Gene/Protein Disease Symptom Drug Enzyme Compound
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 28,634 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To test the role of inorganic phosphate (Pi) in downregulation of myocardial contractile force at the onset of ischemia, Pi of rat hearts was determined with 31P nuclear magnetic resonance spectroscopy. Forty cycles of brief hypoperfusion (30% of baseline flow for 33 s) were used to achieve a time resolution of 0.512 s for comparing dynamic changes in Pi and contractile force. Initial control values of left ventricular developed pressure (LVP), heart rate, and oxygen consumption were 136 +/- 11 mmHg, 236 +/- 4 beats/min, and 95 +/- 3 microl O2 x min(-1) x g(-1); these values were unchanged at the end of the experiment. During the first 10 s of hypoperfusion, Pi increased at a rate (percentage of the total observed change) faster than the decrease in LVP; Pi and LVP then changed at the same rate during the remainder of the hypoperfusion. ADP did not change in advance of LVP. Intracellular pH did not change. The results indicate that Pi plays an important role in initiating the downregulation of myocardial contractile force at the onset of ischemia. Perfusion pressure also declined faster than LVP at the onset of ischemia, indicating potential importance of vascular collapse in contractile downregulation during early ischemia.
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PMID:Correlation between myocardial contractile force and cytosolic inorganic phosphate during early ischemia. 908 9

The kinetics of folding of a tryptophan containing mutant of the IgG binding domain of protein L were characterized using stopped-flow circular dichroism, stopped-flow fluorescence, and HD exchange coupled with high-resolution mass spectrometry. Both the thermodynamics and kinetics of folding fit well to a simple two-state model: (1) Guanidine induced equilibrium denaturation transitions measured by fluorescence and circular dichroism were virtually superimposable. (2) The kinetics of folding/unfolding were single exponential under all conditions examined, and the rate constants obtained using all probes were similar. (3) Mass spectra from pulsed HD exchange refolding experiments showed that a species with very little protection from exchange is converted to a fully protected species (the native state) at a rate very similar to that of the overall change in tryptophan fluorescence; no intervening partially protected species were observed. (4) Rate constants (in H2O) and m values for folding and unfolding determined by fitting observed relaxation rates obtained over a broad range of denaturant concentrations to a two-state model were consistent with the equilibrium parameters deltaG and m: -RT ln(k(u)/k(f))/deltaG(U)H2O = 1.02; (m(u) + m(f))/m = 1.08. In contrast to results with a number of other proteins, there was no deviation from linearity in plots of ln k(obs) versus guanidine at low guanidine concentrations, both in the presence and absence of 0.4 M Na2SO4, suggesting that significantly stabilized intermediates do not accumulate during folding. Although all of the change in fluorescence signal during folding in phosphate buffer was accounted for by the simple exponential describing the overall folding reaction, fluorescence-quenching experiments using sodium iodide revealed a small reduction in the extent of quenching of the protein within the first two milliseconds after initiation of refolding in low concentrations of guanidine, suggesting a partial collapse of the unfolded chain may occur under these conditions. Comparison with results on the structurally and functionally similar IgG binding domain of streptococcal protein G show intriguing differences in the folding of the two proteins.
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PMID:Kinetics of folding of the IgG binding domain of peptostreptococcal protein L. 911 17

Hemoglobin (Hb) induces heme oxygenase-1 (HO-1), which catalyzes the breakdown of heme to bilirubin, and ferritin. Rats pretreated with Hb have been shown to survive lethal doses of lipopolysaccharide (LPS; see L. Otterbein, S. L. Sylvester, and A. M. Choi. Am. J. Respir. Cell Mol. Biol. 13: 595-601, 1995). The physiological basis of this increased survival and the mechanism(s) involved in the protection against LPS by Hb are unknown. Here we investigated 1) the effects of Hb on the hemodynamic and biochemical parameters of LPS-induced tissue injury and 2) the mechanism(s) by which Hb conferred protection against shock and tissue injury. Hb-treated rats maintained normal mean arterial blood pressure, whereas control rats experienced cardiovascular collapse after a lethal dose of LPS. Hepatic and renal functions, peripheral white blood cells, serum lactate dehydrogenase, and phosphate also remained normal after LPS in Hb-treated rats. Hb also attenuated LPS-induced neutrophil alveolitis and tumor necrosis factor-alpha levels. Pretreatment with both desferoxamine, which, like ferritin, can bind iron, and with exogenous apoferritin failed to protect against LPS. In contrast, treatment with Hb plus desferoxamine, which induced HO-1 but not ferritin, did protect against LPS. Treatment with iron-dextran, which induced ferritin but not HO-1, did not protect against LPS. We conclude that Hb pretreatment reduces the inflammatory and physiological consequences of LPS and that the Hb-induced protection against LPS is dependent on HO-1 and not ferritin induction.
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PMID:Mechanism of hemoglobin-induced protection against endotoxemia in rats: a ferritin-independent pathway. 912 78

