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PubMed1985

Magnetic relaxation of solvent protons by Cu2+- and VO2+-substituted transferrin: theoretical analysis and biochemical implications.

Measurements of the magnetic field dependence of the longitudinal nuclear magnetic relaxation rates of solvent protons (NMRD profiles) in solutions of paramagnetic proteins have contributed significantly to the elucidation of the physical biochemistry of a number of metalloprotein systems. In many cases, NMRD profiles were used as indicators of chemical state, both static and dynamic [cf. Brewer, C. F., Brown, R. D., III, & Koenig, S. H. (1983) J. Biomol. Struct. Dyn. 1, 961-997], in part because a proper theoretical description of the data, with realistic assumptions for a model system, was computationally intractable. This has been particularly true for Cu2+-protein complexes, attributable in part to the S = 1/2 ground-state configuration of the Cu2+ ions; significant progress in interpreting such data has been made only recently [Bertini, I., Briganti, F., Luchinat, C., Mancini, M., & Spina, G. (1985) J. Magn. Reson. 63, 41-55]. We report NMRD profiles for solutions of Cu2+ - and VO2+-substituted human transferrin, both S = 1/2 ions, as well as computations that include the effects of the anisotropic hyperfine interactions of the paramagnetic ions with their respective nuclei. The description of the data that results from these computations is quite good, sufficiently so that one can say with confidence that the protons that contribute to the relaxation are rather distant (approximately 3.5 A) from the ions and in rapid exchange (approximately 10(8) s-1) with solvent. A possible view, consistent with what is known of the biochemistry of these substituted transferrins, is that relaxation occurs in the second coordination sphere: the exchanging entity is a water molecule hydrogen bonded to a donor atom of the metal ion complex.

Copper↗
PubMed2002

Solvent effects on the electronic absorption spectra and acid strength of some substituted pyridinols.

The electronic absorption spectra of some substituted pyridinols in organic solvents of different polarities are studied. Also, the solvent effects on the intramolecular charge transfer bands are discussed using various solvent parameters. The acid-base equilibria of the compounds used are studied spectrophotometrically in various mixed aqueous solvents at 25 degrees C and 0.1 M ionic strength (NaClO4). Furthermore, the influence of the solvents on the dissociation constants and tautomeric equilibria of a pyridinol derivatives are discussed. The effect of molecular structure of the pyridinols on the pK's is also examined.

Acids↗
PubMed1983

Biomolecular-solvent stereodynamic coupling probed by deuteration.

Thermodynamic interpretation of experiments with isotopically perturbed solvent supports the view that solvent stereodynamics is directly relevant to thermodynamic stability of biomolecules. According with the current understanding of the structure of the aqueous solvent, in any stereodynamic configuration of the latter, connectivity pathways are identifiable for their topologic and order properties. Perturbing the solvent by isotopic substitution or, e.g., by addition of co-solvents, can therefore be viewed as reinforcing or otherwise perturbing these topologic structures. This microscopic model readily visualizes thermodynamic interpretation. In conclusion, the topologic stereodynamic structures of connectivity pathways in the solvent, as modified by interaction with solutes, acquire a specific thermodynamic and biological significance, and the problem of thermodynamic and functional stability of biomolecules is seen in its full pertinent phase space.

Deuterium↗
PubMed1992

Critical functional role of the COOH-terminal ends of longitudinal hydrophobic strips in alpha-helices of T4 lysozyme.

The sensitivity of bacteriophage T4 lysozyme function to amino acid substitutions at defined positions in and around the longitudinal, hydrophobic strips of 9 alpha-helices was assessed after systematic replacement of each residue in the protein with a series of 13 amino acids. The hydrophobic strips were defined by identifying the longitudinal sectors in the helices with the highest mean residue hydrophobicities. Sensitivity to mutation (the percentage of replacements leading to loss of function) was calculated for each residue in the following positions: whole protein, helices, hydrophobic strips, other positions within the helices, and various positions within the hydrophobic strips as well as their extensions beyond the helices. Substitutions at positions in the hydrophobic strips led more frequently to loss of function than substitutions in the protein as a whole. One subset, the COOH-terminal hydrophobic strip residues, is apparently critical; substitutions of these residues (but not of their NH2-terminal counterparts) led at least as frequently to loss of function as substitutions of solvent-inaccessible residues, and nearly as frequently as substitutions of the most highly conserved residues.

