n), n = 2, 3) of copper(II)-diimine complexes.

Electrospray ionization of mixtures of isomeric and isobaric amino acids was investigated with the goal of distinguishing and quantifying the components. Isomeric amino acids leucine and isoleucine were readily distinguished and quantified in 90 : 10 to 10 : 90 binary mixtures using two-stage (MS(2)) and three-stage (MS(3)) tandem mass spectrometric dissociations of ternary Cu(2+)-2, 2'-bipyridyl (bpy) complexes, [Cu(AA - H)bpy](+). The complexes self-assembled in solution upon mixing the components and provided a convenient means of efficient derivatization that increased the efficiency of amino acid ionization by electrospray and shifted the mass of the analytes to a region which was free of solvent interferences. Low-energy dissociations of [Cu(AA - H)bpy](+) complexes in a quadrupole ion trap were achieved at >90% conversions and >80% trapping efficiencies for the MS(2) and MS(3) precursor and fragment ions. Isobaric amino acids glutamine and lysine were also distinguished through MS(2) and MS(3) of their ternary complexes with Cu(2+) and bpy. ESI of [Cu(Gln - H)bpy](+) was enhanced in the presence of [Cu(Lys - H)bpy](+), which resulted in non-linear response at low Lys concentrations.

Copper↗
PubMed1999

Conformational change of ascidiacyclamide caused by asymmetric modification for an isoleucine residue: structural analyses of [Gly], [Leu], and [Phe]ascidiacyclamides by x-ray diffraction and NMR spectroscopy.

Ascidiacyclamide, a cytotoxic cyclic peptide from tunicate, is composed of unusual amino acids and has a repeated sequence, c[-thiazole-D-Val-oxazoline-L-Ile-]2 ([Ile]ASC). The symmetric chemical structure has been assumed to be correlated with the cytotoxicity, and it is reasonable to consider that the disturbance of its structure from the C2 symmetry results in the changes of conformation and activity. In order to quantitatively estimate the molecular conformation-activity relationship, an isoleucine residue was substituted by Gly, Leu, or Phe to disturb the C2 symmetry. The conformations of three derivatives were examined by nmr spectroscopy and the crystal structure of [Leu]ASC was also analyzed by x-ray diffraction method. The 1H-nmr experiments and the constrained molecular dynamics simulations showed the twisted "figure 8" conformers for [Gly] and [Phe]ASCs and the "square" conformer for [Leu]ASC in the DMSO solution. The x-ray crystal analysis of [Leu]ASC also revealed the square form similar to the solution structure. On the other hand, their cytotoxic activities were measured using L1210 leukemia cells and were related with the bulkiness and/or hydrophobicity of the side chain of the substituted amino acid; [Phe] > or = [Ile] > [Leu] >> [Gly]ASCs. As an attempt to consider the correlation between the activity and conformer, the accessible surface area (ASA) was calculated for each derivative to estimate the size or bulkiness of its conformation. Although the ASAs of nmr structures were not directly related to the type of conformer (figure 8 or square form), it was an important probe to consider the cytotoxicity of each derivative.

Amino Acid Substitution↗
PubMed1980

In-beam electron impact mass spectrometry of N-carbobenzoxy derivatives of oligopeptides composed of leucine and isoleucine.

The characteristics of the in-beam electron impact mass spectra of 13 N-carbobenzoxyoligopeptides (up to pentapeptides) composed mainly of leucine and isoleucine, and their alkyl and N-hydroxysuccinimide esters are described. In the cases of di- and tripeptide derivatives, each in-beam electron impact spectrum exhibited an abundant [M + 1]+ peak as well as amino-acyl fragments. However, in the case of pentapeptides the in-beam spectra measured under the routine conditions corresponded to the conventional electron impact spectra of the cyclopeptide derivatives formed by thermal cyclization in the mass spectrometer and few [M + 1]+ ions of the original peptides were observed. From the studies on temperature spectral change of in-beam electron impact spectra it became clear that rapid heating of the sample over the temperature range 200-300 degrees C gave abundant [M + 1]+ ions as well as fragment ions originating from the thermally intact peptide as the major peaks in the spectrum.

Isoleucine↗
PubMed1982

The identification of (E)-2-methylglutaconic acid, a new isoleucine metabolite, in the urine of patients with beta-ketothiolase deficiency, propionic acidaemia and methylmalonic acidaemia.

The identification of (E)-2-methylglutaconic acid, a 'new' metabolite of isoleucine, is described. The substance was detected in urine samples from patients with propionic acidaemia, methylmalonic acidaemia and so-called beta-ketothiolase deficiency; in the majority of cases together with N-tiglylglycine. (E)-2-Methylglutaconic acid is thought to be the end product of the 3-methylcrotonyl-CoA carboxylase-catalysed carboxylation of tiglyl-CoA. Prerequisites for the quantitative gas chromatographic analysis of the unstable 2- (and 3-) methyl-glutaconic acid ditrimethylsilyl ester are given.

