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Frankfurt am Main, Germany

Rekittke I.,Justus Liebig University | Jomaa H.,Justus Liebig University | Ermler U.,Max Planck Institute For Biophysik
FEBS Letters | Year: 2012

Isoprenoid precursor biosynthesis occurs through the mevalonate or the methylerythritol phosphate (MEP) pathway, used i.e.; by humans and by many human pathogens, respectively. In the MEP pathway, 2-C-methyl-d-erythritol-2,4-cyclo- diphosphate (MEcPP) is converted to (E)-1-hydroxy-2-methyl-but-2-enyl-4- diphosphate (HMBPP) by the iron-sulfur cluster enzyme HMBPP synthase (GcpE). The presented X-ray structure of the GcpE-MEcPP complex from Thermus thermophilus at 1.55 Å resolution provides valuable information about the catalytic mechanism and for rational inhibitor design. MEcPP binding inside the TIM-barrel funnel induces a 60° rotation of the [4Fe-4S] cluster containing domain onto the TIM-barrel entrance. The apical iron of the [4Fe-4S] cluster ligates with the C3 oxygen atom of MEcPP. © 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Celsi F.,International School for Advanced Studies | D'errico A.,International School for Advanced Studies | D'errico A.,Max Planck Institute For Biophysik | Menini A.,International School for Advanced Studies
Chemical Senses | Year: 2012

The rodent vomeronasal organ plays an important role in many social behaviors. Using the calcium imaging technique with the dye fluo-4 we measured intracellular calcium concentration changes induced by the application of sulfated steroids to neurons isolated from the vomeronasal organ of female mice. We found that a mix of 10 sulfated steroids from the androgen, estrogen, pregnanolone, and glucocorticoid families induced a calcium response in 71% of neurons. Moreover, 31% of the neurons responded to a mix composed of 3 glucocorticoid-derived compounds, and 28% responded to a mix composed of 3 pregnanolone-derived compounds. Immunohistochemistry showed that neurons responding to sulfated steroids expressed phosphodiesterase 4A, a marker specific for apical neurons expressing V1R receptors. None of the neuron that responded to 1 mix responded also to the other, indicating a specificity of the responses. Some neurons responded to more than 1 individual component of the glucocorticoid-derived mix tested at high concentration, suggesting that these neurons are broadly tuned, although they still displayed strong specificity, remaining unresponsive to high concentrations of the ineffective compounds. © The Author 2012. Published by Oxford University Press. All rights reserved.

Ardevol A.,University of Barcelona | Ardevol A.,Max Planck Institute For Biophysik | Rovira C.,University of Barcelona | Rovira C.,Catalan Institution for Research and Advanced Studies
Journal of the American Chemical Society | Year: 2015

Carbohydrate-active enzymes such as glycoside hydrolases (GHs) and glycosyltransferases (GTs) are of growing importance as drug targets. The development of efficient competitive inhibitors and chaperones to treat diseases related to these enzymes requires a detailed knowledge of their mechanisms of action. In recent years, sophisticated first-principles modeling approaches have significantly advanced in our understanding of the catalytic mechanisms of GHs and GTs, not only the molecular details of chemical reactions but also the significant implications that just the conformational dynamics of a sugar ring can have on these mechanisms. Here we provide an overview of the progress that has been made in the past decade, combining molecular dynamics simulations with density functional theory to solve these sweet mysteries of nature. © 2015 American Chemical Society.

Parey K.,Max Planck Institute For Biophysik | Parey K.,Max Planck Institute For Terrestrische Mikrobiologie | Warkentin E.,Max Planck Institute For Biophysik | Kroneck P.M.H.,University of Konstanz | Ermler U.,Max Planck Institute For Biophysik
Biochemistry | Year: 2010

A vital process in the biogeochemical sulfur cycle is the dissimilatory sulfate reduction pathway in which sulfate (SO42-) is converted to hydrogen sulfide (H2S). Dissimilatory sulfite reductase (dSir), its key enzyme, hosts a unique siroheme-[4Fe-4S] cofactor and catalyzes the six-electron reduction of sulfite (SO32-) to H 2S. To explore this reaction, we determined the X-ray structures of dSir from the archaeon Archaeoglobus fulgidus in complex with sulfite, sulfide (S2-), carbon monoxide (CO), cyanide (CN-), nitrite (NO2-), nitrate (NO3-), and phosphate (PO43-). Activity measurements indicated that dSir of A. fulgidus reduces, besides sulfite and nitrite, thiosulfate (S 2O32-) and trithionate (S3O 62-) and produces the latter two compounds besides sulfide. On this basis, a three-step mechanism was proposed, each step consisting of a two-electron transfer, a two-proton uptake, and a dehydration event. In comparison, the related active site structures of the assimilatory sulfite reductase (aSir)- and dSir-SO32- complexes reveal different conformations of Argα170 and Lysα211 both interacting with the sulfite oxygens (its sulfur atom coordinates the siroheme iron), a sulfite rotation of ∼60° relative to each other, and different access of solvent molecules to the sulfite oxygens from the active site cleft. Therefore, solely in dSir a further sulfite molecule can be placed in van der Waals contact with the siroheme-ligated sulfite or sulfur-oxygen intermediates necessary for forming thiosulfate and trithionate. Although reported for dSir from several sulfate-reducing bacteria, the in vivo relevance of their formation is questionable. © 2010 American Chemical Society.

Tamura H.,Max Planck Institute For Terrestrische Mikrobiologie | Tamura H.,Research Institute for Biological science RIBS Okayama | Salomone-Stagni M.,EMBL Hamburg | Fujishiro T.,Max Planck Institute For Terrestrische Mikrobiologie | And 6 more authors.
Angewandte Chemie - International Edition | Year: 2013

Inhibition mechanism: Isocyanides strongly inhibit [Fe]-hydrogenase. X-ray crystallography and X-ray absorption spectroscopy revealed that the isocyanide binds to the trans position, versus the acyl carbon of the Fe center, and is covalently bound to the pyridinol hydroxy oxygen. These results also indicated that the hydroxy group is essential for H2 activation. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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