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PubMed1982

Chlorpromazine, methotrimeprazine, and metabolites. Structural changes accompanying the loss of neuroleptic potency by ring sulfoxidation.

The 3-dimensional molecular structures of methotrimeprazine, methotrimeprazine sulfoxide, and chlorpromazine sulfoxide were examined by X-ray crystallography. Previous studies of their dopamine receptor binding affinities have indicated that both chlorpromazine sulfoxide and methotrimeprazine sulfoxide lack neuroleptic potency. The crystal structures of methotrimeprazine and its sulfoxide were similar to the previously published structure of chlorpromazine. The sulfoxide metabolite of chlorpromazine, on the other hand, had a different conformation of the side chain. A boat axial conformation of the sulfoxy group was found for both metabolites. The crystal structures suggest that the apparent loss of neuroleptic potency by biotransformation of the phenothiazine drugs to their ring sulfoxides is caused by the introduction of the sulfoxide group itself, and not by concurrent conformational changes in the rest of the molecule.

Animals↗

PubMed2003

Solid-state NMR reveals structural changes in phospholamban accompanying the functional regulation of Ca2+-ATPase.

Calcium transport across the sarcoplasmic reticulum of cardiac myocytes is regulated by a reversible inhibitory interaction between the Ca2+-ATPase and the small transmembrane protein phospholamban (PLB). A nullcysteine analogue of PLB, containing isotope labels in the transmembrane domain or cytoplasmic domain, was reconstituted into membranes in the absence and presence of the SERCA1 isoform of Ca2+-ATPase for structural investigation by cross-polarization magic-angle spinning (CP-MAS) NMR. PLB lowered the maximal hydrolytic activity of SERCA1 and its affinity for calcium in membrane preparations suitable for structural analysis by NMR. Novel backbone amide proton-deuterium exchange CP-MAS NMR experiments on the two PLB analogues co-reconstituted with SERCA1 indicated that labeled residues Leu42 and Leu44 were situated well within the membrane interior, whereas Pro21 and Ala24 lie exposed outside the membrane. Internuclear distance measurements on PLB using rotational resonance NMR indicated that the sequences Pro21-Ala24 and Leu42-Leu44 adopt an alpha-helical structure in pure lipid bilayers, which is unchanged in the presence of Ca2+-ATPase. By contrast, rotational echo double resonance (REDOR) NMR experiments revealed that the sequence Ala24-Gln26 switches from an alpha-helix in pure lipid membranes to a more extended structure in the presence of SERCA1, which may reflect local structural distortions which change the orientations of the transmembrane and cytoplasmic domains. These results suggest that Ca2+-ATPase has a long-range effect on the structure of PLB around residue 25, which promotes the functional association of the two proteins.

Amino Acid Sequence↗

PubMed1994

5-Fluorouracil induces structural changes in rat liver tRNA.

5-fluorouracil (FUra) has been shown to modulate the aminoacylation function of rat liver tRNA. The present study was aimed at studying the structure-function relationship of FUra-substituted tRNA. Male Wistar rats (2-3 month old) were given a single i.p. injection of FUra at 50, 250, or 500 mg/kg body wt. and FUra-substituted total liver tRNA, i.e. tRNA(FUra50, 250, and 500, respectively, were isolated 3 h later. Normal tRNA (tRNA(N)) was isolated from saline-treated control rats. Thermal denaturation studies showed higher melting temperatures for tRNA(FUra) compared to tRNA(N). Heat denaturation followed by renaturation of total tRNA did not affect the activity of tRNA(N) and tRNA(FUra50), where as tRNA(FUra250 and 500) lost 35% and 72% of activity, respectively, compared to the corresponding group of non-denatured tRNA. Antibodies specific to rat liver tRNA recognized normal and FUra-substituted tRNA in the order of tRNA(N) > tRNA(FUra50) > or = tRNA(FUra250) > tRNA(FUra500) in an avidin-biotin micro-enzyme linked immunosorbant assay. tRNA(N) or tRNA(FUra50) preincubated with tRNA antiserum showed 74% and 59% of aminoacylation activity, respectively, compared to that of corresponding tRNA preincubated with normal rabbit IgG. However, activities of similarly treated tRNA(FUra250 and 500) were not affected. The observations of possible changes in the secondary structure of rat liver tRNA upon incorporation of FUra are discussed.