Algorithms↗
PubMedDate not supplied

Reversible and irreversible interactions of a cisplatin analog bearing a 1,2-diphenylethylenediamine ligand with plasma and plasma proteins in vitro.

The cisplatin analog [meso-1,2-bis(2,6-dichloro-4-hydroxyphenyl) ethylenediamine]dichloroplatinum(II) [PtCl2(1)], by virtue of its estrogenic 1,2-diphenylethylenediamine ligand 1, was intended to function as a cytotoxic estrogen. This article reports on the reversible and irreversible interactions of this compound with plasma and plasma proteins in vitro. At 37 degrees C [PtCl2(1)] is > 99% reversibly bound to proteins in plasma. At 0 degree C [PtCl2(1)] reversibly binds to albumin at specific binding sites not shared by 1. By use of HPLC the in vitro half-life of total [PtCl2(1)] in plasma was found to be 35 min at 37 degrees C, which is approximately 1/3 the half-life reported for cisplatin under similar conditions. To understand this decreased stability, irreversible reactions of [PtCl2(1)] with albumin and plasma globulins were investigated. The reaction rate of [PtCl2(1)] with albumin is independent of the protein concentration and is comparable to the rate of the first Pt-Cl hydrolysis reaction. Thus, [PtCl2(1)], like cisplatin, reacts irreversibly with albumin through a solvent-assisted SN2 substitution pathway. Because the hydrolysis rate for [PtCl2(1)] is 40% slower than for cisplatin, irreversible reactions of [PtCl2(1)] with albumin cannot account for the decreased stability of the compound in plasma. alpha-Globulins undergo substitution reactions with [PtCl2(1)] by both solvent-assisted and direct SN2 pathways. The half-life of [PtCl2(1)] in the presence of alpha-globulins at concentrations normally present in plasma (6-16 g/liter) is from 41 to 22 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Alpha-Globulins↗
PubMed2003

Characterization of an Fe III-OOH species and its decomposition product in a bleomycin model system.

To model the mononuclear Fe(III)-OOH species identified in the catalytic cycle of the anticancer drug bleomycin, the iron chemistry of the pentadentate ligand N-[bis(2-pyridylmethyl)aminoethyl]pyridine-2-carboxamide (H-PaPy(3)) has been investigated. The complex [Fe(III)(PaPy(3))OCH(3)](ClO(4)) was reacted with H(2)O(2) to form a red species (lambda(max)=480 nm, epsilon=1800 M(-1) cm(-1)) with an S=1/2 EPR signal at g=2.25, 2.17, and 1.95. This species has been identified by electrospray ionization mass spectrometry as [Fe(III)(PaPy(3))OOH](ClO(4)) and further characterized by resonance Raman and EXAFS analysis. The decomposition of this intermediate leads to the modification of the ligand, as revealed by (1)H NMR. One hydrogen atom is substituted by a solvent-derived methoxy group. The substitution at this site is a result of the two-electron oxidation of the ligand following the heterolytic cleavage of the O-O bond of the Fe(III)-OOH species. This is a plausible mechanism to rationalize related ligand modifications that have been proposed in the decay of activated bleomycin.

Amides↗
PubMed2003

Sample preparation effects in matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry of partially depolymerised methyl cellulose.

Methyl cellulose (MC) was partially depolymerised and the oligomers thus obtained were studied by matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOFMS). The depolymerisation was either enzymatic or acidic. Fractions of enzymatically depolymerised MC were collected from size-exclusion chromatography and subjected to a sample preparation investigation. Several MALDI matrices and solvents were evaluated. The results showed that the solvent choice had a significant effect on the measured degree of substitution (DS). Aprotic solvents produced higher DS values, which was most likely due to poor solubility of species with low DS. The obtained signal intensity, however, did not correlate with the solubility but seemed to be more dependent on certain matrix/solvent combinations. All the matrices attempted produced mass spectra with sufficient signal intensity for accurate peak area calculation. The choice of matrix did not have any significant effect on the measured DS. Sample spots obtained from organic solvents had a more homogeneous distribution of the analyte and smaller crystals than those obtained from water. This increased both the reproducibility and peak resolution and in addition the analysis time was shorter. DS measurements were performed on two acidically depolymerised MCs with different nominal DS values. It was easy to distinguish between the two MCs, and the measured DS values agreed well with the values supplied by the manufacturers.

Biopolymers↗
PubMed2001

Regioselectively substituted 6-O- and 2,3-di-O-acetyl-6-O-triphenylmethylcellulose: its chain dynamics and hydrophobic association in polar solvents.

