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Biomedical subjects

M L Kirk

Publications and source records attributed to M L Kirk.

13 recordsLinked to original sources
PubMed2000

Electronic structure studies of oxomolybdenum tetrathiolate complexes: origin of reduction potential differences and relationship to cysteine-molybdenum bonding in sulfite oxidase.

Electronic absorption, magnetic circular dichroism, and resonance Raman spectroscopies have been used to determine the nature of oxomolybdenum-thiolate bonding in (PPh4)[MoO(SPh)4] (SPh = phenylthiolate) and (HNEt3)[MoO(SPh-PhS)2] (SPh-PhS = biphenyl-2,2'-dithiolate). These compounds, like all oxomolybdenum tetraarylthiolate complexes previously reported, display an intense low-energy charge-transfer feature that we have now shown to be comprised of multiple S-->Mo dxy transitions. The integrated intensity of this low-energy band in [MoO(SPh)4]- is approximately twice that of [MoO(SPh-PhS)2]-, implying a greater covalent reduction of the effective nuclear charge localized on the molybdenum ion of the former and a concomitant negative shift in the Mo(V)/Mo(IV) reduction potential brought about by the differential S-->Mo dxy charge donation. However, this is not observed experimentally; the Mo(V)/Mo(IV) reduction potential of [MoO(SPh)4]- is approximately 120 mV more positive than that of [MoO(SPh-PhS)2]- (-783 vs -900 mV). Additional electronic factors as well as structural reorganizational factors appear to play a role in these reduction potential differences. Density functional theory calculations indicate that the electronic contribution results from a greater sigma-mediated charge donation to unfilled higher energy molybdenum acceptor orbitals, and this is reflected in the increased energies of the [MoO(SPh-PhS)2]- ligand-to-metal charge-transfer transitions relative to those of [MoO(SPh)4]-. The degree of S-Mo dxy covalency is a function of the O identical to Mo-S-C dihedral angle, with increasing charge donation to Mo dxy and increasing charge-transfer intensity occurring as the dihedral angle decreases from 90 to 0 degree. These results have implications regarding the role of the coordinated cysteine residue in sulfite oxidase. Although the O identical to Mo-S-C dihedral angles are either approximately 59 or approximately 121 degrees in these oxomolybdenum tetraarylthiolate complexes, the crystal structure of the enzyme reveals an O identical to Mo-SCys-C angle of approximately 90 degrees. Thus, a significant reduction in SCys-Mo dxy covalency is anticipated in sulfite oxidase. This is postulated to preclude the direct involvement of coordinated cysteine in coupling the active site into efficient superexchange pathways for electron transfer, provided the O identical to Mo-SCys-C angle is not dynamic during the course of catalysis. Therefore, we propose that a primary role for coordinated cysteine in sulfite oxidase is to statically poise the reduced molybdenum center at more negative reduction potentials in order to thermodynamically facilitate electron transfer from Mo(IV) to the endogenous b-type heme.

Binding Sites↗
PubMed2000

An MCD spectroscopic study of the molybdenum active site in sulfite oxidase: insight into the role of coordinated cysteine.

Temperature-dependent magnetic circular dichroism (MCD) spectroscopy has been used for the first time to probe the electronic structure of the Mo active site in sulfite oxidase (SO). The enzyme was poised in the catalytically relevant [Mo(V):Fe(II)] state by anaerobic reduction of the enzyme with the natural substrate, sulfite, in the absence of the physiological oxidant cytochrome c. The [Mo(V):Fe(II)] state is of particular importance, as it is proposed to be a catalytic intermediate in the oxidative half reaction, where SO is reoxidized to the resting [Mo(VI):Fe(III)] state by two sequential one-electron transfers to cytochrome c. The MCD spectrum of the enzyme shows no charge transfer transitions below approximately 17000 cm(-1). This has been interpreted to result from (1) a severe reduction in ene-1,2-dithiolate sulfur in-plane and out-of-plane p orbital mixing, (2) a decrease in the dithiolate sulfur out-of-plane p-Mo d(xy) orbital overlap, and (3) an orthogonal orientation between the vertical cysteine sulfur p (perpendicular to the Mo-Scys sigma-bond) and Mo d(xy) orbitals. The spectroscopically determined cysteine sulfur p-Mo d(xy) bonding scheme in the [Mo(V):Fe(II)] state is consistent with the crystallographically determined O-Mo-Scys-C dihedral angle of approximately 90 degrees and precludes a covalent interaction between the vertical cysteine sulfur p orbital and Mo d(xy), effectively decoupling the cysteine from an effective through-bond electron transfer pathway. We have tentatively assigned a 22250 cm(-1) positive C-term feature in the MCD as the cysteine S(sigma)-->Mo d(xy) charge transfer that becomes allowed by a combination of configuration interaction and low-symmetry; however, the orbital overlap is anticipated to be quite small due to the near orthogonality of these orbitals. Therefore, we propose that the primary role of the coordinated cysteine is to decrease the effective nuclear charge on Mo by charge donation to the metal, statically poising the active site at more negative reduction potentials during electron transfer (ET) regeneration. Finally, the results of this study are consistent with the pyranopterin ene-1,2-dithiolate acting to couple the Mo site into efficient superexchange pathways for ET regeneration following oxygen atom transfer to the substrate.

