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Modified B12 derivates as novel inhibitors of B12 dependant enzymes and allosteric catalysts

English title Modified B12 derivates as novel inhibitors of B12 dependant enzymes and allosteric catalysts
Applicant Zelder Felix
Number 149108
Funding scheme Project funding (Div. I-III)
Research institution Institut für Chemie Universität Zürich
Institution of higher education University of Zurich - ZH
Main discipline Inorganic Chemistry
Start/End 01.01.2014 - 31.12.2015
Approved amount 139'872.00
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All Disciplines (2)

Discipline
Inorganic Chemistry
Nutritional Research, Vitaminology

Keywords (2)

Bioinorganic Chemistry; Cofactor

Lay Summary (German)

Lead
Das Ziel dieses Projektes ist die Entwicklung einer neuen Klasse von biomimetischen Protein-Kofaktor Komplexen.
Lay summary

 

Kofaktoren sind  essentielle Bestandteile vieler wichtiger enzymatischer Reaktionen. Das Forschungsprojekt hat das Ziel, neue Modellkomplexe für solche biologischen Systeme zu entwickeln.

Die Ergebnisse werden neue Einblicke in biologische Prozesse gewähren und es wird erwartet, dass sie auch für die Entwicklung von neuen Katalysatoren von grossem Interesse sein werden.

 

 

Direct link to Lay Summary Last update: 16.01.2014

Responsible applicant and co-applicants

Employees

Name Institute

Publications

Publication
Modulating the cobalt redox potential through imidazole hydrogen bonding interactions in a supramolecular biomimetic protein-cofactor model
Sonnay Marjorie, Fox Thomas, Blacque Olivier, Zelder Felix (2016), Modulating the cobalt redox potential through imidazole hydrogen bonding interactions in a supramolecular biomimetic protein-cofactor model, in Chemical Science, 7, 3836-3842.
Antivitamins for Medicinal Applications.
Zelder Felix, Sonnay Marjorie, Prieto Lucas (2015), Antivitamins for Medicinal Applications., in Chembiochem : a European journal of chemical biology, 16(9), 1264-78.

Collaboration

Group / person Country
Types of collaboration
PD. H. Brandl/ University of Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Buckel/ Universität Marburg Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Awards

Title Year
CMSZH Travel Award from the Graduate School of Chemical and Molecular Sciences Zurich 2015
SCNAT/SCS Chemistry Travel Award from the Swiss Academy of Sciences 2015

Associated projects

Number Title Start Funding scheme
137708 Modified B12 derivates as novel inhibitors of B12 dependant enzymes and allosteric catalysts 01.01.2012 Project funding (Div. I-III)
137708 Modified B12 derivates as novel inhibitors of B12 dependant enzymes and allosteric catalysts 01.01.2012 Project funding (Div. I-III)

Abstract

The role of vitamin B12 derivatives as cofactors in human enzymatic processes has been under deep investigation. X-ray experiments were of great interest in this domain and led to the resolution of the binding mode between B12 cofactor and the enzyme methionine synthase. Interestingly, the enzyme appears to bind the cofactor by the mean of a histidine residue, which coordinates to the lower face of the Co centre of the B12 cofactor, and thus replaces the natural backbone. The cofactor is therefore in a “base-off/histidine-on” form. Furthermore, this histidine residue is part of a proton shuttle formed of three amino acids, which allows the uptake of a proton from the solvent and its transfer to the buried histidine. The reversible protonation of this amino acid leads either to (1) stabilization or to (2) reactivity enhancement of various intermediates in the enzymatic process. By coordinating the cofactor through its lower face, the enzyme has thus the ability to tune the cofactor reactivity and stability. Better understanding of this reversible protonation and its influence on the reactivity of the cofactor is desired and is expected to yield to important new insights into the enzymatic cofactor activation.We thus proposed a modified backbone derivative of vitamin B12 terminated by an imidazole base (PiB12) as biomimetic model of the “base-off/his-on” constitution. The histidine deprotonation process and its influence on the molecule reactivity can thus be studied with various PiB12 derivatives, using pH titration and cyclic voltammetry. Further modifications of the peptide loop lead to a PiB12 derivative mimicking methionine`s synthase catalytic triad at the lower face of the protein bound cofactor. This switchable PiB12 derivative allows triggering reactivity at the upper face by the reversible formation of a remote hydrogen bonding network at the opposite site.
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