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Most of biological oxygen reduction is catalyzed by the heme‐copper oxygen reductases. These enzymes are redox‐driven proton pumps that take part in generating the proton gradient in both prokaryotes and mitochondria that drives synthesis of ATP. The enzymes have been divided into three evolutionarily‐related groups: the A‐, B‐, and C‐families. Recent comparative studies suggest that all oxygen reductases perform the same chemistry for oxygen reduction and comprise the same essential elements of the proton pumping mechanism, such as the proton loading and kinetic gating sites, which, however, appear to be different in different families. All species of the A‐family, however, demonstrate remarkable similarity of the central processing unit of the enzyme, as revealed by their recent crystal structures. Here we demonstrate that cytochrome c oxidases (CcO) of such diverse organisms as a mammal (bovine heart mitochondrial CcO), photosynthetic bacteria (Rhodobacter sphaeroides CcO), and soil bacteria (Paracoccus denitrificans CcO) are not only structurally similar, but almost identical in microscopic electrostatics and thermodynamics properties of their key amino‐acids. By using pKa calculations of some of the key residues of the catalytic site, D‐ and K‐ proton input, and putative proton output channels of these three different enzymes, we demonstrate that the microscopic properties of key residues are almost identical, which strongly suggests the same mechanism in these species. The quantitative precision with which the microscopic physical properties of these enzymes have remained constant despite different evolutionary routes undertaken is striking. Proteins 2010. © 2010 Wiley‐Liss, Inc. 相似文献
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Carlyn A. Figueiredo Paulina C. Drohomyrecky Stephen D. S. McCarthy Danila Leontyev Xue-Zhong Ma Donald R. Branch Shannon E. Dunn 《PloS one》2014,9(7)
Background
Intravenous immunoglobulin (IVIg) has been used to treat a variety of autoimmune disorders including multiple sclerosis (MS); however its mechanism of action remains elusive. Recent work has shown that interleukin-11 (IL-11) mRNAs are upregulated by IVIg in MS patient T cells. Both IVIg and IL-11 have been shown to ameliorate experimental autoimmune encephalomyelitis (EAE), an animal model of MS. The objective of this study was to determine whether the protective effects of IVIg in EAE occur through an IL-11 and IL-11 receptor (IL-11R)-dependent mechanism.Methods
We measured IL-11 in the circulation of mice and IL-11 mRNA expression in various organs after IVIg treatment. We then followed with EAE studies to test the efficacy of IVIg in wild-type (WT) mice and in mice deficient for the IL-11 receptor (IL-11Rα−/−). Furthermore, we evaluated myelin-specific Th1 and Th17 responses and assessed spinal cord inflammation and demyelination in WT and IL-11Rα−/− mice, with and without IVIg treatment. We also examined the direct effects of mouse recombinant IL-11 on the production of IL-17 by lymph node mononuclear cells.Results
IVIg treatment induced a dramatic surge (>1000-fold increase) in the levels of IL-11 in the circulation and a prominent increase of IL-11 mRNA expression in the liver. Furthermore, we found that IL-11Rα−/− mice, unlike WT mice, although initially protected, were resistant to full protection by IVIg during EAE and developed disease with a similar incidence and severity as control-treated IL-11Rα−/− mice, despite initially showing protection. We observed that Th17 cytokine production by myelin-reactive T cells in the draining lymph nodes was unaffected by IVIg in IL-11Rα−/− mice, yet was downregulated in WT mice. Finally, IL-11 was shown to directly inhibit IL-17 production of lymph node cells in culture.Conclusion
These results implicate IL-11 as an important immune effector of IVIg in the prevention of Th17-mediated autoimmune inflammation during EAE. 相似文献
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