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A perspective on free radical autoxidation: the physical organic chemistry of polyunsaturated fatty acid and sterol peroxidation.
Porter NA
(2013) J Org Chem 78: 3511-24
MeSH Terms: Chemistry, Physical, Dehydrocholesterols, Fatty Acids, Unsaturated, Free Radicals, Heterocyclic Oxides, Humans, Oxidative Stress, Peroxides, Sterols
Show Abstract · Added March 7, 2014
This Perspective describes advances from the author's laboratory on the free radical reactions of organic compounds with molecular oxygen. Polyunsaturated fatty acids (PUFAs) and sterols are particularly prone to undergo radical chain oxidation, and evidence suggests that this process, known as lipid peroxidation, occurs in vivo under a variety of conditions that are the result of an oxidative stress. Cyclic peroxides, hydroperoxides, and epoxy alcohols are major products formed from peroxidation, and the basic mechanisms of product formation are now reasonably well understood. These mechanisms include reversible addition of oxygen to carbon radicals, rearrangement and cyclization of allyl and pentadienyl peroxyl radicals, and homolytic substitution of carbon radicals on the peroxide bond. A physical organic approach to the problem of free radicals in biology and medicine is highlighted in this Perspective with stereochemical, kinetic, and extrathermodynamic probes applied to the study of mechanism. A radical clock permits the determination of free radical propagation rate constants, and 7-dehydrocholesterol, the immediate biosynthetic precursor of cholesterol, is found by this clock to be one of the most oxidizable lipids known. The consequences of the extreme reactivity of 7-dehydrocholesterol on human health is the focus of a current research theme in the author's laboratory.
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9 MeSH Terms
Recognition dynamics up to microseconds revealed from an RDC-derived ubiquitin ensemble in solution.
Lange OF, Lakomek NA, Farès C, Schröder GF, Walter KF, Becker S, Meiler J, Grubmüller H, Griesinger C, de Groot BL
(2008) Science 320: 1471-5
MeSH Terms: Amino Acid Motifs, Animals, Anisotropy, Chemical Phenomena, Chemistry, Physical, Crystallography, X-Ray, Entropy, Kinetics, Models, Molecular, Nuclear Magnetic Resonance, Biomolecular, Protein Binding, Protein Conformation, Protein Structure, Tertiary, Solutions, Ubiquitin, Xenopus laevis
Show Abstract · Added January 24, 2015
Protein dynamics are essential for protein function, and yet it has been challenging to access the underlying atomic motions in solution on nanosecond-to-microsecond time scales. We present a structural ensemble of ubiquitin, refined against residual dipolar couplings (RDCs), comprising solution dynamics up to microseconds. The ensemble covers the complete structural heterogeneity observed in 46 ubiquitin crystal structures, most of which are complexes with other proteins. Conformational selection, rather than induced-fit motion, thus suffices to explain the molecular recognition dynamics of ubiquitin. Marked correlations are seen between the flexibility of the ensemble and contacts formed in ubiquitin complexes. A large part of the solution dynamics is concentrated in one concerted mode, which accounts for most of ubiquitin's molecular recognition heterogeneity and ensures a low entropic complex formation cost.
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16 MeSH Terms
Development of improved nanoparticulate polyelectrolyte complex physicochemistry by nonstoichiometric mixing of polyions with similar molecular weights.
Hartig SM, Carlesso G, Davidson JM, Prokop A
(2007) Biomacromolecules 8: 265-72
MeSH Terms: Biocompatible Materials, Chemistry, Physical, Colloids, Electrolytes, Hydrogen-Ion Concentration, Ions, Macromolecular Substances, Microscopy, Electron, Transmission, Molecular Weight, Nanoparticles, Peptides, Polymers, Solubility, Water
Show Abstract · Added December 10, 2013
Water-based, biodegradable polyelectrolyte complex dispersions (PECs) prepared by mixing oppositely charged polyions are advantageous drug delivery systems due to constituent biocompatibility and nanoparticulate architectures. Reaction phase environmental parameters dictate PEC physicochemical properties, and specifically, complexation between polyelectrolytes having significantly different molecular weights leads to formation of water-insoluble aggregates. Starting with this fact, four-component similar and dissimilar molecular weight PEC chemistries were applied and compared with and without frequency-induced dispergation. The goal was to define nanoparticulate PEC systems with desirable characteristics for use in biological systems. Results show PEC formulations from precursors with similar low molecular weights yielded dispersions with suitable physicochemical characteristics, as verified by photon correlation spectroscopy and TEM, presumably due to efficient ion pairing. Similar low molecular weight PECs fabricated with dispergation exhibited pH-independent stability, as validated by charge and size measurements. These physicochemical advantages lead to an ideal delivery platform.
