Publications by authors named "Jacques Kumutima"

3 Publications

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p53 Is Potentially Regulated by Cyclophilin D in the Triple-Proline Loop of the DNA Binding Domain.

Biochemistry 2021 Mar 16;60(8):597-606. Epub 2021 Feb 16.

The multifunctional protein p53 is the central molecular sensor of cellular stresses. The canonical function of p53 is to transcriptionally activate target genes in response to, for example, DNA damage that may trigger apoptosis. Recently, p53 was also found to play a role in the regulation of necrosis, another type of cell death featured by the mitochondrial permeability transition (mPT). In this process, p53 directly interacts with the mPT regulator cyclophilin D, the detailed mechanism of which however remains poorly understood. Here, we report a comprehensive computational investigation of the p53-cyclophilin D interaction using molecular dynamics simulations and associated analyses. We have identified the specific cyclophilin D binding site on p53 that is located at proline 151 in the DNA binding domain. As a peptidyl-prolyl isomerase, cyclophilin D binds p53 and catalyzes the isomerization of the peptide bond preceding proline 151. We have also characterized the effect of such an isomerization and found that the p53 domain in the state is overall more rigid than the state except for the local region around proline 151. Dynamical changes upon isomerization occur in both local and distal regions, indicating an allosteric effect elicited by the isomerization. We present potential allosteric communication pathways between proline 151 and distal sites, including the DNA binding surface. Our work provides, for the first time, a model for how cyclophilin D binds p53 and regulates its activity by switching the configuration of a specific site.
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http://dx.doi.org/10.1021/acs.biochem.0c00946DOI Listing
March 2021

A distal ligand mutes the interaction of hydrogen sulfide with human neuroglobin.

J Biol Chem 2017 04 28;292(16):6512-6528. Epub 2017 Feb 28.

From the Department of Biological Chemistry and

Hydrogen sulfide is a critical signaling molecule, but high concentrations cause cellular toxicity. A four-enzyme pathway in the mitochondrion detoxifies HS by converting it to thiosulfate and sulfate. Recent studies have shown that globins like hemoglobin and myoglobin can also oxidize HS to thiosulfate and hydropolysulfides. Neuroglobin, a globin enriched in the brain, was reported to bind HS tightly and was postulated to play a role in modulating neuronal sensitivity to HS in conditions such as stroke. However, the HS reactivity of the coordinately saturated heme in neuroglobin is expected to be substantially lower than that of the 5-coordinate hemes present in myoglobin and hemoglobin. To resolve this discrepancy, we explored the role of the distal histidine residue in muting the reactivity of human neuroglobin toward HS. Ferric neuroglobin is slowly reduced by HS and catalyzes its inefficient oxidative conversion to thiosulfate. Mutation of the distal His residue to alanine promotes rapid binding of HS and its efficient conversion to oxidized products. X-ray absorption, EPR, and resonance Raman spectroscopy highlight the chemically different reaction options influenced by the distal histidine ligand. This study provides mechanistic insights into how the distal heme ligand in neuroglobin caps its reactivity toward HS and identifies by cryo-mass spectrometry a range of sulfide oxidation products with 2-6 catenated sulfur atoms with or without oxygen insertion, which accumulate in the absence of the His ligand.
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http://dx.doi.org/10.1074/jbc.M116.770370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5399104PMC
April 2017

Hydrogen Sulfide Oxidation by Myoglobin.

J Am Chem Soc 2016 07 30;138(27):8476-88. Epub 2016 Jun 30.

Department of Pharmaceutical Science, Wayne State University , Detroit, Michigan 48201-2417, United States.

Enzymes in the sulfur network generate the signaling molecule, hydrogen sulfide (H2S), from the amino acids cysteine and homocysteine. Since it is toxic at elevated concentrations, cells are equipped to clear H2S. A canonical sulfide oxidation pathway operates in mitochondria, converting H2S to thiosulfate and sulfate. We have recently discovered the ability of ferric hemoglobin to oxidize sulfide to thiosulfate and iron-bound hydropolysulfides. In this study, we report that myoglobin exhibits a similar capacity for sulfide oxidation. We have trapped and characterized iron-bound sulfur intermediates using cryo-mass spectrometry and X-ray absorption spectroscopy. Further support for the postulated intermediates in the chemically challenging conversion of H2S to thiosulfate and iron-bound catenated sulfur products is provided by EPR and resonance Raman spectroscopy in addition to density functional theory computational results. We speculate that the unusual sensitivity of skeletal muscle cytochrome c oxidase to sulfide poisoning in ethylmalonic encephalopathy, resulting from the deficiency in a mitochondrial sulfide oxidation enzyme, might be due to the concentration of H2S by myoglobin in this tissue.
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http://dx.doi.org/10.1021/jacs.6b03456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5464954PMC
July 2016