Two kinds of regioselectively substituted cellulose derivatives, i.e., 6-O-triphenylmethylcellulose (6TC) and 2,3-di-O-acetyl-6-O-triphenylmethylcellulose (2,3Ac6TC), were prepared via cellulose. In these samples, C-6 position hydroxyls in the anhydroglucose units (AGU) along the cellulose chain were selectively substituted by the hydrophobic triphenylmethyl groups, but C-2 and -3 position hydroxyls remained in 6TC or were substituted completely by O-acetyls in 2,3Ac6TC. Their chain dynamics in polar solvents, dimethyl sulfoxide (DMSO) and N,N-dimethylacetamide (DMAc), in dilute solution were investigated by dynamic light scattering in the viewpoint of cluster formation. The results were compared with those of cellulose diacetates (CDA) in DMAc where three hydroxyls in the AGU were statistically substituted up to 2.44 by O-acetyls but hydroxyls at C-6 positions remained predominantly. It was found that 6TC and 2,3Ac6TC formed a dynamic structure about 10 times larger than single chains and that the structure would be a temporary and local association due to concentration fluctuations (dynamic structures) which were originated from the hydrophobic interactions between intermolecular triphenylmethyl groups. The dynamics and structures were in clear contrast to those of CDA where a solvent-mediated hydrogen bonding between intermolecular C-6 position hydroxyls was essential to cluster formation. The present structures were so weak as to dissipate easily under low shear field.

Macromolecular Substances↗
PubMed2002

Control of the conformational equilibria in aza-cis-decalins: structural modification, solvation, and metal chelation.

A series of amino alcohol- and diamino-cis-decalins were synthesized and their conformational properties investigated. The equilibrium distributions of the conformational isomers were measured via NMR spectroscopy. The equilibrium ratios depend on the position of the substituents on the decalin ring system and the solvent. The 7-substituted 1-aza-cis-decalins are more likely to adopt the N-in form than the 5-substituted analogues. The N-in form is generally favored in nonpolar solvents, while the N-out form is favored in polar solvents. Complexation with LiClO4 and Et2Zn alters the equilibrium to favor the N-in decalin conformer. Both conformers coordinate lithium ions such that "on/off" conformational switching is not observed for these decalins. Comparison of the results with complexation studies of (-)-sparteine allows the criteria for an ideal "on/off" conformational switch to be defined.

Alcohols↗
PubMed2005

Microwave-assisted solvent-free synthesis of 3-[(4-substituted piperazin-1-yl)alkyl] imidazo[2,1-b][1,3]benzothiazol-2(3H)-ones as serotonin3 (5-HT3) receptor antagonists.

A series of novel 3-[(4-substituted piperazin-1-yl)alkyl]imidazo[2,1-b][1,3]benzothiazol-2(3H)-ones were prepared by microwave irradiation using alumina as solid support and also by a conventional method. The compounds were characterized by spectral data and the purity was ascertained by microanalysis. The synthesized compounds were evaluated for 5-hydroxytryptamine3 antagonisms in a longitudinal muscle-myenteric plexus preparation from guinea pig ileum against the 5-hydroxytryptamine3 agonist, 2-methyl-5-hydroxytryptamine. Among the test compounds, 3-[2-(4-methylpiperazin-1-yl)ethyl]imidazo[2,1-b][1,3]benzothiazol-2(3H)-one (3b) showed most favorable 5-hydroxytryptamine3 antagonism (pA2 6.7) in the isolated guinea pig ileum.

Animals↗
PubMed1985

Correlation between octanol solvent distribution ratio and liquid chromatographic retention for some 7- and 9-substituted 1-methyl-isoguanines.

Octanol/aqueous buffer solvent distribution ratio and liquid chromatographic retention in a primarily aqueous phase were determined and correlated to estimated substituent Hansch pi values for a series of 1-methyl-isoguanines. Substituent connectivity values (simple, valence, and bond length) were also computed and factored into the correlation equation between known in vitro activity data and these lipophilic parameters. The liquid chromatographic retention data were best correlated with measured activity accounting for 61% of the variation while distribution ratio and Hansch pi accounted for 56% or 52%, respectively, when each was considered alone. Valence connectivity accounted for 30% of the variation alone but did not add significantly to the equations when factored with the other parameters.

Binding, Competitive↗
PubMed2000

Substrate and solvent isotope effects on the fate of the active oxygen species in substrate-modulated reactions of putidamonooxin.