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14 MeSH Terms
Quantitative observation of backbone disorder in native elastin.
Pometun MS, Chekmenev EY, Wittebort RJ
(2004) J Biol Chem 279: 7982-7
MeSH Terms: Animals, Cattle, Chemical Phenomena, Chemistry, Physical, Deuterium, Elasticity, Elastin, Magnetic Resonance Spectroscopy, Proline, Protein Structure, Secondary, Spectrum Analysis, Thermodynamics, Water
Show Abstract · Added March 5, 2014
Elastin is a key protein in soft tissue function and pathology. Establishing a structural basis for understanding its reversible elasticity has proven to be difficult. Complementary to structure is the important aspect of flexibility and disorder in elastin. We have used solid-state NMR methods to examine polypeptide and hydrate ordering in both elastic (hydrated) and brittle (dry) elastin fibers and conclude (i) that tightly bound waters are absent in both dry and hydrated elastin and (ii) that the backbone in the hydrated protein is highly disordered with large amplitude motions. The hydrate was studied by (2)H and (17)O NMR, and the polypeptide by (13)C and (2)H NMR. Using a two-dimensional (13)C MAS method, an upper limit of S < 0.1 was determined for the backbone carbonyl group order parameter in hydrated elastin. For comparison, S approximately approximately 0.9 in most proteins. The former result is substantiated by two additional observations: the absence of the characteristic (2)H spectrum for stationary amides and "solution-like" (13)C magic angle spinning spectra at 75 degrees C, at which the material retains elasticity. Comparison of the observed shifts with accepted values for alpha-helices, beta-sheets, or random coils indicates a random coil structure at all carbons. These conclusions are discussed in the context of known thermodynamic properties of elastin and, more generally, protein folding. Because coacervation is an entropy-driven process, it is enhanced by the observed backbone disorder, which, we suggest, is the result of high proline content. This view is supported by recent studies of recombinant elastin polypeptides with systematic proline substitutions.
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13 MeSH Terms
NMR determination of the conformation of a trimethylene interstrand cross-link in an oligodeoxynucleotide duplex containing a 5'-d(GpC) motif.
Dooley PA, Zhang M, Korbel GA, Nechev LV, Harris CM, Stone MP, Harris TM
(2003) J Am Chem Soc 125: 62-72
MeSH Terms: Base Pairing, Base Sequence, Chemical Phenomena, Chemistry, Physical, Computer Simulation, CpG Islands, Cross-Linking Reagents, Cyclopropanes, DNA, Malondialdehyde, Models, Chemical, Models, Molecular, Nuclear Magnetic Resonance, Biomolecular, Nucleic Acid Conformation, Oligodeoxyribonucleotides, Thermodynamics
Show Abstract · Added May 29, 2014
Malondialdehyde interstrand cross-links in DNA show strong preference for 5'-d(CpG) sequences. The cross-links are unstable and a trimethylene cross-link has been used as a surrogate for structural studies. A previous structural study of the 5'-d(CpG) cross-link in the sequence 5'-d(AGGCGCCT), where G is the modified nucleotide, by NMR spectroscopy and molecular dynamics using a simulated annealing protocol showed the guanine residues and the tether lay approximately in a plane such that the trimethylene tether and probably the malondialdehyde tether, as well, could be accommodated without major disruptions of duplex structure [Dooley et al. J. Am Chem. Soc. 2001, 123, 1730-1739]. The trimethylene cross-link has now been studied in a GpC motif using the reverse sequence. The structure lacks the planarity seen with the 5'-d(CpG) sequence and is skewed about the trimethylene cross-link. Melting studies indicate that the trimethylene cross-link is thermodynamically less stable in the GpC motif than in the 5-d(CpG). Furthermore, lack of planarity of the GpC cross-link precludes making an isosteric replacement of the trimethylene tether by malondialdehyde. A similar argument can be used to explain the 5'-d(CpG) preference for interchain cross-linking by acrolein.
