Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Resonance assignments for interleukin 1 beta at neutral pH were made by using three-dimensional NMR in combination with specific labeling and double-labeling methods with stable isotopes. On the basis of the present assignments, 15N single-quantum coherence spectra of N-terminal truncated and fusion mutants were compared with that of the wild-type. Although these mutants have reduced biological activity, they showed 15N-SQC spectra similar to that of the wild-type. However, small but significant chemical shift changes were observed for amino acid residues within a loop 86-99, in spite of the modification at the N-terminus, supporting the idea that this loop forms a biologically active part of interleukin 1 beta. Receptor-binding activity was studied for mutants (Asp-93)-, (Leu-93)- and des-(Arg-98)interleukin 1 beta's. The results show significant loss of the receptor-binding activity. The N-terminus, the C-terminus, and the loop 86-99 form a part of the open end of a beta-barrel [Finzel, B. C., Clancy, L. L., Holland, D. R., Muchmore, S. W., Watenpaugh, K. D., & Einspahr, H. M. (1989) J. Mol. Biol. 209, 779-791; Clore, G. M., Wingfield, P. T., & Gronenborn, A. M. (1991) Biochemistry 30, 2315-2323], which forms the receptor-binding site of IL-1 beta.
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PMID:Stable isotope aided nuclear magnetic resonance study to investigate the receptor-binding site of human interleukin 1 beta. 153 68

Modules which share the same consensus sequence are assumed to have common structural features, at the secondary and tertiary level. In order to test the extent of such similarities, it is necessary to examine the structures of several examples from each module family. Recently, the first three-dimensional structure of a complement control protein (CCP) module (the 16th repeat of human factor H, H16) was determined using a combination of two-dimensional NMR and simulated annealing [Norman, D.G., Barlow, P.N., Baron, M., Day, A.J., Sim, R.B., & Campbell, I.D. (1991) J. Mol. Biol. 219, 717-725]. Using the same techniques, the three-dimensional structure of a second CCP module (the 5th repeat of human factor H, H5) has now been determined. The primary sequence of H5 contains 17 residues which are identical and in equivalent position to those in H16. Thirteen of these 17 are part of the consensus sequence. The similarities between the secondary structure of H5 and that of H16 are extensive. This implies that the consensus sequence dictates a particular secondary structure. The tertiary structure of H5, a compact hydrophobic core wrapped in beta-strand and sheet, bears much overall resemblance to that of H16. However, there is a deletion in the first strand of H5, and an insertion in a loop, resulting in slightly shorter overall length. This is associated with a rearrangement of residues within the hydrophobic core. The side chain of the highly conserved Tyr29, which occupies a central position within the core of H16, lies on the periphery of the core of H5.
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PMID:Solution structure of the fifth repeat of factor H: a second example of the complement control protein module. 153 52

Down's syndrome (DS) is a human genetic disease caused by triplication of the distal third of chromosome 21 and overexpression of an unknown number of genes residing in it. The gene for the liver-type subunit of phosphofructokinase (PFKL), a key glycolytic enzyme, maps to this region and the product is overproduced in DS erythrocytes and fibroblasts. These facts, together with abnormalities which occur in DS glycolysis, make PFKL overexpression a candidate for causing some aspects of the DS phenotype. A cellular model for examining the consequences of PFKL overexpression in DS was constructed by transfecting rat PC12 cells with the human PFKL cDNA. Phosphofructokinase (PFK) isolated from PFKL-overexpressing clones was more inhibited by ATP and citrate and less activated by fructose-6-phosphate than control PFK; similar results were obtained when PFK preparations from DS and control fibroblasts were compared. In vivo NMR measurements determined that cells overexpressing PFKL performed glycolysis 40% faster than controls. These results show that overexpression of PFKL is the cause for altered biochemical regulatory characteristics of PFK in DS fibroblasts and can result in enhancement of glycolysis rates. It is also shown that increased gene dosage can exert its influence not merely by enhancing the amounts of gene products but also by altering their biochemical nature.
Somat Cell Mol Genet 1992 Mar
PMID:Gene dosage and Down's syndrome: metabolic and enzymatic changes in PC12 cells overexpressing transfected human liver-type phosphofructokinase. 153 71