Asymmetric phosphate neutralization has been hypothesized to play a role in DNA bending by proteins. Neutralization is thought to involve salt bridges between the negatively charged phosphate backbone of duplex DNA and the cationic amino acids of an approaching protein. According to this model, the resulting unbalanced charge distribution along the duplex DNA induces the double helix to collapse toward the neutralized surface. Previous work has confirmed that DNA bending is induced by the asymmetric incorporation of racemic methylphosphonate linkages creating a neutral region on one face of duplex DNA. Neutralization was accomplished by substitution of three consecutive phosphodiesters on each strand, arranged across one minor groove of the DNA (a total of six neutralized phosphates). We now measure DNA bending induced by a more diffuse patch of neutralization (alternating neutralized and anionic phosphates) and explore the effect of methylphosphonate stereochemistry. DNA duplexes with patches of alternating methylphosphonate and phosphodiester linkages are less bent than DNAs wherein consecutive phosphates are neutralized. Furthermore, duplexes neutralized by incorporation of pure (RP)-methylphosphonate isomers are bent approximately 30% less than duplexes neutralized by racemic methylphosphonates.
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PMID:Effects of neutralization pattern and stereochemistry on DNA bending by methylphosphonate substitutions. 922 Sep 55

This review is concerned with the structures and mechanisms of a superfamily of regulatory GTP hydrolases (G proteins). G proteins include Ras and its close homologs, translation elongation factors, and heterotrimeric G proteins. These proteins share a common structural core, exemplified by that of p21ras (Ras), and significant sequence identity, suggesting a common evolutionary origin. Three-dimensional structures of members of the G protein superfamily are considered in light of other biochemical findings about the function of these proteins. Relationships among G protein structures are discussed, and factors contributing to their low intrinsic rate of GTP hydrolysis are considered. Comparison of GTP- and GDP-bound conformations of G proteins reveals how specific contacts between the gamma-phosphate of GTP and the switch II region stabilize potential effector-binding sites and how GTP hydrolysis results in collapse (or reordering) of these surfaces. A GTPase-activating protein probably binds to and stabilizes the conformation of its cognate G protein that recognizes the transition state for hydrolysis, and may insert a catalytic residue into the G protein active site. Inhibitors of nucleotide release, such as the beta gamma subunit of a heterotrimeric G protein, bind selectively to and stabilize the GDP-bound state. Release factors, such as the translation elongation factor, Ts, also recognize the switch regions and destabilize the Mg(2+)-binding site, thereby promoting GDP release. G protein-coupled receptors are expected to operate by a somewhat different mechanism, given that the GDP-bound form of many G protein alpha subunits does not contain bound Mg2+.
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PMID:G protein mechanisms: insights from structural analysis. 924 20

Transcription activation is thought to require DNA bending to promote the interaction of upstream activators and the basal transcription machinery. Previous experiments have shown that some members of the bZIP family of DNA binding proteins bend DNA, while others do not. We are exploring the possibility that electrostatic effects play a role in these differences. The yeast bZIP transcription factor GCN4 does not induce DNA bending in vitro. Substitution of basic residues for three neutral amino acids of GCN4 confers the ability to bend DNA. This result is consistent with a model of induced DNA bending wherein excess positive charge in proximity to one face of the double helix neutralizes local phosphate diester anions resulting in a laterally asymmetric charge distribution along the DNA. Previous data suggest that such an unbalanced charge distribution results in collapse of the DNA toward the neutralized surface. Interpretations of the present data are discussed. Our result supports the hypothesis that electrostatic interactions can play a key role in DNA bending by bZIP proteins.
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PMID:DNA bending by GCN4 mutants bearing cationic residues. 925 97

