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PubMed2006

A fragment molecular-orbital-multicomponent molecular-orbital method for analyzing HD isotope effects in large molecules.

We have developed a fragment molecular orbital (FMO)-multi-component MO (MC_MO) method to analyze isotope effect due to differences between the quantum effects of protons and deuterons for large molecules such as proteins and DNA. The FMO-MC_MO method enables the determination of both the electronic and the protonic (deuteronic) wave functions simultaneously, and can directly express isotope effects, including coupling effects between nuclei and electrons. In our calculations of two polyglycines, which serve as prototypes for biological molecules, by this method, we clearly observed the geometrical relaxation induced by the HD isotope effect in the intramolecular hydrogen bonding portions of the molecules. The HD isotope effect on the interfragment interaction energy, including that of the hydrogen bonding parts, was also demonstrated: the hydrogen bond was weakened by replacement of hydrogen with deuterium. We also developed electrostatic potential approximations for use in the FMO-MC_MO calculations, and the accuracy of the energy differences induced by the isotope effect was independent of the approximation level of the FMO-MC_MO. Our results confirmed that the FMO-MC_MO method is a powerful tool for the detailed analysis of changes in hydrogen bonding and interaction energies induced by the HD isotope effect for large biological molecules.

Journal Article↗
PubMed2006

Mass-dependent and non-mass-dependent isotope effects in ozone photolysis: resolving theory and experiments.

In addition to the anomalous (17)O and (18)O isotope effects in the three-body ozone formation reaction O+O(2)+M, isotope effects in the destruction of ozone by photolysis may also play a role in determining the isotopic composition of ozone and other trace gases in the atmosphere. While previous experiments on ozone photolysis at 254 nm were interpreted as evidence for preferential loss of light ozone that is anomalous (or "non-mass-dependent"), recent semiempirical theoretical calculations predicted a preferential loss of heavy ozone at that wavelength that is mass dependent. Through photochemical modeling results presented here, we resolve this apparent contradiction between experiment and theory. Specifically, we show that the formation of ozone during the UV photolysis experiments is not negligible, as had been assumed, and that the well-known non-mass-dependent isotope effects in ozone formation can account for the non-mass-dependent enrichment of the heavy isotopologs of ozone observed in the experiment. Thus, no unusual non-mass-dependent fractionation in ozone photolysis must be invoked to explain the experimental results. Furthermore, we show that theoretical predictions of a mass-dependent preferential loss of the heavy isotopologs of ozone during UV photolysis are not inconsistent with the experimental data, particularly if mass-dependent isotope effects in the chemical loss reactions of ozone during the photolysis experiments or experimental artifacts enrich the remaining ozone in (17)O and (18)O. Before the calculated fractionation factors can be quantitatively evaluated, however, further investigation of possible mass-dependent isotope effects in the reactions of ozone with O((1)D), O((3)P), O(2)((1)Delta), and O(2)((1)Sigma) is needed through experiments we suggest here.

Journal Article↗
PubMed1997

On the mechanism of D-amino acid oxidase. Structure/linear free energy correlations and deuterium kinetic isotope effects using substituted phenylglycines.