Acetyl-CoA C-Acyltransferase↗
PubMed2005

Full-capillary sample stacking/sweeping-MEKC for the separation of naphthalene-2,3-dicarboxaldehyde-derivatized tryptophan and isoleucine.

In an attempt to improve the sensitivity of detection in capillary electrophoresis (CE), a novel online sample-concentration method, full-capillary sample stacking (FCSS)/sweeping-micellar electrokinetic chromatography (sweeping-MEKC) mode, is proposed. Naphthalene-2,3-dicarboxaldehyde (NDA)-derivatized tryptophan and isoleucine were selected as model compounds. In the initial step, the weakly acidic compounds, dissolved in a low-conductivity buffer (35.1 microS/cm; apparent ph (pH*) in a mixed solution of acetonitrile/methanol/water, 4.6), fill the entire capillary, two vials of a high-conductivity buffer (2.06 mS/cm; pH* 2.0) are placed on each end, and a negative polarity is then applied. Under these conditions, the direction of the electroosmotic flow (EOF) is toward the inlet. Meanwhile, the anionic analytes move in the reverse direction and are neutralized and stacked at the boundary of a dynamic pH-junction (between the sample matrix and the nonmicellar background solution (BGS)). When the sample concentration is completed, the BGS is quickly changed to solutions containing SDS-BGS for the subsequent separation. Since the mobility of SDS-analytes is then greater than the EOF, the following steps occur by the sweeping (for focusing) and MEKC (for separation) mode. Using these steps, a full-capillary sample injection/separation can be achieved.

Chromatography, Micellar Electrokinetic Capillary↗
PubMed1991

Two PDGF-B chain residues, arginine 27 and isoleucine 30, mediate receptor binding and activation.

PDGF may be involved in the pathogenesis of a variety of disorders including atherosclerosis and certain types of cancer. There is currently little understanding of the molecular structure of PDGF and of the critical amino acid residues involved in receptor binding and cell activation. Two such PDGF-B chain residues, arginine 27 and isoleucine 30, have been identified by a site-directed mutagenesis programme. Substitutions in these positions can lead to PDGF mutants defective in both receptor affinity and cell activation as judged by displacement of [125I]PDGF-BB, mitogenic assay and inositol lipid turnover. Circular dichroism and fluorescence spectroscopy show that such mutations do not disrupt the structure of PDGF.

3T3 Cells↗
PubMed2005

Theoretical study of the gas-phase structures of sodiated and cesiated leucine and isoleucine: zwitterionic structure disfavored in kinetic method experiments.

The most stable charge-solvated (CS) and zwitterionic (ZW) structures of sodiated and cesiated leucine and isoleucine were studied by density functional theory methods. According to the Boltzmann distribution in gas phase, both forms of LeuNa+ and IleNa+ exist, but in LeuCs+ and IleCs+, the ZW forms are dominant. Results for the sodiated compounds are consistent with the relationship found between decrease in relative stability of CS versus ZW form and aliphatic amino acid side chain length. The observed degeneracy in energy for IleNa+ conformers is at odds with kinetic method results. Additional calculations showed that kinetic method structural determinations for IleNa+ do not reflect relative order of populations in the lowest energy conformers. Since complexation of cationized amino acids into ion-bound dimers disfavors ZW structure by approximately 8 kJ mol(-1), it is suggested that for energy close conformers of sodium-cationized amino acids, the kinetic method may not be reliable for structural determinations.

Cesium↗
PubMed1995

Two naturally occurring amino acid substitutions in the human 5-HT1A receptor: glycine 22 to serine 22 and isoleucine 28 to valine 28.

The human 5-HT1A receptor was screened for naturally occurring mutations. The PCR product of the 5-HT1A receptor gene was digested with several restriction enzymes and evaluated by single-strand conformational polymorphism (SSCP) analysis. Comparison of the SSCP electrophoretic pattern with a restriction map of the 5-HT1A receptor allowed localization of the polymorphic sites facilitating their identification by sequence analysis. Two polymorphisms were identified in the human 5-HT1A receptor gene that altered amino acid composition. The polymorphisms encode amino acid substitutions in the 5-HT1A receptor of a glycine to serine at amino acid 22 and an isoleucine to valine at amino acid 28, respectively. Both polymorphisms alter the extracellular amino terminal domain of the 5-HT1A receptor. The polymorphic 5-HT1A alleles have been found in American and Finnish Caucasians and in native American Indians. This is the first report of a polymorphism in the human 5-HT1A receptor gene that alters the structure of the 5-HT1A receptor protein composition.