We have previously found (P. B. Garlick, T. R. Brown, R. H. Sullivan and K. Ugurbil, J. Mol. Cell Cardiol. 15, 855-858 (1983)) that two peaks could be observed in the phosphate region of NMR spectra of isolated, perfused rat hearts. Upon valinomycin treatment, an increase in the peak at 2.8 ppm in the phosphate region (phosphocreatine set at -2.52 ppm) had been observed. We have now confirmed our hypothesis that this peak originates from the mitochondrial phosphate by: (i) determination of myocardial mitochondrial phosphate contents using density gradient centrifugation in non-aqueous solvents; and (ii) quantitative electron microscopy of the heart tissue. Thus, we conclude that mitochondrial and cytosolic phosphate can be distinguished from each other in 31P NMR spectra of isolated, perfused rat hearts.
NMR Biomed
PMID:Evidence that mitochondrial phosphate is visible in 31P NMR spectra of isolated, perfused rat hearts. 155 Jul 7

An alamethicin, secreted by the fungus Trichoderma viride and containing a glutamine at position 18 instead of the usual glutamic acid, has been uniformly labeled with 15N and purified by HPLC. The extent of 15N incorporation at individual backbone and side-chain sites was found to vary from 85% to 92%, as measured by spin-echo difference spectroscopy. The proton NMR spectrum of the peptide dissolved in methanol was assigned using correlation spectroscopies and nuclear Overhauser enhancements (NOE) measured in the rotating frame. The 15N resonances were assigned by the 2D 1H-15N correlation via heteronuclear multiple-quantum coherence experiment. NOEs and 3JNHC alpha H coupling constants strongly suggest that, in methanol, from Aib-3 to Gly-11, the peptide adopts a predominantly helical conformation, in agreement with previous 1H NMR studies [Esposito, G., Carver, J.A, Boyd, J., & Campbell, I.D. (1987) Biochemistry 26, 1043-1050; Banerjee, U., Tsui, F.-P., Balasubramanian, T.N., Marshall, G.R., & Chan, S I. (1983) J. Mol. Biol. 165, 757-775]. The conformation of the carboxyl terminus (12-20) is less well determined, partly because the amino acid composition reduces the number of NOEs and coupling constants which can be determined by 1H NMR spectroscopy. The 3JNHC alpha H in the C-terminus suggest the possibility of conformational averaging at Leu-12, Val-15, and Gln-19, an interpretation which is supported by a recent molecular dynamics simulation of the peptide [Fraternalli, F. (1990) Biopolymers 30, 1083-1099].(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Uniform 15N labeling of a fungal peptide: the structure and dynamics of an alamethicin by 15N and 1H NMR spectroscopy. 155

The heme vinyl substituents in a shark (Galeorhinus japonicus) myoglobin in its met-cyano form (MbCN) have been characterized by NMR and the results were compared with those of the well-studied sperm whale (Physter catodon) myoglobin. Their orientation has been inferred from NOE connectivities and the analysis of the hyperfine shifts based on the principal magnetic tensor determined by MATDUHM (Magnetic Anisotropy Tensor Orientation Determination Utilizing the Heme Methyls) [Yamamoto, Y., Nanai, N. and Chujo, R.(1990) J. Chem. Soc., Chem. Commun. 1556-1557]. It has been shown that the C3-vinyl group is oriented roughly orthogonal to the heme plane in both G. japonicus and P. catodon MbCNs at 35 degrees C and their C8-vinyl groups, on the other hand, are close to in-plane orientation. Although CO form of myoglobin (MbCO) and MbCN have been thought to be isostructural to each other, the C8-vinyl orientation for P. catodon MbCN is found to be different from the orthogonal orientation indicated in the crystal structure analysis of MbCO [Hanson, J.C. and Schoenborn, B.P. (1981) J. Mol. Biol. 153, 117-146]. Their mobility has been characterized quantitatively from the study of time-dependent NOE build-up between the selected pair of the vinyl proton resonances. It has been revealed that the heme C3- and C8-vinyl groups of approximately 1 mM G. japonicus MbCN at 45 degrees C undergo internal motion with the correlation time of 1.9 and 2.4 ns, respectively. Therefore, their oscillatory motion is faster by a factor of 4-5 compared with the protein overall tumbling. Difference in the internal mobility between the two vinyl groups in the active site of this Mb is attributed to their differential contact with the apo-protein.
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PMID:Orientation and mobility of the heme vinyl groups in myoglobins with the aid of NOE and MATDUHM NMR. 156 83