The kinetic mechanism of the reaction of D-amino acid oxidase (EC 1.4.3.3) from Trigonopsis variabilis with [alpha-1H]- and [alpha-2H]phenylglycine has been determined. The pH dependence of Vmax is compatible with pKa values of approximately 8.1 and >9.5, the former of which is attributed to a base which should be deprotonated for efficient catalysis. The deuterium isotope effect on turnover is approximately 3.9, and the solvent isotope effect approximately 1.6. The reductive half-reaction is biphasic, the first, fast phase, k2, corresponding to substrate dehydrogenation/enzyme flavin reduction and the second to conversion/release of product. Enzyme flavin reduction consists in an approach to equilibrium involving a finite rate for k-2, the reversal of k2. k2 is 28.8 and 4.6 s-1 for [alpha-1H]- and [alpha-2H]phenylglycine, respectively, yielding a primary deuterium isotope effect approximately 6. The solvent deuterium isotope effect on the apparent rate of reduction for [alpha-1H]- and [alpha-2H]phenylglycine is approximately 2.8 and approximately 5. The rates for k-2 are 4.2 and 0.9 s-1 for [alpha-1H]- and [alpha-2H]phenylglycine, respectively, and the corresponding isotope effect is approximately 4.7. The isotope effect on alpha-H and the solvent one thus behave multiplicatively consistent with a highly concerted process and a symmetric transition state. The k2 and k-2 values for phenylglycines carrying the para substituents F, Cl, Br, CH3, OH, NO2 and OCH3 have been determined. There is a linear correlation of k2 with the substituent volume VM and with sigma+; k-2 correlates best with sigma or sigma+ while steric parameters have little influence. This is consistent with the transition state being structurally similar to the product. The Bronsted plot of DeltaG versus DeltaG0 allows the estimation of the intrinsic DeltaG0 as approximately 58 kJ.M-1. From the linear free energy correlations, the relation of DeltaG versus DeltaG0 and according to the theory of Marcus it is concluded that there is little if any development of charge in the transition state. This, together with the recently solved three-dimensional structure of D-amino acid oxidase from pig kidney (Mattevi, A., Vanoni, M.A., Todone, F., Rizzi, M., Teplyakov, A., Coda, A., Bolognesi, M., and Curti, B. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 7496-7501), argues against a carbanion mechanism in its classical formulation. Our data are compatible with transfer of a hydride from the substrate alphaC-H to the oxidized flavin N(5) position, although, clearly, they cannot prove it.

D-Amino-Acid Oxidase↗
PubMed2005

Use of dual isotope tracers in biomedical research.

Biomedical stable isotope studies involve administration of tracer and measurement of isotope enrichment in blood, urine, feces or breath. The aim of the studies is to gather quantitative information about a specific metabolic function. However, the measured isotope enrichment may be affected by other metabolic events than only this function. In this case, a correction is necessary. The best approach is to add a second tracer simultaneously which is known to be metabolised by all interfering metabolic events but not by the function of interest. This dual isotope approach also enables simultaneous measurement of two interrelated functions. A summary of selected applications involving dual isotope tracer studies is presented. The applications deal with energy expenditure (doubly labelled water technique), cholesterol absorption, starch and lactose digestion, fat digestion, bile acid metabolism and the combination of stable and radioactive carbon isotopes in breath testing.

Bile Acids and Salts↗
PubMed1984

Comparison of isotope dilution and excretion methods for determining the half-life of ascorbic acid in the guinea pig.

The half-life of ascorbic acid (AA) in guinea pigs was investigated by the isotope dilution and excretion methods. The dilution method measures [1-14C]AA disappearance from the plasma, whereas the excretion method measures the elimination of [1-14C]AA and the metabolites from the body. Two groups of animals underwent both isotope studies in reverse order. Animals were conditioned to the experimental procedures and fed 2.5 mg AA/100 g body weight orally to maintain a daily intake of the vitamin independent of food consumption. The two isotope procedures imposed similar stress on the animals, as determined by plasma cortisol levels and body weight changes. The AA half-life calculations of the rapidly exchangeable pool by the isotope dilution method yielded values of 1.23 and 0.34 hours for the two groups, respectively. The half-life of the slowly exchangeable pool for the two groups was 60.2 and 65.8 hours, respectively. The half-life of AA in the rapidly exchangeable pool, as measured by the excretion studies, was 4.57-8.75 hours. For the slowly exchangeable pool, it was 146-149 hours. The longer half-life of both pools obtained with the excretion method indicates that the isotope is disappearing from the plasma more rapidly than it is being excreted. This suggests that a portion of the [1-14C]AA leaving the plasma is removed to a body pool that is not sampled by the isotope excretion method.

Animals↗
PubMed1996

Correlations between stable carbon-isotope abundance and hydraulic conductivity in Douglas-fir across a climate gradient in Oregon, USA.