The PU.1 transcription factor is a member of the Ets family of DNA binding proteins. PU.1 binds to DNA via a loop-helix-loop domain and functions in the differentiation of hematopoietic cells. The structure of a PU.1-DNA complex was recently reported (Kodandapani, R., Pio, F., Ni, C.-Z., Piccialli, G., Klemsz, M., McKercher, S., Maki, R., and Ely, K. (1996) Nature 380, 456-460). The DNA in this complex is deformed by 8 degrees as it curves around the protein. The pattern of electrostatic contacts between PU.1, and its DNA binding site suggests that laterally asymmetric phosphate neutralization accompanies PU.1 binding. Because of our previous studies showing that such neutralization can induce bending in naked DNA, we have explored the effect of phosphate neutralization by substituting neutral methylphosphonate internucleoside linkages at relevant positions within DNA containing the PU.1 binding sequence. Consistent with the prediction that DNA will collapse toward its partially neutralized surface, DNA neutralized at seven positions to simulate PU.1 binding is observed to bend by 28 degrees . The directions of DNA curvature are slightly different in the co-crystal versus the partially neutralized duplexes. The electrostatic component of the binding energy appears more than enough to account for the DNA bending observed in the PU.1-DNA complex.
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PMID:Role of asymmetric phosphate neutralization in DNA bending by PU.1. 939 94

DNA architecture has been shown to be important for cellular processes such as activation of transcription, recombination, and replication. Many proteins reconfigure the shape of duplex DNA upon binding. Previous experiments have shown that some members of the eukaryotic bZIP family of DNA binding proteins appear to bend DNA, while others do not. We are exploring the role of electrostatic effects in DNA bending by bZIP proteins. The yeast bZIP transcription factor GCN4 does not induce DNA bending in vitro. Previously we substituted basic residues for three neutral amino acids in GCN4 to produce a GCN4 derivative that bends DNA by approximately 15 degrees. This result is consistent with a model of induced DNA bending wherein excess positive charge in proximity to one face of the double helix neutralizes local phosphate diester anions resulting in a laterally-asymmetric charge distribution along the DNA. Such an unbalanced charge distribution can result in collapse of the DNA toward the neutralized surface. We now present a more comprehensive analysis of electrostatic effects in DNA bending by GCN4 derivatives. It is shown that the direction and extent of DNA bending by these derivatives are a linear function of the charges of the amino acids adjacent to the basic domain of the protein. This relation holds over the charge range +6 (16 degrees bend toward the minor groove) to -6 (25 degrees bend toward the major groove).
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PMID:Electrostatic effects in DNA bending by GCN4 mutants. 945 97

Lacticin 3147 is a broad-spectrum bacteriocin produced by Lactococcus lactis subsp. lactis DPC3147 (M. P. Ryan, M. C. Rea, C. Hill, and R. P. Ross, Appl. Environ. Microbiol. 62:612-619, 1996). Partial purification of the bacteriocin by hydrophobic interaction chromatography and reverse-phase fast protein liquid chromatography revealed that two components are required for full activity. Lacticin 3147 is bactericidal against L. lactis, Listeria monocytogenes, and Bacillus subtilis; at low concentrations of the bacteriocin, bactericidal activity is enhanced when target cells are energized. This finding suggests that the presence of a proton motive force promotes the interaction of the bacteriocin with the cytoplasmic membrane, leading to the formation of pores at these low lacticin 3147 concentrations. These pores were shown to be selective for K+ ions and inorganic phosphate. The loss of these ions resulted in immediate dissipation of the membrane potential and hydrolysis of internal ATP, leading to an eventual collapse of the pH gradient at the membrane and ultimately to cell death. Our results suggest that lacticin 3147 is a pore-forming bacteriocin which acts on a broad range of gram-positive bacteria.
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PMID:Lacticin 3147, a broad-spectrum bacteriocin which selectively dissipates the membrane potential. 946 77

Previous electrophoretic experiments suggest that the AP-1 site in duplex DNA bends in response to the pattern of amino acid charges distal to the basic region in bound bZIP proteins. The extent and direction of apparent DNA bending are consistent with the prediction that DNA will collapse locally upon asymmetric phosphate charge neutralization. To prove that asymmetric phosphate neutralization could produce the observed degree of DNA bending, the present experiments partially substitute anionic phosphate diesters in the AP-1 site with various numbers of neutral methylphosphonate linkages. DNA bending is induced toward the neutralized face of DNA. The degree of DNA bending induced by methylphosphonate substitution (approximately 3.5 degrees per neutralized phosphate) is comparable to that induced by GCN4 variants carrying increasing numbers of additional basic amino acids. It is plausible, therefore, that asymmetric phosphate neutralization is the cause of DNA bending in such complexes.
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PMID:Effects of phosphate neutralization on the shape of the AP-1 transcription factor binding site in duplex DNA. 958 Jun 78


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