Acylation↗

PubMed2001

X-ray structure analyses of photosynthetic reaction center variants from Rhodobacter sphaeroides: structural changes induced by point mutations at position L209 modulate electron and proton transfer.

The structures of the reaction center variants Pro L209 --> Tyr, Pro L209 --> Phe, and Pro L209 --> Glu from the photosynthetic purple bacterium Rhodobacter sphaeroides have been determined by X-ray crystallography to 2.6-2.8 A resolution. These variants were constructed to interrupt a chain of tightly bound water molecules that was assumed to facilitate proton transfer from the cytoplasm to the secondary quinone Q(B) [Baciou, L., and Michel, H. (1995) Biochemistry 34, 7967-7972]. However, the amino acid exchanges Pro L209 --> Tyr and Pro L209 --> Phe do not interrupt the water chain. Both aromatic side chains are oriented away from this water chain and interact with three surrounding polar side chains (Asp L213, Thr L226, and Glu H173) which are displaced by up to 2.6 A. The conformational changes induced by the bulky aromatic rings of Tyr L209 and Phe L209 lead to unexpected displacements of Q(B) compared to the wild-type protein. In the structure of the Pro L209 --> Tyr variant, Q(B) is shifted by approximately 4 A and is now located at a position similar to that reported for the wild-type reaction center after illumination [Stowell, M. H. B., et al. (1997) Science 276, 812-816]. In the Pro L209 --> Phe variant, the electron density map reveals an intermediate Q(B) position between the binding sites of the wild-type protein in the dark and the Pro L209 --> Tyr protein. In the Pro L209 --> Glu reaction center, the carboxylic side chain of Glu L209 is located within the water chain, and the binding site of Q(B) remains unchanged compared to the wild-type structure.

Amino Acid Substitution↗

PubMed2004

Structural changes in gill DNA reveal the effects of contaminants on Puget Sound fish.

Structural differences were identified in gill DNA from two groups of English sole collected from Puget Sound, Washington, in October 2000. One group was from the industrialized Duwamish River (DR) in Seattle and the other from relatively clean Quartermaster Harbor (QMH). Chemical markers of sediment contamination [e.g., polynuclear aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs)] established that the DR was substantially more contaminated than QMH. The levels of these chemicals in the sediments of both sites were consistent with levels of cytochrome P450 1A (CYP1A) expression in the gills of English sole from the same sites. Structural differences in gill DNA between the groups were evinced via statistical models of Fourier transform-infrared (FT-IR) spectra. Marked structural damage was found in the gill DNA of the DR fish as reflected in differences in base functional groups (e.g., C-O and NH2) and conformational properties (e.g., arising from perturbations in vertical base stacking interactions). These DNA differences were used to discriminate between the two fish groups through principal components analysis of mean FT-IR spectra. In addition, logistic regression analysis allowed for the development of a "DNA damage index" to assess the effects of contaminants on the gill. The evidence implies that environmental chemicals contribute to the DNA changes in the gill. The damaged DNA is a promising marker for identifying, through gill biopsies, contaminant effects on fish.

Animals↗

PubMed1987

Structural changes in the dental and periodontal tissues of the rat incisor following application of orthodontic loads.