Stomatal conductance in trees is related to both foliar carbon-isotope abundance and stem hydraulic properties. By combining these relationships, I hypothesized that carbon-isotope abundance in foliage should vary with limitations to water movement through supporting branches. I sampled Douglas-fir branches (Pseudotsuga menziesii (Mirb.) Franco) from six sites across a climate gradient in Oregon, USA for foliar carbon-isotope abundance and stem hydraulic properties. I used a forest growth model to quantify climate-induced stomatal limitations, expressed as reduced potential transpiration, across the gradient. Foliar stable carbon-isotope abundance showed a strong inverse relationship with branch specific conductivity (hydraulic conductivity per unit functional sapwood area) and leaf-specific conductivity (hydraulic conductivity per unit leaf area). Foliar stable carbon-isotope abundance was correlated with modeled reductions in potential transpiration; however, the inclusion of leaf-specific conductivity improved the correlation by more than 30%. Combined, leaf-specific conductivity and climate-induced stomatal constraints explained 84% of the variation in foliar isotope abundance in 1994 foliage. This model was confirmed on foliage classes 1990-1993.

Journal Article↗
PubMed1999

Effects of water status and soil fertility on the C-isotope signature in Pinus radiata.

The efficiency with which trees use water is a major determinant of growth under water-limited conditions. We investigated whether increased access to water and nutrients alters water-use efficiency in Pinus radiata D. Don. Intrinsic transpiration efficiency, defined here as the ratio of CO(2) assimilated and water transpired at a given vapor pressure deficit, is determined by the difference between ambient atmospheric CO(2) concentration (c(a)) and leaf intercellular CO(2) concentration (c(i)). The mean value of c(i)/c(a) can be inferred from an analysis of carbon isotope discrimination (Delta) in wood samples. A total of 117 trees, growing at sites with widely varying soil and climatic conditions in Australia and New Zealand, were cored and distinct annual rings were analyzed for their carbon isotope ratio, and correlated with rainfall during the July-June growing season in the year in which the wood was grown. Where possible, carbon isotope ratios were compared for different years within the same trees. The c(i)/c(a) ratio decreased with decreasing water availability, suggesting that intrinsic transpiration efficiency increased with decreasing water availability. An increase in growing season rainfall of 900 mm resulted in an increase in Delta of about 2.0 per thousand, corresponding to a decrease in intrinsic transpiration efficiency of approximately 24%. A stronger relationship was obtained when carbon isotope discrimination was expressed as a function of the ratio of rainfall to potential transpiration. Carbon isotope discrimination was also negatively correlated with mean annual vapor pressure deficit at different sites. In contrast, nutrient availability had no significant effect on carbon isotope discrimination.

Journal Article↗
PubMed1976

Isotope angiography: technique, validation and value in the assessment of arterial reconstruction.

Isotope angiography performed by intravenous injection of technetium 99m pertechnetate has been demonstrated to be of value in the diagnosis and management of a variety of disorders of the large arteries. An improved technique of isotope angiography is described and the technique validated (53 cases) in normal and diseased arteries by correlating it with conventional contrast arteriography and/or operative findings. Peripheral arteries as far distal as the wrist or mid-calf have been accurately visualized and quantitation of isotope arrival times and total isotope activity in different parts of the arterial tree has provided a means of evaluating the hemodynamic significance of stenosing lesions. Thirty-nine arterial reconstructions were studied by this technique. Seven of 27 (26%) clinically patent arterial reconstructions were found to be harboring significant and potentially dangerous imperfections which were clinically unsuspected. Nine of 12 (75%) arterial reconstructions thought clinically to be occluded were demonstrated to be patent, obviating the need for invasive contrast arteriography. Isotope angiography may be used with no risk for the immediate postoperative and long-term evaluation of arterial reconstructions. Only those patients with abnormalities identified on isotope angiography need have conventional contrast arteriography for further delineation of the abnormality so that it may be repaired before it causes failure of the reconstruction.

Aneurysm↗
PubMed1993

Photosynthetic Fractionation of the Stable Isotopes of Oxygen and Carbon.