Animals↗
PubMed2000

Control of oxo-molybdenum reduction and ionization potentials by dithiolate donors.

The compounds (L-N3)MoO(qdt) and (L-N3)MoO(tdt) [(L-N3) = hydrotris(3,5-dimethyl-1-pyrazolyl)borate; tdt = toluene-3,4-dithiolate; qdt = quinoxaline-2,3-dithiolate] have been studied by cyclic voltammetry and photoelectron, magnetic circular dichroism, and electronic absorption spectroscopies, and the experimental data have been interpreted in the context of ab initio molecular orbital calculations on a variety of dithiolate dianion ligands. The PES data reveal very substantial differences between (L-N3)MoO(qdt) and (L-N3)MoO(tdt) in that the first ionization (originating from the Mo dxy orbital) for (L-N3)MoO(qdt) is about 0.8 eV to deeper binding energy than that of (L-N3)MoO(tdt). This stabilizing effect is also reflected in the solution reduction potentials, where (L-N3)MoO(qdt) is approximately 220 mV easier to reduce than (L-N3)MoO(tdt). A direct correlation between the relative donating ability of a given dithiolate ligand and the reduction potential of the (L-N3)MoO(dithiolate) complex has been observed, and a linear relationship exists between the calculated Mulliken charge on the S atoms of the dithiolate dianion and the Mo reduction potential. The study confirms previously communicated work (Helton, M. E.; Kirk, M. L. Inorg. Chem. 1999, 38, 4384-4385) that suggests that anisotropic covalency contributions involving only the out-of-plane S orbitals of the coordinated dithiolate control the Mo reduction potential by modulating the effective nuclear charge of the metal, and this has direct relevance to understanding the mechanism of ferricyanide inhibition in sulfite oxidase. Furthermore, these results indicate that partially oxidized pyranopterins may play a role in facilitating electron and/or atom transfer in certain pyranopterin tungsten enzymes which catalyze formal oxygen atom transfer reactions at considerably lower potentials.

Binding Sites↗
PubMed1992

Adipose tissue metabolism in obesity: lipase action in vivo before and after a mixed meal.

Physiological actions of insulin include suppression of fat mobilization from adipose tissue and activation of adipose tissue lipoprotein lipase. Here, we report measurements of adipose tissue hormone-sensitive lipase (HSL) and lipoprotein lipase (LPL) action in vivo in 10 normal and eight obese subjects, with the latter group having varying degrees of glucose intolerance. HSL and LPL actions (per gram of adipose tissue) were similar in the two groups, after an overnight fast. In the normal subjects, HSL action was suppressed after a meal (by 75% +/- 6% between 60 to 300 minutes, P less than .01), and the action of LPL was increased (clearance of circulating triacylglycerol [TAG] increased by 140% +/- 57% at 300 minutes, P less than .05). Despite hyperinsulinemia, these responses were blunted in the obese subjects (P less than .05 for each change being less than in normal group). The adipose tissue of the obese subjects showed continued nonesterified fatty acid (NEFA) release at a time when NEFA mobilization was completely suppressed in the normal group. Both impaired suppression of HSL and low fractional retention of fatty acids for reesterification within the adipose tissue contributed to this abnormal NEFA release. Impaired activation of LPL was associated with a greater absolute increase in plasma TAG concentration postprandially in the obese. In obese subjects, adipose tissue HSL and LPL fail to respond to immunoreactive insulin postprandially, which may be an important maladaptation in terms of lipoprotein metabolism and risk of coronary heart disease.