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16 MeSH Terms
DNA interchain cross-links formed by acrolein and crotonaldehyde.
Kozekov ID, Nechev LV, Moseley MS, Harris CM, Rizzo CJ, Stone MP, Harris TM
(2003) J Am Chem Soc 125: 50-61
MeSH Terms: Acrolein, Aldehydes, Chemical Phenomena, Chemistry, Physical, Chromatography, High Pressure Liquid, CpG Islands, Cross-Linking Reagents, DNA, DNA Adducts, Electrophoresis, Capillary, Nuclear Magnetic Resonance, Biomolecular, Spectrometry, Mass, Electrospray Ionization, Stereoisomerism, Substrate Specificity
Show Abstract · Added May 29, 2014
Acrolein and higher alpha,beta-unsaturated aldehydes are bifunctional genotoxins. The deoxyguanosine adduct of acrolein, 3-(2-deoxy-beta-d-erythro-pentofuranosyl)-5,6,7,8-tetrahydro-8-hydroxypyrimido[1,2-a]purin-10(3H)-one (8-hydroxy-1,N(2)-propanodeoxyguanosine, 2a), is a major DNA adduct formed by acrolein. The potential for oligodeoxynucleotide duplexes containing 2a to form interchain cross-links was evaluated by HPLC, CZE, MALDI-TOF, and melting phenomena. Interchain cross-links represent one of the most serious types of damage in DNA since they are absolute blocks to replication. In oligodeoxynucleotides containing the sequence 5'-dC-2a, cross-linking occurred in a slow, reversible manner to the extent of approximately 50%. Enzymatic digestion to form 3-(2-deoxy-beta-d-erythro-pentofuranosyl)-5,6,7,8-tetrahydro-8-(N(2)-2'-deoxyguanosinyl)pyrimido[1,2-a]purin-10(3H)one (5a) and reduction with NaCNBH(3) followed by enzymatic digestion to give 1,3-bis(2'-deoxyguanosin-N(2)-yl)propane (6a) established that cross-linking had occurred with the exocyclic amino group of deoxyguanosine. It is concluded that the cross-link is a mixture of imine and carbinolamine structures. With oligodeoxynucleotide duplexes containing the sequence 5'-2a-dC, cross-links were not detected by the techniques enumerated above. In addition, (15)N-(1)H HSQC and HSQC-filtered NOESY spectra carried out with a duplex having (15)N-labeling of the target amino group established unambiguously that a carbinolamine cross-link was not formed. The potential for interchain cross-link formation by the analogous crotonaldehyde adduct (2b) was evaluated in a 5'-dC-2b sequence. Cross-link formation was strongly dependent on the configuration of the methyl group at C6 of 2b. The 6R diastereomer of 2b formed a cross-link to the extent of 38%, whereas the 6S diastereomer cross-linked only 5%.
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14 MeSH Terms
Comparative analysis of the noncollagenous NC1 domain of type IV collagen: identification of structural features important for assembly, function, and pathogenesis.