Isotope discrimination during photosynthetic exchange of O2 and CO2 was measured using enzyme, thylakoid, and whole cell preparations. Evolved oxygen from isolated spinach thylakoids was isotopically identical (within analytical error) to its source water. Similar results were obtained with Anacystis nidulans Richter and Phaeodactylum tricornutum Bohlin cultures purged with helium. For consumptive reactions, discrimination ([delta], where 1 + [delta]/1000 equals the isotope effect, k16/k18 or k12/k13) was determined by analysis of residual substrate (O2 or CO2). The [delta] for the Mehler reaction, mediated by ferredoxin or methylviologen, was 15.3[per mille (thousand) sign]. Oxygen isotope discrimination during oxygenation of ribulose-1,5-bisphosphate (RuBP) catalyzed by RuBP carboxylase/oxygenase (Rubisco) was 21.3[per mille (thousand) sign] and independent of enzyme source, unlike carbon isotope discrimination: 30.3[per mille (thousand) sign] for spinach enzyme and 19.6 to 23[per mille (thousand) sign] for Rhodospirillum rubrum and A. nidulans enzymes, depending on reaction conditions. The [delta] for O2 consumption catalyzed by glycolate oxidase was 22.7[per mille (thousand) sign]. The expected overall [delta] for photorespiration is about 21.7[per mille (thousand) sign]. Consistent with this, when Asparagus sprengeri Regel mesophyll cells approached the compensation point within a sealed vessel, the [delta]18O of dissolved O2 came to a steady-state value of about 21.5[per mille (thousand) sign] relative to the source water. The results provide improved estimates of discrimination factors in several reactions prominent in the global O cycle and indicate that photorespiration plays a significant part in determining the isotopic composition of atmospheric oxygen.

Journal Article↗
PubMed1999

Observations of hydrogen and oxygen isotopes in leaf water confirm the craig-gordon model under wide-ranging environmental conditions

The Craig-Gordon evaporative enrichment model of the hydrogen (deltaD) and oxygen (delta(18)O) isotopes of water was tested in a controlled-environment gas exchange cuvette over a wide range (400 per thousand deltaD and 40 per thousand delta(18)O) of leaf waters. (Throughout this paper we use the term "leaf water" to describe the site of evaporation, which should not be confused with "bulk leaf water" a term used exclusively for uncorrected measurements obtained from whole leaf water extractions.) Regardless of how the isotopic composition of leaf water was achieved (i.e. by changes in source water, atmospheric vapor deltaD or delta(18)O, vapor pressure gradients, or combinations of all three), a modified version of the Craig-Gordon model was shown to be sound in its ability to predict the deltaD and delta(18)O values of water at the site of evaporation. The isotopic composition of atmospheric vapor was shown to have profound effects on the deltaD and delta(18)O of leaf water and its influence was dependent on vapor pressure gradients. These results have implications for conditions in which the isotopic composition of atmospheric vapor is not in equilibrium with source water, such as experimental systems that grow plants under isotopically enriched water regimes. The assumptions of steady state were also tested and found not to be a major limitation for the utilization of the leaf water model under relatively stable environmental conditions. After a major perturbation in the deltaD and delta(18)O of atmospheric vapor, the leaf reached steady state in approximately 2 h, depending on vapor pressure gradients. Following a step change in source water, the leaf achieved steady state in 24 h, with the vast majority of changes occurring in the first 3 h. Therefore, the Craig-Gordon model is a useful tool for understanding the environmental factors that influence the hydrogen and oxygen isotopic composition of leaf water as well as the organic matter derived from leaf water.

Journal Article↗
PubMed1975

Isotope Fractionation in Photosynthetic Bacteria during Carbon Dioxide Assimilation.

The delta (PDB) (13)C values have been determined for the cellular constituents and metabolic intermediates of autotrophically grown Chromatium vinosum. The isotopic composition of the HCO(3) (-) in the medium and the carbon isotopic composition of the bacterial cells change with the growth of the culture. The delta (PDB) (13)C value of the HCO(3) (-) in the media changes from an initial value of -6.6 per thousand to +8.1 per thousand after 10 days of bacterial growth and the delta (PDB) (13)C value of the bacterial cells change from -37.5 per thousand to -29.2 per thousand in the same period. The amount of carbon isotope fractionation during the synthesis of hexoses by the photoassimilation of CO(2) has a range of -15.5 per thousand at time zero to -22.0 per thousand after 10 days. This range of fractionation compares to the range of carbon isotope fractionation for the synthesis of sugars from CO(2) by ribulose 1,5-diphosphate carboxylase and the Calvin cycle.The amount of carbon isotope fractionation during the synthesis of aspartic acid from CO(2) is -24.9 per thousand at time zero and -15.0 per thousand after 10 days of bacterial growth. This amount of fractionation is in the range of carbon isotope fractionation for the synthesis of C(4) amino acids by a double carboxylation through ribulose 1,5-diphosphate and phosphoenolpyruvate carboxylase.