To assess the effect of carteolol, a beta-blocker, on ischemia and reperfusion, changes in the ultrastructure of myocytes and energy metabolism were studied by 31P-NMR in 41 pig hearts without collateral circulation. The left anterior descending coronary artery was occluded for 20 min and reperfused for 120 min in three groups: seven pigs (group 1, no treatment with carteolol; group 2, pre-ischemia treatment with carteolol (10 micrograms/kg); group 3, post-ischemia treatment with carteolol before reperfusion). Other groups of five pigs were killed after 120 min of ischemia (group 4, no treatment; group 5, pre-ischemia treatment) or 20 min of ischemia (group 6, no treatment; group 7, pre-ischemia treatment). After 20 min of ischemia, ATP was higher in groups 2 (76 +/- 9% of the baseline value) than in group 1 (59 +/- 5%) and group 3 (60 +/- 10%). However, the difference disappeared after 30 min of ischemia. After 120 min of reperfusion, ATP showed much better recovery in group 2 (92 +/- 9%) than in groups 1 (66 +/- 7%) and 3 (68 +/- 10%). Ischemic injury, as viewed by light and electron microscopy, was milder in group 7 than in group 6 after 20 min occlusion, but the myocytes were almost normal after 120 min reperfusion in groups 1 to 3. The heart rate, blood pressure and rate pressure product showed no significant difference among the groups. These results indicate that pre-ischemia treatment with carteolol provided protection against ischemic cellular injury and accelerated the repletion of ATP during reperfusion, but the post-ischemia treatment did not lead to recovery of ATP. Therefore, the favorable effect during reperfusion of pre-ischemia treatment with carteolol depends on its protective effect during ischemia.
J Mol Cell Cardiol 1992 Jan
PMID:Protective effect of carteolol, a beta-blocker, on myocardial cellular damage in ischemic and reperfused pig hearts: assessment with gated in vivo 31-phosphorus magnetic resonance spectroscopy and electron microscopy. 156 29

Previous studies using hypoperfusion and 2-deoxyglucose infusion have revealed a biphasic relationship between myocardial energy status and adenosine release (RADO). As energy charge ([ATP] + 1/2[ADP])/([ATP] + [ADP] + [AMP]) or phosphorylation potential ([ATP]/[ADP][Pi]) is lowered there is an initial increase in RADO, but RADO declines from peak levels during severe energy depletion. This study examined the hypothesis that the same pattern of RADO exists during graded hypoxia. Isolated guinea-pig hearts were perfused at constant flow and exposed to mild (30% O2) and severe (0% O2) hypoxia in the presence of norepinephrine (NE, 6 x 10(-8) M). Phosphorylation potential and energy charge were determined using 31P-NMR spectroscopy and adenosine release into coronary venous effluent was measured. Graded hypoxia lowered energy charge and phosphorylation potential, and raised RADO. Although severe hypoxia plus NE lowered energy charge and phosphorylation potential to levels equivalent to those associated with decreased RADO during hypoperfusion or 2-deoxyglucose treatment, RADO during severe hypoxia was greater than during mild hypoxia. HCl was infused during severe hypoxia in order to reproduce the low intracellular pH seen during hypoperfusion, but HCl increased RADO rather than decreasing it. We conclude that during hypoxia, RADO does not have a biphasic relationship to phosphorylation potential or energy charge, suggesting that the regulation of adenosine formation cannot be explained solely in terms of these variables. Furthermore, intracellular acidosis is not responsible for inhibiting RADO at low phosphorylation potential and energy charge during hypoperfusion because it has no effect on RADO during severe hypoxia.
J Mol Cell Cardiol 1992 Jan
PMID:Adenosine formation and myocardial energy status during graded hypoxia. 156 32