Netzer KO, Suzuki K, Itoh Y, Hudson BG, Khalifah RG
(1998) Protein Sci 7: 1340-51
MeSH Terms: Algorithms, Amino Acid Sequence, Chemical Phenomena, Chemistry, Physical, Collagen, Consensus Sequence, Gelatinases, Matrix Metalloproteinase 2, Matrix Metalloproteinase 3, Metalloendopeptidases, Molecular Sequence Data, Peptide Fragments, Phylogeny, Protein Structure, Secondary, Sequence Alignment, Structure-Activity Relationship, Tissue Inhibitor of Metalloproteinases
Show Abstract · Added December 10, 2013
Type IV collagen alpha1-alpha6 chains have important roles in the assembly of basement membranes and are implicated in the pathogenesis of Goodpasture syndrome, an autoimmune disorder, and Alport syndrome, a hereditary renal disease. We report comparative sequence analyses and structural predictions of the noncollagenous C-terminal globular NC1 domain (28 sequences). The inferred tree verified that type IV collagen sequences fall into two groups, alpha1-like and alpha2-like, and suggested that vertebrate alpha3/alpha4 sequences evolved before alpha1/alpha2 and alpha5/alpha6. About one fifth of NC1 residues were identified to confer either the alpha1 or alpha2 group-specificity. These residues accumulate opposite charge in subdomain B of alpha1 (positive) and alpha2 (negative) sequences and may play a role in the stoichiometric chain selection upon type IV collagen assembly. Neural network secondary structure prediction on multiple aligned sequences revealed a subdomain core structure consisting of six hydrophobic beta-strands and one short alpha-helix with a significant hydrophobic moment. The existence of opposite charges in the alpha-helices may carry implications for intersubdomain interactions. The results provide a rationale for defining the epitope that binds Goodpasture autoantibodies and a framework for understanding how certain NC1 mutations may lead to Alport syndrome. A search algorithm, based entirely on amino acid properties, yielded a possible similarity of NC1 to tissue inhibitor of metalloproteinases (TIMP) and prompted an investigation of a possible functional relationship. The results indicate that NC1 preparations decrease the activity of matrix metalloproteinases 2 and 3 (MMP-2, MMP-3) toward a peptide substrate, though not to [14C]-gelatin. We suggest that an ancestral NC1 may have been incorporated into type IV collagen as an evolutionarily mobile domain carrying proteinase inhibitor function.
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17 MeSH Terms
Kinetics of ferric cytochrome P450 reduction by NADPH-cytochrome P450 reductase: rapid reduction in the absence of substrate and variations among cytochrome P450 systems.
Guengerich FP, Johnson WW
(1997) Biochemistry 36: 14741-50
MeSH Terms: Animals, Chemical Phenomena, Chemistry, Physical, Cytochrome P-450 CYP1A2, Cytochrome P-450 CYP3A, Cytochrome P-450 Enzyme System, Cytochromes b5, Electron Transport, Ferric Compounds, Humans, Kinetics, Microsomes, Liver, Mixed Function Oxygenases, Models, Biological, NADPH-Ferrihemoprotein Reductase, Oxidation-Reduction, Rabbits, Recombinant Fusion Proteins
Show Abstract · Added March 5, 2014
The reduction of ferric cytochrome P450 (P450) to ferrous is the first chemical step in almost all P450 reactions, and many characteristics of this step have been reported. Reduction kinetics of rabbit and human P450s were measured in a variety of systems. As reported earlier, P450 reduction is biphasic in microsomes and some purified P450 systems. However, this is not an inherent property of P450s, and some low- and high-spin iron P450s were reduced with single-exponential kinetics. Contrary to a generalized view, the presence of substrate is not necessary for rapid reduction of all P450s. Also, low-spin heme can be reduced as rapidly as high-spin in several P450s. P450s varied considerably in their reduction behavior, and even a single P450 showed remarkably different reduction kinetics when placed in various environments. P450 3A4 reduction was examined in liver microsomes, a reconstituted system, a fusion protein in which it was linked to NADPH-P450 reductase, and baculovirus and bacterial membranes in which P450 3A4 and NADPH-P450 reductase were coexpressed; the systems differed considerably in terms of the need for the substrate testosterone and cytochrome b5 (b5) for reduction and as to whether reduction was rate-limiting in the overall catalytic cycle. When b5 was included in reconstituted systems, it reduction kinetics were linked with those of some P450s. This behavior could be simulated in kinetic models in which electrons flowed from the ferrous P450.CO complex to oxidized b5. Overall, the kinetics of ferric P450 reduction cannot be generalized among different P450s in various systems, and concepts regarding influence of substrate, reaction sequence, and a rate-limiting step are not very universal.