Journal Article↗
PubMed1984

Carbon, hydrogen, and oxygen isotope ratios of cellulose from plants having intermediary photosynthetic modes.

Carbon and hydrogen isotope ratios of cellulose nitrate and oxygen isotope ratios of cellulose from species of greenhouse plants having different photosynthetic modes were determined. When hydrogen isotope ratios are plotted against carbon isotope ratios, four clusters of points are discernible, each representing different photosynthetic modes: C(3) plants, C(4) plants, CAM plants, and C(3) plants that can shift to CAM or show the phenomenon referred to as CAM-cycling. The combination of oxygen and carbon isotope ratios does not distinguish among the different photosynthetic modes. Analysis of the carbon and hydrogen isotope ratios of cellulose nitrate should prove useful for screening different photosynthetic modes in field specimens that grew near one another. This method will be particularly useful for detection of plants which show CAM-cycling.

Journal Article↗
PubMed1991

Evidence for a nonstatistical carbon isotope distribution in natural glucose.

The relative carbon isotope content (delta(13)C value) in each position of glucose from a C(4) plant (maize starch) and a C(3) plant (sugar beet sucrose) has been determined by stepwise chemical and biochemical degradation of the molecule and stable isotope ratio measurement of the fragments. The suitability of the degradation methods has been tested through their chemical yield and isotope balance. The results from both methods agreed perfectly, revealing a defined and reproducible (13)C distribution in glucose from both origins. Most prominent was a relative (13)C enrichment by 5 to 6 delta-units in position 4 and a depletion by about 5 delta-units in carbon 6. As possible reasons for these nonstatistical isotope distributions, isotope effects of the aldolase, the triose phosphate isomerase, and the transketolase reactions during carbohydrate biosynthesis are discussed. The practical importance of the results in regard to isotope distributions in secondary plant products as a means for food authenticity control is outlined.

Journal Article↗
PubMed2005

Oxidation of caffeine by CYP1A2: isotope effects and metabolic switching.

Caffeine (1,3,7-trimethylxanthine) has previously been shown to undergo metabolic switching in vivo when the N-1 or the N-7 methyl groups were trideuteromethylated [Horning et al. (1976) Proceedings of the Second International Conference on Stable Isotopes, pp 41-54]. We have examined the effect of replacing the N-3 methyl group with a trideuteromethyl group. The corresponding isotope effects can then be used to distinguish the kinetic mechanism by which four primary metabolites can be formed from one substrate by one cytochrome P450 (P450). We have synthesized 3-CD3-caffeine and 3-CD3-7-CD3-caffeine as well as trideuteromethylated analogs of each of the in vitro metabolites formed by cytochrome P4501A2. The observed competitive isotope effects for the metabolites, which do not result from deuterium abstraction (theobromine, theophylline), demonstrate that the nondissociative mechanism applies to caffeine metabolism by cytochrome P4501A2. Thus, there must be equilibration of the kinetically distinguishable activated P450-substrate complexes at rates competitive with hydrogen abstraction. The true isotope effects for the N-3 demethylation of caffeine were derived from the ratios of the amount of paraxanthine relative to the amount of theobromine or theophylline. The resultant ratios indicate that these isotope effects are essentially intrinsic. Observation of the isotope effects on N-3 demethylation was facilitated by branching to the minor in vitro metabolites as well as water formation. Product release is not rate-limiting for this system.

Caffeine↗
PubMed2000

Secular variation of iron isotopes in north atlantic deep water

A high-precision iron isotope time series for a ferromanganese crust demonstrates that the iron isotope composition in North Atlantic Deep Water has changed substantially over the past 6 million years and that iron isotope variations in the crust are closely correlated to those of lead isotopes. The close correlation between the two isotope series indicates that the observed iron isotope variations predominantly reflect those of iron input from terrigenous sources and provides no evidence for biologically induced mass fractionation within North Atlantic Deep Water.

Journal Article↗
PubMed2006

Combined ultrasound and isotope scanning is more informative in the diagnosis of congenital hypothyroidism than single scanning.