Using 4-methoxybenzoate monooxygenase from Pseudomonas putida, the substrate deuterium isotope effect on product formation and the solvent isotope effect on the stoichiometry of oxygen uptake, NADH oxidation, product and/or H2O2 (D2O2) formation for tight couplers, partial uncouplers, and uncouplers as substrates were measured. These studies revealed for the true, intrinsic substrate deuterium isotope effect on the oxygenation reaction a k1H/k2H ratio of < 2.0, derived from the inter- and intramolecular substrate isotope effects. This value favours a concerted oxygenation mechanism of the substrate. Deuterium substitution in a tightly coupling substrate initiated a partial uncoupling of oxygen reduction and substrate oxygenation, with release of H2O2 corresponding to 20% of the overall oxygen uptake. This H2O2 (D2O2) formation (oxidase reaction) almost completely disappeared when the oxygenase function was increased by deuterium substitution in the solvent. The electron transfer from NADH to oxygen, however, was not affected by deuterium substitution in the substrate and/or the solvent. With 4-trifluoromethylbenzoate as uncoupling substrate and D2O as solvent, a reduction (peroxidase reaction) of the active oxygen complex was initiated in consequence of its extended lifetime. These additional two electron-transfer reactions to the active oxygen complex were accompanied by a decrease of both NADH oxidation and oxygen uptake rates. These findings lead to the following conclusions: (a) under tightly coupling conditions the rate-limiting step must be the formation time and lifetime of an active transient intermediate within the ternary complex iron/peroxo/substrate, rather than an oxygenative attack on a suitable C-H bond or electron transfer from NADH to oxygen. Water is released after the monooxygenation reaction; (b) under uncoupling conditions there is competition in the detoxification of the active oxygen complex between its protonation (deuteronation), with formation of H2O2 (D2O2) and its further reduction to water. The additional two electron-transfer reactions onto the active oxygen complex then become rate limiting for the oxygen uptake rate.

Bacterial Proteins↗
PubMed2001

The problem of a solvent exposable disulfide when preparing Co(II)-substituted metallo-beta-lactamase L1 from Stenotrophomonas maltophilia.

In an effort to prepare Co(II)-substituted metallo-beta-lactamase L1 from Stenotrophomonas maltophilia for future spectroscopic and mechanistic studies, two methods for the preparation of Co(II)-L1 were tested. Method A involved adding CoCl2 directly to apo-L1 under anaerobic conditions. The resulting enzyme contained 1.9 moles of cobalt and exhibited very little activity, and UV-Vis, 1H NMR, and EPR studies indicated that most of the cobalt in this sample was Co(III). Method B involved reducing the single and unique disulfide bridge in L1 with tris(carboxyethyl)phosphine prior to adding CoCl2. The resulting enzyme was pink, contained 2.5 moles of cobalt per mole of enzyme, and exhibited kcat and Km values of 18+1 s(-1) and 10+/-1 microM, respectively, when using nitrocefin as the substrate. UV-Vis, 1H NMR, and EPR studies revealed that this enzyme sample contained high-spin Co(II). The UV-Vis spectra also provided evidence for Co(II) bound to one or both of the reduced cysteines. Efforts to block this non-specific Co(II) binding site using a chemical modification agent or site-directed mutagenesis were unsuccessful. The data presented here demonstrate the problem of solvent-exposed disulfides when preparing Co(II)-substituted enzymes and offers a convenient method to circumvent the problem.

Base Sequence↗
PubMed2000

The H(2)(18)O solvent-induced isotope shift in (19)F NMR.

The H(2)(16)O/H(2)(18)O solvent-induced isotope shifts ((18)O SIIS) of the (19)F NMR signals of a number of fluorine compounds have been measured. These isotope shifts are observed to be upfield, downfield, or zero, depending on the specific compound and the precise solution conditions. At 25 degrees C and with an (18)O enrichment of 86%, the (18)O SIIS of several fluorinated amino acids were in the range of 0.0014-0.0018 ppm downfield. 5-Fluorouridine displays a significantly wider range of (18)O SIIS values. A 5-fluorouridine-labeled 16-mer RNA also displayed observable (18)O SIIS values, but the characteristics of these were significantly modified from those of free 5-fluorouridine. The experimental observations are consistent with the (18)O SIIS being composed of upfield and downfield components, with the relative contributions of these determining the size and direction of the overall isotope shift. This is discussed in terms of a combination of van der Waals interactions between the fluorine atom and the solvent, electrical and hydrogen bonding effects, and the perturbations to these due to (18)O substitution in the solvent water. This isotope effect promises to be a highly useful tool in a range of (19)F NMR studies.

