Cytochrome c oxidase, the terminal enzyme in the respiratory chain, reduces molecular oxygen to water and stores the released energy through electrogenic chemistry and proton pumping across the ...membrane. Apart from the heme-copper binuclear center, there is a conserved tyrosine residue in the active site (BNC). The tyrosine delivers both an electron and a proton during the O–O bond cleavage step, forming a tyrosyl radical. The catalytic cycle then occurs in four reduction steps, each taking up one proton for the chemistry (water formation) and one proton to be pumped. It is here suggested that in three of the reduction steps the chemical proton enters the center of the BNC, leaving the tyrosine unprotonated with radical character. The reproprotonation of the tyrosine occurs first in the final reduction step before binding the next oxygen molecule. It is also suggested that this reduction mechanism and the presence of the tyrosine are essential for the proton pumping. Density functional theory calculations on large cluster models of the active site show that only the intermediates with the proton in the center of the BNC and with an unprotonated tyrosyl radical have a high electron affinity of similar size as the electron donor, which is essential for the ability to take up two protons per electron and thus for the proton pumping. This type of reduction mechanism is also the only one that gives a free energy profile in accordance with experimental observations for the amount of proton pumping in the working enzyme.
Siegbahn and Blomberg examine various quantum chemical studies of proton-coupled electron transfer in metalloenzymes. They also detail cytochrome c oxidase, photosystem II, and ribonucleotide ...reductase.
The technology behind positron emission tomography (PET) and the most widely used tracer, 2-deoxy-2-18Ffluoro-D-glucose (FDG), were both conceived in the 1970s, but the latest decade has witnessed a ...rapid emergence of FDG-PET as an effective imaging technique. This is not least due to the emergence of hybrid scanners combining PET with computed tomography (PET/CT). Molecular imaging has enormous potential for advancing biological research and patient care, and FDG-PET/CT is currently the most widely used technology in this domain. In this review, we discuss contemporary applications of FDG-PET and FDG-PET/CT as well as novel developments in quantification and potential future indications including the emerging new modality PET/magnetic resonance imaging.
Purpose
Arterial inflammation and vascular calcification are regarded as early prognostic markers of cardiovascular disease (CVD). In this study we investigated the relationship between CVD risk and ...arterial inflammation (
18
F-FDG PET/CT imaging), vascular calcification metabolism (Na
18
F PET/CT imaging), and vascular calcium burden (CT imaging) of the thoracic aorta in a population at low CVD risk.
Methods
Study participants underwent blood pressure measurements, blood analyses, and
18
F-FDG and Na
18
F PET/CT imaging. In addition, the 10-year risk for development of CVD, based on the Framingham risk score (FRS), was estimated. CVD risk was compared across quartiles of thoracic aorta
18
F-FDG uptake, Na
18
F uptake, and calcium burden on CT.
Results
A total of 139 subjects (52 % men, mean age 49 years, age range 21 – 75 years, median FRS 6 %) were evaluated. CVD risk was, on average, 3.7 times higher among subjects with thoracic aorta Na
18
F uptake in the highest quartile compared with those in the lowest quartile of the distribution (15.5 % vs. 4.2 %;
P
< 0.001). CVD risk was on average, 3.7 times higher among subjects with a thoracic aorta calcium burden on CT in the highest quartile compared with those in the lowest two quartiles of the distribution (18.0 % vs. 4.9 %;
P
< 0.001). CVD risk was similar in subjects in all quartiles of thoracic aorta
18
F-FDG uptake.
Conclusion
Our findings indicate that an unfavourable CVD risk profile is associated with marked increases in vascular calcification metabolism and vascular calcium burden of the thoracic aorta, but not with arterial inflammation.
Hemodynamically significant coronary artery disease is an important indication for revascularization. Stress myocardial perfusion imaging is a noninvasive alternative to invasive fractional flow ...reserve for evaluating hemodynamically significant coronary artery disease. The aim was to determine the diagnostic accuracy of myocardial perfusion imaging by single-photon emission computed tomography, echocardiography, MRI, positron emission tomography, and computed tomography compared with invasive coronary angiography with fractional flow reserve for the diagnosis of hemodynamically significant coronary artery disease.