Alleles↗
PubMed1981

Technetium coordination state as a factor of stability in 99mTc-complexes used in hepatobiliary system: comparative studies on 99mTc-complexes of pyridoxal with glutamate (Tc-PG) and isoleucine (Tc-PI).

Studies on 99mTc-Penicillamine (Tc-Pen) have given us some insight into the significance of the technetium coordination state in hepatobiliary clearance behavior. A 99mTc-complex of pyridoxal and glutamate (Tc-PG) prepared by Baker et al. (1975) using an autoclaving process or by a Sn-Resin kit method (Horiuchi 1981) was compared with a 99mTc-complex of pyridoxal and isoleucine (Tc-PI) prepared by the method of Kato and Hazue (1978) through an intermediate compound of stannous ion, at room temperature. Tc-PG and TcPI complexes analyzed by thin layer chromatography, sephadex column chromatography (G-15), octanol extraction, and ligand exchange reaction showed different chemical properties. Their biological evaluation also demonstrated great differences in biodistribution in mice, metabolic studies, protein binding, and rat bile excretion. Tc-PG was estimated as an hepatobiliary agent with strong metal-ligand binding, inert to ligand exchange reaction with Pen at physiological pH; the likely occurrence of technetium in a mononuclear or dinuclear state providing the great stability observed in its biological and in vivo behavior was compared with the relatively weaker binding observed in Tc-PI, a highly lipophilic complex of high liver partition but of low stability, denoting its different chemical characteristics. The technetium coordination state in radiopharmaceuticals is responsible for the integrity of the molecule while in the blood pool and its relevance in impaired liver uptake is discussed.

Animals↗
PubMed1976

Significance of a new type of human fetal hemoglobin carrying a replacement isoleucine replaced by threonine at position 75 )E 19) of the gamma chain.

A new type of hemoglobin F, in which isoleucine in position 75 (E 19) of the gamma chain is replaced by a threonine residue, has been found in 29 out of 32 homozygotes for beta thalassemia. The amount of this hemoglobin ranges from traces to 40% of the total Hb F. The same gamma75 Thr chain is also present in the Hb F of 40% of normal newborns and premature infants examined, of one 14-week-old fetus and in one out of 3 patients with aplastic anemia and raised levels of Hb F. Our results strongly suggest that the synthesis of this new chain is under the control of a gamma gene nonallelic with those coding for Agamma and Ggamma chains.

Adult↗
PubMed1977

Detection of messenger RNA from the isoleucine--valine operons of Salmonella typhimurium by heterologous DNA-RNA hybridization: involvement of transfer RNA in transcriptional repression.

A hybridization assay using Escherichia coli K-12 DNA isolated from the specialized transducing bacteriophage gammaCI857St68h80 dilv was used to examine the rate of synthesis of the messenger RNA's (mRNA) derived from the isoleucine-valine (ilv) gene cluster of Salmonella typhimurium. In all cases examined, changes in ilv enzyme levels could be correlated with changes in the rate of synthesis of ilv mRNA. Several well characterized regulatory mutants of S. typhimurium had rates of synthesis of ilv mRNA 3 to 8-fold higher than the repressed wild-type strain. The increased rates of ilv mRNA synthesis found in a hisT strain as well as in isoleucyl-and leucyl-tRNA SYNTHETASE MUTANTS, STRONGLY SUGGESTS A ROLE FOR BRANCHED-CHAIN AMINOACYL-TRNA's in transcriptional control.

Coliphages↗
PubMed1979

Propionyl-CoA carboxylase deficiency with overflow of metabolites of isoleucine catabolism at all levels.

An 11-year old girl with spastic paraplegia and mental retardation has suffered from attacks of metabolic acidosis since the age of 18 months. "Ketotic hyperglycinemia" was diagnosed when she was 3 years old. Reinvestigation at 9 1/2 years included a two-day load with L-isoleucine, and propionyl-CoA carboxylase assay in cultured fibroblasts. The following compounds increased following the load: 3-hydroxypropionic acid, 2-methyl-3-hydroxybutyric acid, 2-ethylhydracrylic acid, 3-hydroxy-n-valeric acid, 3-oxo-n-valeric acid, 2-methyl-3-oxobutyric acid, 2-oxo-3-methylvaleric acid, 2-methyl-3-oxovaleric acid, N-tiglylglycine, methylcitric acid and butanone. Small amounts of alloisoleucine appeared in plasma. Propionyl-CoA carboxylase deficiency was suggested by this metabolite pattern and demonstrated in cultured fibroblasts.