The present study deals with the morphometric changes in the loaded rat incisor and its supporting structures 3 months after load removal. The material examined was limited to that part of the tooth that is located between 8 and 20 mm from the tooth apex. Of the ten albino rats in whom laterointrusive loads (19 +/- 0.6 g) were applied to the lower left incisor for a period of 2 weeks, the rate of tooth eruption returned to normal in four animals (group A); in six rats, eruption remained grossly impaired (group B). These two groups were compared with a control group of four rats in whom the incisors were allowed to erupt normally during the 3 months of the experiment. The left mandibles were dissected and fixed; the incisors were demineralized, embedded in paraplast, and cut into transverse serial sections of 6 micron, which were used to produce a three-dimensional reconstruction of all tissue components by means of computerized histomorphometry. The parameters of pulp and dentin, and the total tooth size and shape in group A were similar to those of the control group. In group B, pulp and dentin were changed significantly, tooth size increased, and the oval shape was altered into a more rounded contour, together with a significant enlargement of the socket. Although the total PDL volumes remained similar in all three groups, the tooth/socket relation, as expressed by PDL width and PDL area at the different tooth sides and at varying distances from tooth apex, diverged from normal significantly in all teeth that had been subjected to loading.

Alveolar Process↗

PubMed1964

STRUCTURAL CHANGES IN ISOLATED LIVER MITOCHONDRIA OF RATS DURING ESSENTIAL FATTY ACID DEFICIENCY.

Liver mitochondria isolated in 0.44 M sucrose from rats deficient in essential fatty acids (EFA) oxidized citrate, succinate, alpha-ketoglutarate, glutamate, and pyruvate at a faster rate than did mitochondria isolated from normal rats; however, the oxidation of malate, caprylate, and beta-hydroxybutyrate was not significantly increased. The mitochondria from deficient rats exhibited an increased ATPase activity and extensive structural damage as revealed by electron microscope examination of thin sections. An increase in citrate oxidation and ATPase activity, together with some structural damage, could be demonstrated as early as the 4(th) week in rats on a fat-free diet. Saturated fat in the diet did not prevent the change in mitochondrial structure but accelerated its appearance. Both the biochemical and structural defects could be reversed within three weeks after feeding deficient rats a source of EFA. In the presence of a phosphate acceptor the effect of EFA deficiency on substrate oxidation was largely eliminated. A trend toward a reduced efficiency of oxidative phosphorylation was noted in mitochondria from EFA-deficient rats, but significant uncoupling was found only in the case of citrate, beta-hydroxybutyrate, and glutamate in the presence of malonate. Together with the increased ATPase activity, the uncoupling of phosphorylation could account for the poor respiratory control found with the deficient preparation. However, EFA deficiency was without effect on the respiration of liver slices, which supports the belief that the observed changes in oxidation and phosphorylation are an artifact resulting from damage sustained by the deficient mitochondria during their isolation.

Adenosine Triphosphatases↗

PubMed1976

Pulmonary fine structural changes in children with tissue hypoxia.

Six children have undergone lung biopsy for evaluation of fine structure. Four children demonstrated increased DAVO2 preoperatively and had marked ultrastructural changes in their lungs. Such changes appear to result from embolization of microthrombi or microaggregates to the lung from under-oxygenated tissue.

Adolescent↗

PubMed1982

Propranolol-induced structural changes in human erythrocyte ghost membranes. A spin label study.

The effect of propranolol on the structure of human erythrocyte membranes was studied using a spin labeling technique. Changes in electron spin resonance spectra of spin labeled membrane proteins were detected at concentration of the drug corresponding to its antihemolytic effect on intact erythrocytes. The character of spectral changes suggests that propranolol-induced alterations in organization of membrane proteins are connected mainly with perturbation of protein sites located on membrane surface. Propranolol also produces a decrease in order parameter of membrane lipids. The disordering effect is, however, small and detectable only at relatively high concentrations of the drug.

Electron Spin Resonance Spectroscopy↗

PubMed1986

Diabetes-induced functional and structural changes in insulin receptors from rat skeletal muscle.