Adipose Tissue↗
PubMed1989

Geographic distribution of heat-related deaths among elderly persons. Use of county-level dot maps for injury surveillance and epidemiologic research.

Mapping is a useful tool for initiating data analysis of relatively infrequent injury events and can lead to interesting hypotheses that can then be tested in further epidemiologic studies. From national death certificate data for the years 1979 through 1985, we made dot maps of fatalities due to excessive heat (International Classification of Diseases code E900) among persons 65 years or older. The maps show clusterings of deaths, particularly in the central, south central, and southeastern sections of the United States, to an extent not fully explained by the population density or temperature extremes. The counties principally affected were highly urbanized and, for races other than white, were relatively poor. Our maps identify counties in which heat-related health problems in the elderly are particularly severe. Public health officials in high-risk areas should undertake heat-wave contingency planning and physicians practicing in such areas should familiarize themselves with the treatment of the spectrum of heat-related illnesses.

Aged↗
PubMed1987

Underreporting of alcohol-related mortality on death certificates of young US Army veterans.

We assessed the validity of death certificate data for alcohol-related mortality in a population-based follow-up study of young, male US Army veterans. In a random sample of more than 18,000 men who entered the service between 1965 and 1971, there were 446 postservice deaths through Dec 31, 1983. For 426 of these deaths, we obtained both the death certificate and all other available medical and legal records pertaining to cause of death. A nosologist recorded each death certificate in accordance with the ninth revision of the International Classification of Diseases. A medical panel, without having access to the death certificates, assigned underlying and contributory causes of death on the basis of a review of only the medical and legal records. The panel recorded 133 alcohol-related deaths, or more than six times the number (21 deaths) determined by the original death certifiers. Omission of elevated blood alcohol levels in deaths due to injury accounts for most of the underreporting of alcohol-related mortality on the death certificates. Our findings suggest that death certificate data grossly underestimate the contribution of alcohol to mortality, especially in the area of injury, and the validity of official vital statistics for alcohol-related deaths would be enhanced if death certifiers incorporated all available antemortem and postmortem diagnostic information.

Adult↗
PubMed1987

Density-dependent timing of defaecation by Rhodnius prolixus, and its implications for the transmission of Trypanosoma cruzi.

Transmission of Trypanosoma cruzi is crucially dependent on the timing of defaecation by their insect vectors. Experimental studies on Rhodnius prolixus nymphs revealed a negative correlation between blood meal weight and defaecation time. Bugs which fed to repletion defaecated on average 7 min after feeding, whereas bugs with interrupted feeds defaecated about 1 h later. As blood meal weight of triatomine bugs is density-dependent, these results suggest that the greatest risk of successful T. cruzi transmission would occur in recently colonized houses where the bug population is still increasing, or in houses recolonized after a vector control attempt.

Animals↗
PubMedDate not supplied

Discrepancies in the reported frequency of cocaine-related deaths, United States, 1983 through 1988.

OBJECTIVE: --To assess the validity of cocaine-related mortality data available from the principal federal sources of information about the frequency of drug abuse deaths in the United States: the national vital statistics system and the Drug Abuse Warning Network (DAWN). DESIGN, SETTING, AND PARTICIPANTS: --We compared the number of cocaine-related deaths reported to national vital statistics and DAWN from 25 metropolitan areas during the years 1983 through 1988. We also compared cocaine-related mortality data reported to national vital statistics with data from all published forensic case series of cocaine-related deaths that occurred during the mid-1980s. RESULTS: --During the 6-year study period, 75% more cocaine-related deaths were reported to DAWN (6057) than to national vital statistics (3466) from the 25 metropolitan areas that were studied. For individual metropolitan areas, the discrepancy between DAWN and vital statistics counts of cocaine-related deaths was as large as a sixfold difference. In six of the seven forensic case series identified in our literature search, the number of cocaine-related deaths exceeded the number of these deaths reported to vital statistics. The largest discrepancy was for cocaine-related deaths in New York, NY, during a 10-month period in 1986 for which 151 deaths were reported in a case series and seven deaths were reported to vital statistics. CONCLUSION: --Improvements in existing public health surveillance systems are needed for (1) full and accurate measurements of the lethal impact of drug abuse epidemics and (2) valid and comprehensive assessments of the effectiveness of national programs designed to prevent drug-related morbidity and mortality.

Cause of Death↗