Animals↗
PubMed2002

Nucleotide variations in the lxd region of Drosophila melanogaster: characterization of a candidate modifier of lifespan.

We have investigated the structure and function of several proteins that might influence adult lifespans in Drosophila melanogaster. The present report focuses on the gene lxd ('low xanthine dehydrogenase'), which lies in a region of chromosome III identified by QTL-mapping as potentially important for lifespan. DNA sequence of a 3780 bp genomic fragment containing the lxd locus reveals differences between long-lived and control inbred lines. In order to determine the importance of nucleotide replacements, the intron/exon boundaries have been determined, based on peptide alignment and conserved amino acids. We identified four exons in the lxd coding region. The deduced amino acid sequence of exon 4 shows 46.5% identity with Escherichia coli MoaC sequences. There are eight nucleotide substitutions in exons differentiating the inbred lines, three in exon 3 and five in exon 4. One of the exon 4 substitutions has resulted in a Thr-Ile replacement at the protein surface, but not entirely solvent exposed. This substitution is potentially a modifier of lifespan via oxygen defense, but since the activities of three molybdoenzymes are unaffected in inbred lines, this possibility seems remote.

Amino Acid Sequence↗
PubMed2003

Reduced exposure to organic solvents by use of water-based paint systems in car repair shops.

OBJECTIVE: The objective of this study was to determine to what extent the substitution of solvent-based paint by water-based paint has reduced potential exposure to organic solvents for spray painters in car repair shops. METHODS: Full-shift personal air sampling (n=79) was carried out over 3 consecutive days in eight car repair shops. Blood samples on the Monday morning (n=26) and at the end of the shift on the Wednesday (n=26), were analysed for organic solvents by headspace techniques. RESULTS: Toluene was the organic solvent detected at the highest geometric mean concentration in air samples when solvent-based paint systems were used (0.8 ppm), whereas xylene was found at the highest level when water-based systems were used (0.25 ppm). Toluene, isopropanol, acetone and butyl acetate were detected at higher concentrations when solvent-based paint was used than when water-based paint was employed. The additive factor, based on Norwegian limit values, was three-times higher for the painters using solvent-based paint (0.15) than for those using water-based paint (0.05). On Wednesday after shift the geometric mean of toluene in blood was significantly higher for the painters using solvent-based paint (0.044 microg/ml) than for the painters using water-based paint (0.007 microg/ml). There was a significant correlation between toluene in personal air samples and toluene in blood samples taken at the end of the shift on the same day. CONCLUSIONS: When solvent-based paint systems were used the additive factor for organic solvent exposure was three-times higher than when water-based systems were employed. The exposure levels of the organic solvents were well below the Norwegian limit values. The significant correlation between the toluene concentration in air and blood samples indicated that the uptake of organic solvents was correspondingly reduced. At the levels of organic solvents presently described the risk of acute and chronic health effects caused by organic solvents is low.

Air Pollutants, Occupational↗
PubMed1996

Peptide synthesis on chitin.

The use of chitin as a support for solid-phase peptide synthesis is described and illustrated by synthesis of four peptides, varying in length from 10 to 29 residues. Syntheses were performed in a continuous-flow peptide synthesizer, using Fmoc chemistry. A cleavable linker, p-[(R,S)-alpha-[1-(9H-fluoren-9-yl)-methoxyformamido]-2,4-di methoxybenzyl]- phenoxyacetic acid, was attached to chitosan at the desired substitution level, and the complex acetylated to yield a linker substituted chitin. The effects of temperature, solvents and degree of linker substitution on the syntheses were studied. Acyl carrier peptide (ACP) synthesis studies indicated that temperature was the single most important parameter. Increasing the temperature of the synthesis from 20 to 55 degrees C resulted in an enormous improvement of this synthesis, with about 90% of the crude product being the correct peptide. Denaturing solvents, such as DMSO, could be used without significant effect on the flow properties of the support. The synthesis of one peptide was mainly improved by lowering the degree of substitution from 0.3 to 0.1 mmol/g, suggesting peptide aggregation was a problem in this case. The results of three syntheses on chitin were comparable with those obtained with a commonly used commercial support. This work shows that, under appropriate conditions, chitin can be utilized directly as a support for peptide synthesis.

Amino Acid Sequence↗