The effect of diabetes on the structure and function of insulin receptors was studied in rats 7 d after streptozotocin injection, using solubilized, partially purified receptors from rat hindlimb muscles. Diabetes increased the number of insulin receptors per gram of muscle 60-70% without apparent change in insulin binding affinity. Incubation of receptors at 4 degrees C with [gamma-32P]ATP and insulin resulted in dose-dependent autophosphorylation of the beta-subunit on tyrosine residues; receptors from diabetic rats showed decreased base-line phosphorylation, as well as a decrease in autophosphorylation at maximally stimulating insulin concentrations. These receptors also showed diminished exogenous substrate kinase activity using histone H2b and angiotensin II as phosphoacceptors. The electrophoretic mobility (sodium dodecyl sulfate-polyacrylamide gel electrophoresis) of a subpopulation of beta-subunits derived from diabetics was slightly decreased; differences in electrophoretic mobility between control- and diabetic-derived beta-subunits were enhanced by generating fragments by partial Staphylococcus aureus V8 protease digestion. Endoglycosidase-H or neuraminidase treatment increased the electrophoretic mobility of beta-subunits in both groups, but only neuraminidase appeared to decrease or abolish differences in electrophoretic mobility between controls and diabetics, suggesting that excess sialilation may account, in part, for the altered mobility of diabetic derived beta-subunits. All structural and functional alterations in insulin receptors were prevented by treating diabetic rats with insulin for 60 h. Peripheral insulin resistance associated with insulinopenic diabetes may be related to modifications in insulin receptor structure, resulting in impaired signal transmission.

Acetylglucosaminidase↗

PubMed1984

Structural changes in the femur with the transition to agriculture on the Georgia coast.

Structural characteristics of the femur are compared in preagricultural (2200 B.C.-A.D. 1150) and agricultural (A.D. 1150-1550) subsistence strategy groups from the Georgia coast. Using an automated technique, cross-sectional geometric properties used in structural analyses (areas, second moments of area) were determined at midshaft and distal to the lesser trochanter in 20 adults from each group. A significant decline in magnitude of almost every geometric property occurs in the agricultural group. The differences between groups are reduced but still significant for many properties after standardizing for bone length differences. In addition, a remodeling of the femoral cortex to one of relatively smaller medullary and subperiosteal diameter, as well as a more circular cross-sectional shape, is characteristic of agricultural femora. Thus, while the relative cross-sectional area of bone remains the same, the spatial distribution of bone area is different in the two groups. The results strongly suggest a relative reduction in mechanical loadings of the femur in the agricultural group, implying different levels and possibly types of activity involving the lower limb in the two groups. The data are also compared with similar data available for the Pecos Pueblo (agricultural) sample. The comparison indicates that types of activity may have been more similar in the two agricultural samples, but that general levels of activity were more similar in the Pecos Pueblo and Georgia coast preagricultural samples.

Agriculture↗

PubMed1989

Functional and structural changes in parotid glands of alcoholic cirrhotic patients.

The parotid gland function and structure was studied in 30 patients with biopsy-proven alcoholic cirrhosis and in 43 age- and sex-matched alcoholic and nonalcoholic control subjects. Mean simulated parotid saliva flow rate was significantly (p less than 0.05) lower in patients with alcoholic cirrhosis as compared with alcoholic and nonalcoholic control subjects. A similar reduction was observed in mean basal parotid saliva flow rate in patients with alcoholic cirrhosis that reached statistical significance (p less than 0.05) in comparison with nonalcoholic control subjects. In addition, the concentration of sodium, bicarbonate, and total proteins in stimulated parotid saliva was significantly (p less than 0.005) lower in patients with alcoholic cirrhosis as compared with the two groups of control subjects. Sialograms in 6 patients with alcoholic cirrhosis did not reveal any obstructive lesion in the primary parotid duct or its branches. Histology of salivary tissue revealed an increase in the interstromal fatty infiltration, edema, and fibrosis without evidence of inflammatory reaction in 5 patients as compared with the control subjects. These data provide evidence for marked parotid gland dysfunction in patients with alcoholic cirrhosis presumably due to metabolic derangement and altered parotid gland structure.