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18 MeSH Terms
Changes in the NMR-derived motional parameters of the insulin receptor substrate 1 phosphotyrosine binding domain upon binding to an interleukin 4 receptor phosphopeptide.
Olejniczak ET, Zhou MM, Fesik SW
(1997) Biochemistry 36: 4118-24
MeSH Terms: Amino Acid Sequence, Antigens, CD, Binding Sites, Chemical Phenomena, Chemistry, Physical, Insulin Receptor Substrate Proteins, Kinetics, Ligands, Magnetic Resonance Spectroscopy, Models, Molecular, Molecular Sequence Data, Phosphopeptides, Phosphoproteins, Phosphotyrosine, Protein Binding, Protein Conformation, Receptors, Interleukin, Receptors, Interleukin-4, Recombinant Proteins, Type C Phospholipases, src Homology Domains
Show Abstract · Added March 5, 2014
Proteins recognize ligands by forming specific intermolecular interactions that often involve solvent exposed residues. Changes in the motional properties of these residues upon binding can affect the conformational entropy of the system and thus are related to the energetics of binding. The role that dynamics plays in ligand recognition can be investigated by comparing the motional properties of a free and ligated protein. NMR relaxation studies are well suited for examining changes in dynamics, especially for motions on a nanosecond to picosecond time scale. Recently, we determined the solution structure of the phosphotyrosine binding (PTB) domain of the insulin receptor substrate (IRS-1) complexed to a tyrosine-phosphorylated peptide derived from the interleukin 4 (IL-4) receptor [Zhou et al., (1996) Nat. Struct. Biol. 3, 388-393]. The peptide binds tightly to the protein in a surface exposed pocket, resulting in the partial burial of many protein residues. Using NMR relaxation studies, the dynamics of the backbone nitrogens of IRS-1 PTB domain were studied in both the free protein and the protein when complexed to the IL-4 receptor phosphopeptide. The backbone nitrogens of many residues that make important contacts to the ligand are motionally restricted in the free and complexed protein. Additional residues become motionally restricted only after ligand binding, including several residues that do not make any direct contacts with the ligand. These observed changes in the dynamics are compared to structural features of the complex.
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21 MeSH Terms
Two-dimensional motion of DNA bands during 120 degrees pulsed-field gel electrophoresis.
Neitzey LM, Hutson MS, Holzwarth G
(1993) Electrophoresis 14: 296-303
MeSH Terms: Chemical Phenomena, Chemistry, Physical, DNA, Electrophoresis, Gel, Pulsed-Field, Fluorescent Dyes, Video Recording
Show Abstract · Added May 20, 2014
The position and velocity of a band of double-stranded, linear DNA from bacteriophage G were measured during 120 degrees pulsed-field gel electrophoresis, using a video micrometer. Both the x and y coordinates were determined simultaneously in the plane of a 1% agarose gel; x is the mean drift direction. For pulse durations T greater than the tube renewal time T*, the path traced by the band of 670 kb DNA in the xy plane was in remarkably good accord with that predicted by Southern's ratchet model. However, the measured instantaneous velocity vx showed a sharp backward spike each time the field changed direction, with amplitude about twice the mean drift velocity. This spike is not consistent with models which assume a constant curvilinear velocity of DNA in a tube, nor with the biased reptation model without fluctuations. The corresponding measurements of vy showed a sharp positive spike with amplitude more than 3 times the plateau velocity in the y direction; neither model predicted this. The sharp velocity spikes are consistent with the idea that, for T > T*, a large fraction of the DNA chains are stretched into U-shaped or herniated configurations. When the field changes direction, the arms of the U's and the hernias recoil rapidly in response to intramolecular DNA chain tension. Because the base of a U or hernia is fixed by gel fibers, the center of mass of the chain recoils backward every time the field changes direction.
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6 MeSH Terms