One of the biotransformation routes of oxymetholone (17 beta-hydroxy-2-hydroxymethylene-17 alpha-methyl-5 alpha-androstan-3-one) in man leads to the formation of 17 beta-hydroxy-17 alpha-methyl-5 alpha-androstan-3-one (mestanolone). To demonstrate that this latter steroid may be formed by decarboxylation of an intermediate metabolite of oxymetholone bearing a 2-carboxylic group, we studied the urinary excretion of oxymetholone acidic metabolites. Five new acidic metabolites are reported here for the first time, among which four are unusual seco steroids resulting from the oxidative cleavage of the A-ring. The most abundant compound is 17 beta-hydroxy-17 alpha-methyl-2,3-seco-5 alpha-androstane-2,3-dioic acid 1, the cumulative excretion of which accounted for 1.52% of the dose. Three other seco diacids were produced in smaller amounts, namely 17 beta-hydroxy-17 alpha-methyl-2,3-seco-5 alpha-androstane-2,4- dicarboxylic acid 3, 17 beta-hydroxy-17 alpha-methyl-1,3-seco-5 alpha-androstane-1,3-dioic acid 4 and 17 beta-hydroxy-17 alpha-methyl-2,4-seco-5 alpha-androstane-2,4-dioic acid 5. The fifth acidic metabolite was identified as 3 alpha, 17 beta-dihydroxy-17 alpha-methyl-5 alpha-androstane-2 beta-carboxylic acid 2. The excretion in urine of these acidic metabolites suggests that the 2-hydroxymethylene group in oxymetholone is readily oxidized to yield the corresponding beta-keto acid which can be (1) decarboxylated to form mestanolone; (2) reduced at C-3 to give compound 2; and (3) further oxidized to afford the unexpected seco diacids 1, 3, 4 and 5. The identity of compounds 1 and 2 was ascertained by GC/MS and 1H and 13C-NMR analysis of reference compounds. The other metabolites were characterized by GC/MS analysis.
J Steroid Biochem Mol Biol 1992 Apr
PMID:Studies on anabolic steroids--8. GC/MS characterization of unusual seco acidic metabolites of oxymetholone in human urine. 156 86

Sequence-specific hydrogen-1 NMR assignments were made to all of the 29 amino acid residues of reactive-site-hydrolyzed Cucurbita maxima trypsin inhibitor I (CMTI-I*) by the application of two-dimensional NMR (2D NMR) techniques, and its secondary structural elements (two tight turns, a 3(10)-helix, and a triple-stranded beta-sheet) were identified on the basis of short-range NOESY cross peaks and deuterium-exchange kinetics. These secondary structural elements are present in the intact inhibitor [Holak, T. A., Gondol, D., Otlewski, J., & Wilusz, T. (1989) J. Mol. Biol. 210, 635-648] and are unaffected by the hydrolysis of the reactive-site peptide bond between Arg5 and Ile6, in accordance with the earlier conclusion reached for CMTI-III* [Krishnamoorthi, R., Gong, Y.-X., Lin, C. S., & VanderVelde, D. (1992) Biochemistry 31, 898-904]. Chemical shifts of backbone hydrogen atoms, peptide NH's, and C alpha H's, of CMTI-I* were compared with those of the intact inhibitor, CMTI-I, and of the reactive-site-hydrolyzed, natural, E9K variant, CMTI-III*. Cleavage of the Arg5-Ile6 peptide bond resulted in changes of chemical shifts of most of the backbone atoms of CMTI-I, in agreement with the earlier results obtained for CMTI-III. Comparison of chemical shifts of backbone hydrogen atoms of CMTI-I* and CMTI-III* revealed no changes, except for residues Glu9 and His25. However, the intact forms of the same two proteins, CMTI-I and CMTI-III, showed small but significant perturbations of chemical shifts of residues that made up the secondary structural elements of the inhibitors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Structural consequences of the natural substitution, E9K, on reactive-site-hydrolyzed squash (Cucurbita maxima) trypsin inhibitor (CMTI), as studied by two-dimensional NMR. 159 21


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