Adult↗

PubMed2004

EXAFS studies of structural changes in fragile glasses of zinc nitrate and nickel nitrate hydrates.

The ionic structures of aqueous solutions of two sets of transition metal nitrates have been studied in the liquid and glass states by EXAFS spectroscopy. Experiments were carried out on Zn(NO3)2.xH2O, with x=2, 6, 12 and NiNO.9HO over the temperature range 30<T(K)<250. The glass transition regime was monitored by means of an in-situ DSC probe. The EXAFS data were analysed by recently developed Monte Carlo procedures, enabling a discussion of the glass structure in terms of pairwise and higher order correlations. Results for the zinc nitrate hydrates show complex behaviour depending on the concentration. This behaviour is explained in terms of first hydration shell stability and NO3- penetration. This result contrasts with that for the equivalent correlation in nickel nitrate, and is taken as evidence for a more extensive free energy landscape of zinc nitrate hydrates. The results are also consistent with the known hydration properties of Zn2+ and Ni2+, and help explain why Zn2+ is biologically active in solution.

Computer Simulation↗

PubMed1998

Bromothymol blue as a probe for structural changes of model membranes induced by hemoglobin.

The effect of methemoglobin on the structure of model membranes composed of phosphatidylcholine and diphosphatidylglycerol (18 : 1, mol : mol) was studied with the help of pH-indicator dye bromothymol blue. The partition coefficients characterizing the dye binding to methemoglobin or model membranes were derived from the pKaalpha dependences on the protein or phospholipid concentration. The observed character of the dye partitioning in the lipid or lipid-protein systems is interpreted in terms of the traditional electrostatic approach and some modern theories of membrane electrostatics. It is assumed that methemoglobin affects the structural and physicochemical parameters of lipid-water interface.

Animals↗

PubMed1996

The organic crystallizing agent 2-methyl-2,4-pentanediol reduces DNA curvature by means of structural changes in A-tracts.

Contemporary predictive models for sequence-dependent DNA structure provide a good estimation of overall DNA curvature in most cases. However, the two current models differ fundamentally in their view of the origin of DNA curvature. An earlier model that associates DNA bending primarily, although not exclusively, with stretches of adenines (A-tracts) is based on results of comparative gel retardation, cyclization kinetics, hydroxyl radical cutting, and other solution measurements. It represents an intersection of wedge and junction models. More recently, a non-A-tract bending model has been proposed, built on structural results from x-ray crystallography and molecular modeling. In this view, A-tracts are proposed to be straight and rigid, whereas mixed sequence DNA is bent. Because a key premise of the non-A-tract bending model is the crystallographic observation that A-tracts are straight, we have examined the effect in solution of 2-methyl-2,4-pentanediol (MPD), an organic solvent used in crystal preparation for crystallographic DNA structure determinations. Using cyclization analysis, DNase I cutting, chemical probing, and electron microscopy on DNA oligomers with and without A-tracts, we show that the presence of MPD in solution dramatically affects A-tracts and that the effect is specific to these sequence elements. Combined with the previous observation that MPD affects gel mobility of curved sequences with A-tracts, our findings support the bent A-tract model and call for caution in the interpretation of crystallographic results on DNA structure as these are presently obtained.

Artifacts↗

PubMed1967

Fine structural changes in uterine smooth muscle and fibroblasts in response to estrogen.