The meta-analysis adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. PubMed, EMBASE, and Web of Science were searched until May 2014. Thirty-seven studies, reporting on 4721 vessels and 2048 patients, were included. Meta-analysis yielded pooled sensitivity, pooled specificity, pooled likelihood ratios (LR), pooled diagnostic odds ratio, and summary area under the receiver operating characteristic curve. The negative LR (NLR) was chosen as the primary outcome. At the vessel level, MRI (pooled NLR, 0.16; 95% confidence interval CI, 0.13-0.21) was performed similar to computed tomography (pooled NLR, 0.22; 95% CI, 0.12-0.39) and positron emission tomography (pooled NLR, 0.15; 95% CI, 0.05-0.44), and better than single-photon emission computed tomography (pooled NLR, 0.47; 95% CI, 0.37-0.59). At the patient level, MRI (pooled NLR, 0.14; 95% CI, 0.10-0.18) performed similar to computed tomography (pooled NLR, 0.12; 95% CI, 0.04-0.33) and positron emission tomography (pooled NLR, 0.14; 95% CI, 0.02-0.87), and better than single-photon emission computed tomography (pooled NLR, 0.39; 95% CI, 0.27-0.55) and echocardiography (pooled NLR, 0.42; 95% CI, 0.30-0.59).
Stress myocardial perfusion imaging with MRI, computed tomography, or positron emission tomography can accurately rule out hemodynamically significant coronary artery disease and can act as a gatekeeper for invasive revascularization. Single-photon emission computed tomography and echocardiography are less suited for this purpose.
The catalytic mechanism of reduction of NO to N2O in the bacterial enzyme nitric oxide reductase has been investigated using hybrid density functional theory and a model of the binuclear center (BNC) ...based on the newly determined crystal structure. The calculations strongly suggest a so-called cis:b3 mechanism, while the commonly suggested trans mechanism is found to be energetically unfavorable. The mechanism suggested here involves a stable cis-hyponitrite, and it is shown that from this intermediate one N–O bond can be cleaved without the transfer of a proton or an electron into the binuclear active site, in agreement with experimental observations. The fully oxidized intermediate in the catalytic cycle and the resting form of the enzyme are suggested to have an oxo-bridged BNC with two high-spin ferric irons antiferromagnetically coupled. Both steps of reduction of the BNC after N2O formation are found to be pH-dependent, also in agreement with experiment. Finally, it is found that the oxo bridge in the oxidized BNC can react with NO to give nitrite, which explains the experimental observations that the fully oxidized enzyme reacts with NO, and most likely also the observed substrate inhibition at higher NO concentrations.
Cellular respiration involves electron transport via a number of enzyme complexes to the terminal Cytochrome
oxidase (C
O), in which molecular oxygen is reduced to water. The free energy released in ...the reduction process is used to establish a transmembrane electrochemical gradient, via two processes, both corresponding to charge transport across the membrane in which the enzymes are embedded. First, the reduction chemistry occurring in the active site of C
O is electrogenic, which means that the electrons and protons are delivered from opposite sides of the membrane. Second, the exergonic chemistry is coupled to translocation of protons across the entire membrane, referred to as proton pumping. In the largest subfamily of the C
O enzymes, the A-family, one proton is pumped for every electron needed for the chemistry, making the energy conservation particularly efficient. In the present study, hybrid density functional calculations are performed on a model of the A-family C
Os. The calculations show that the redox-active tyrosine, conserved in all types of C
Os, plays an essential role for the energy conservation. Based on the calculations a reaction mechanism is suggested involving a tyrosyl radical (possibly mixed with tyrosinate character) in all reduction steps. The result is that the free energy released in each reduction step is large enough to allow proton pumping in all reduction steps without prohibitively high barriers when the gradient is present. Furthermore, the unprotonated tyrosine provides a mechanism for coupling the uptake of two protons per electron in every reduction step, i.e. for a secure proton pumping.
There is, in general, very good experience using hybrid DFT to study mechanisms of enzyme reactions containing transition metals. For redox reactions, the B3LYP* functional, which has 15% exact ...exchange, has been shown to be particularly accurate. Still, there are some cases which have turned out to be quite difficult with large errors. In the present study, the effects of van der Waals interaction have been investigated for these cases, using the empirical formula of Grimme. The results are encouraging.
Objective
Air pollution is now recognized as an important independent risk factor for cardiovascular morbidity and mortality and may be responsible for up to 3 million premature deaths each year ...worldwide. The mechanisms underlying the observed effects are poorly understood but are likely to be multifactorial. Here, we review the acute and chronic effects of air pollution exposure on the cardiovascular system and discuss how these effects may explain the observed increases in cardiovascular morbidity and mortality.
The full sequence of intermediates in the water oxidation process in photosystem II has recently been characterized by model calculations, in good agreement with experiments. In the present paper, ...the energy diagram obtained is used as a benchmark test for several density functionals. Only the results using B3LYP with 15% or 20% show good agreement with experiments. The other functionals tried show errors for some energy levels as large as 20–30 kcal/mol. The reason for these large errors is that the error for three consecutive oxidations of Mn(III) to Mn(IV) accumulates as the cluster is oxidized.
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