BACKGROUND: Thyroid imaging is helpful in confirming the diagnosis of congenital hypothyroidism and in establishing the aetiology. Although isotope scanning is the standard method of imaging, ultrasound assessment may be complementary. AIM: To determine the strengths and weaknesses of thyroid ultrasound and isotope scanning in neonates with thyroid stimulating hormone (TSH) elevation. METHODS: Babies from the West of Scotland with raised capillary TSH (>15 mU/l) on neonatal screening between January 1999 and 2004 were recruited. Thyroid dimensions were measured using ultrasonography, and volumes were calculated. Isotope scanning was carried out with a pinhole collimator after an intravenous injection of 99m-technetium pertechnetate. RESULTS: 40 infants (29 female) underwent scanning at a median of 17 days (range 12 days to 15 months). The final diagnosis was athyreosis (n = 11), ectopia (n = 12), hypoplasia (n = 8; 3 cases of hemi-agenesis), dyshormonogenesis (n = 5), transient hypothyroidism (n = 2), transient hyperthyrotropinaemia (n = 1) and uncertain status with gland in situ (n = 1). 6 infants had discordant scans with no isotope uptake but visualisation of thyroid tissue on ultrasound. This was attributed to TSH suppression from thyroxine (n = 3); maternal blocking antibodies (n = 1); cystic degeneration of the thyroid (n = 1); and possible TSH receptor defect (n = 1). CONCLUSIONS: Isotope scanning was superior to ultrasound in the detection of ectopic tissue. However, ultrasound detected tissue that was not visualised on isotope scanning, and showed abnormalities of thyroid volume and morphology. We would therefore advocate dual scanning in newborns with TSH elevation as each modality provides different information.

Congenital Hypothyroidism↗
PubMed1986

Gluconeogenesis from labeled carbon: estimating isotope dilution.

To estimate the rate of gluconeogenesis from steady-state incorporation of labeled 3-carbon precursors into glucose, isotope dilution must be considered so that the rate of labeling of glucose can be quantitatively converted to the rate of gluconeogenesis. An expression for the value of this isotope dilution can be derived using mathematical techniques and a model of the tricarboxylic acid (TCA) cycle. The present investigation employs a more complex model than that used in previous studies. This model includes the following pathways that may affect the correction for isotope dilution: 1) flux of 3-carbon precursor to the oxaloacetate pool via acetyl-CoA and the TCA cycle; 2) flux of 4- or 5-carbon compounds into the TCA cycle; 3) reversible flux between oxaloacetate (OAA) and pyruvate and between OAA and fumarate; 4) incomplete equilibrium between OAA pools; and 5) isotope dilution of 3-carbon tracers between the experimentally measured pool and the precursor for the TCA-cycle OAA pool. Experimental tests are outlined which investigators can use to determine whether these pathways are significant in a specific steady-state system. The study indicated that flux through these five pathways can significantly affect the correction for isotope dilution. To correct for the effects of these pathways an alternative method for calculating isotope dilution is proposed using citrate to relate the specific activities of acetyl-CoA and OAA.

Acetyl Coenzyme A↗
PubMed1994

Relationship between balance and dual tracer isotopic measurements of calcium absorption and excretion.

Calcium (Ca) absorption was measured by the balance method and the dual tracer isotopic method in 462 studies of adult women. Results for both fractional absorption and net Ca balance were similar using the 2 methods. Slightly higher values (mean difference, 0.031 +/- 0.092) were found for fractional absorption measured by the balance method than by the isotopic method. No differences in fractional absorption between the methods were seen at a fractional absorption less than 25%. Variability in the data was greater from the balance than the isotopic method. Endogenous fecal Ca excretion was directly related to Ca intake, with an estimated value of 70-80 mg/day for a Ca intake less than 200 mg/day. These findings support the usefulness and accuracy of isotope-based measures of mineral absorption. No evidence is found from these or previous data to suggest that the process of isotopic equilibration falsely increases estimates of absorption or endogenous excretion in tracer studies. Isotopic techniques allow studies of calcium absorption in diverse populations and evaluation of unique aspects of mineral metabolism not accessible through other techniques.

Absorption↗