The fine structure of the estrogen-primed uterus was examined in two series of rats, with emphasis upon the alterations in smooth muscle cells and fibroblasts. The first series of animals were mature animals that were sacrificed at diestrus or estrus. The second series consisted of prepubertal rats (57-70 g) that received subcutaneous injections of estradiol-17 beta in 20% alcohol. Four groups of animals received the hormone twice daily for 3 days for a total dose of 0.06, 0.6, 6.0, or 60.0 microg, respectively. An estrogenic response was observed in all groups as indicated by an increase in uterine weight. Control groups consisted of either untreated animals or animals receiving 20% alcohol. All animals were sacrificed on the 4th day. The fibroblasts and smooth muscle cells in the controls were similar to their counterparts in the mature animal in diestrus. They were small, contained relatively little rough endoplasmic reticulum, and the connective tissue cells appeared like fibrocytes. All of the estrogen-treated animals were similar in appearance and were comparable to their counterparts in the mature animal in estrus. Both the smooth muscle cells and the fibroblasts were increased in size, demonstrated a marked enlargement and dilation of ergastoplasmic cisternae, and contained increased numbers of attached and free cytoplasmic ribosomes. The presence of an extensive rough endoplasmic reticulum in the smooth muscle cells of the stimulated uterus is in marked contrast to the appearance of these cells in other tissues. These observations correlate with previous biochemical studies by other workers, in which estrogens have been shown to promote the synthesis of uterine RNA, collagen, and noncollagenous protein, and suggest that smooth muscle cells may participate in the synthesis of connective tissue proteins.

Age Factors↗

PubMed1969

Effects of acriflavine on the mitochondria and kinetoplast of Crithidia fasciculata. Correlation of fine structure changes with decreased mitochondrial enzyme activity.

The effects of acriflavine on the fine structure and function of the mitochondria and the kinetoplast in Crithidia fasciculata have been investigated. A mitochondrial fraction was prepared by differential centrifugation of cells broken by grinding with neutral alumina. Isolated mitochondria or intact cells revealed by spectrophotometric measurements the presence of cytochromes a + a(3), b, c(555) and o. After cells were grown in acriflavine for 3-4 days, the fine structure of the mitochondria and their cytochrome content were affected. Cells grown in 5.0 microM acriflavine had a threefold decrease in cytochrome a + a(3) and decreased respiratory activity. The mitochondrial preparation from these cells had a fivefold decrease in cytochrome a + a(3) and a less but significant decrease of other cytochromes present. There was also a decrease in the mitochondrial enzyme activities of NADH, succinic and L-alpha-glycerophosphate oxidases, and succinic and L-alpha-glycerophosphate dehydrogenases. Dyskinetoplastic cells could be demonstrated after growth in 1.0 microM acriflavine. At 5 microM, 80-90% of the cells were dyskinetoplastic. The kinetoplastic DNA was condensed, nonfibrillar, and did not incorporate thymidine-(3)H. The mitochondria in these cells had few cristae and were shorter and more swollen than the controls. Acriflavine may induce the fine structure effects we have observed and may affect the formation of the mitochondria in C. fasciculata.

Acridines↗

PubMed1987

Intestinal structural changes in African green monkeys after long term psyllium or cellulose feeding.

Intestinal structure of male adult African Green monkeys (Cercopithecus aethiops ssp vervets) was studied after 3 1/2 yr of consuming diets containing 10% psyllium husk or cellulose. Scanning electron microscopy (SEM) identified mild damage (cellular swelling and disarray, and microvillar denudation and disarray) at villous tips throughout the small intestine in the psyllium-fed monkeys. The cellulose group had similar duodenal damage. Differences were not found in colons by SEM. By light microscopy, jejunum had shorter villi with psyllium feeding, based upon villous height (P less than 0.05), and length around a sectioned villus (P less than 0.1), but not based upon the number of enterocytes per villus. Jejunal and ileal circular and longitudinal muscle layer thicknesses were increased in psyllium-fed monkeys. Colonic mucosal height was significantly (P less than 0.05) reduced and muscle layer thickness was mildly reduced in the psyllium-fed monkeys. Group differences were not found in intestinal weight or length or in the weight of small intestinal mucosal scrapings. Psyllium husk may cause epithelial cell loss and muscle layer hypertrophy in the jejunum and ileum and thinning of the colonic wall after prolonged feeding.

Animals↗