Acidosis↗
PubMed1977

Alpha-isopropylmalate synthase from Alcaligenes eutrophus H 16. III. Endproduct inhibition and its relief by valine and isoleucine.

The alpha-isopropylmalate synthase (EC 4.1.3.12) from Alcaligenes eutrophus H 16 was inhibited by L-leucine and alpha-ketoisocaproate. The extent of inhibition was influenced by substrate- and inhibitor concentrations as well as by the pH. Intermediary plateaus, which always appeared in the inhibition curves, suggested cooperative effects. The maximal Hill coefficient was found to be two. At low concentrations of leucine the inhibition mechanism was of the competitive type with respect to substrate acetyl coenzyme A and of the noncompetitive type with respect to substrate alpha-ketoisovalerate. The inhibition was specifically relieved by the addition of valine or isoleucine. The anomalous effect of temperature on enzyme activity was diminished by leucine. The Arrhenius energy of the reaction increased from about 11 kcal/mole in the absence of leucine to about 18 kcal/mole in the presence of leucine. The further addition of valine reversed this effect. The physiological relevance of the alpha-ketoisocaproate-mediated inhibition is discussed.

2-Isopropylmalate Synthase↗
PubMed1993

Mitochondrial 2-methylacetoacetyl-CoA thiolase deficiency: an inborn error of isoleucine and ketone body metabolism.

A review is presented of 22 published cases of verified or probable mitochondrial 2-methylacetoacetyl-CoA thiolase deficiency, a disorder of isoleucine and ketone body metabolism. The clinical expression, characterized by ketoacidosis, vomiting and lethargy, is highly variable. Typical age of onset is between 6 and 24 months. The disorder, which has been observed in several ethnic groups, is apparently inherited as an autosomal, recessive trait. The prognosis is relatively good if acute episodes of ketoacidosis and dehydration are adequately treated. There is abnormal urinary excretion of 2-methyl-3-hydroxybutyric acid, tiglylglycine, and in some instances also 2-methyl-acetoacetic acid. However, such a pattern of organic aciduria has also been found in cases with normal thiolase activity. Genetic complementation analyses have demonstrated considerable heterogeneity. The cDNA for human methyl-acetoacetyl-CoA thiolase has been cloned and sequenced. Studies in one patient showed a G-to-A substitution at position 1138 of the mRNA, causing 347Ala to Thr change in the mature enzyme. Studies in other patients have shown variable enzyme amount and/or stability.

Acetyl-CoA C-Acyltransferase↗
PubMed1990

The effect of plasma valine, isoleucine and leucine on the control of the flux through tyrosine- and tryptophan-hydroxylase in the brain.

The effect of increasing blood levels of valine, isoleucine and leucine on the fluxes through tyrosine and tryptophan hydroxylase in brain has been calculated and analysed in terms of flux control coefficients. It is concluded that any beneficial effect of increasing the concentration of these amino acids in phenylketonuria patients is not due to a decrease in brain phenylalanine or an improved neurotransmitter synthesis through tyrosine or tryptophan hydroxylase.

Blood-Brain Barrier↗
PubMed1977

Leucine and isoleucine as in vitro precursors for lipid synthesis by rat aorta.

The in vitro conversion of 14C-labeled leucine, isoleucine, and pyruvate to specific lipids was compared in rat aorta, diaphragm, anf fat pad. Total lipid specific radioactivity from all precursors was greatest in aorta. The ratio of label incorporated into polar lipids vs. neutral lipids by aorta was generally several-fold that incorporated by muscle and fat pad. The labeling of sterols in the aorta from 14C-leucine and pyruvate was equivalent. It is concluded that leucine may be a substantial precursor to polar lipids and to sterols in rat aorta.

Animals↗
PubMed1990

Conversion of ammonia or urea into essential amino acids, L-leucine, L-valine, and L-isoleucine using artificial cells containing an immobilized multienzyme system and dextran-NAD. L-lactic dehydrogenase for coenzyme recycling.

A multienzyme system consisting of leucine dehydrogenase (EC 1.4.1.9), L-lactic dehydrogenase (EC 1.1.1.27), urease (EC 3.5.1.5), and dextran-NAD+ was microencapsulated within artificial cells. This system could convert ammonia and urea into essential amino acids, L-leucine, L-valine, and L-isoleucine. L-lactate acted as a cosubstrate for the regeneration of dextran-NADH. Greater concentrations of L-lactate favored the higher conversion ratios. The effects of ammonium salts and urea on reaction rate were also studied. The relative reaction rates in ammonium salts solutions were 44.6-78.8% of those in urea solutions. More than 90% of the original activity was retained when artificial cells were kept at 4 degrees C for 6 wk.

Amino Acid Oxidoreductases↗