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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 137708
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 01.01.2012 - 31.12.2013
Approved amount 115'444.00
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All Disciplines (2)

Discipline
Inorganic Chemistry
Nutritional Research, Vitaminology

Keywords (5)

vitamin B12; inhibitor; biomimetic; mechanism; cyanide

Lay Summary (English)

Lead
Lay summary

The synthesis of modified vitamin B12 derivatives for medical applications has recently gained considerable attention. Since rapidly proliferating cells demand high amounts of  B12, the development of inhibitors of B12 dependent enzymes, so called anti-vitamins seems to be very attractive and has not been explored sufficiently enough. The project aims towards the development of a new class of these compounds that develop cytostatic or cytotoxic activity in vivo.

In a second part of the project, we study biomimetic B12 complexes to gain insights into the mechanism of B12 dependent enzymes. The third objective is to apply these derivatives for improved cyanide detection.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Name Institute

Publications

Publication
Chemistry and Bioactivity of an Artificial Adenosylpeptide B12 Cofactor
Felix Zelder, Kai Zhou, Rene Oetterli, Helmut Brandl, Fredrick Lyatuu, Wolfgang Buckel (2012), Chemistry and Bioactivity of an Artificial Adenosylpeptide B12 Cofactor, in ChemBioChem, 2052-2055.
Peptide B12: emerging trends at the interface of inorganic chemistry, chemical biology and medicine
Zelder Felix, Sonnay Marjorie, Zhou Kai (2012), Peptide B12: emerging trends at the interface of inorganic chemistry, chemical biology and medicine, in Dalton Transactions, 854-862.

Collaboration

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

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
1st symposium on functional metal complexes that bind to biomolecules Talk given at a conference 10.09.2013 Barcelona, Spain Zelder Felix;
ICBIC 16 2013 Talk given at a conference 26.07.2013 Grenoble, France Zelder Felix;
Insitutsvortrag Individual talk 03.07.2013 Wien, Austria Zelder Felix;
Polish Academy of Sciences Vortragsreihe Individual talk 26.04.2013 Warschau, Poland Zelder Felix;
Seventh International Conference on Porphyrins and Phtalocyanines ICPP-7 Talk given at a conference 06.07.2012 Jeju Island, Korea, Korean Republic (South Korea) Zelder Felix;
Kolloquium der Chemischen Institute Individual talk 22.05.2012 Heidelberg, Germany Zelder Felix;
Fakultätsvortrag Universität Wien Individual talk 14.05.2012 Wien, Austria Zelder Felix;
Chemiedozententagung Talk given at a conference 06.03.2012 Freiburg im Breisgau, Germany Zelder Felix;


Associated projects

Number Title Start Funding scheme
149108 Modified B12 derivates as novel inhibitors of B12 dependant enzymes and allosteric catalysts 01.01.2014 Project funding (Div. I-III)
144964 Upgrade of the UZH NMR Core Facility 01.12.2012 R'EQUIP
149108 Modified B12 derivates as novel inhibitors of B12 dependant enzymes and allosteric catalysts 01.01.2014 Project funding (Div. I-III)

Abstract

Cobalamines (Cbl) are essential for the metabolism in mammals and most other forms of life. The interplay between different coordination geometries and redox states triggers cellular uptake as well as reactivity in cofactor-catalysed reactions. We propose to develop imidazole-modified B12 derivatives for two different projects: As biomimetic models of cobalamin-protein complexes and inhibitors of B12-dependant reactions (i) as well as bioinspired catalysts for cyanide detection by signal amplification (ii). In the first project, we intend to investigate modified B12 derivatives as biomimetic models of the “base off-histidine on” binding mode in cobalamin-protein complexes. A postulated proton shuttle mechanism that modulates reactivity in cofactor-catalysed reactions will be tested. New insights into the mode of enzymatic activation are expected. These studies may have implication for the rational design of organometallic catalysts.We also propose a new strategy for the development of inhibitors of B12 dependant reactions. We suggest developing modified B12 derivatives that bind to an important hydrophobic binding pocket and block coincidentally ligation to the protein. Thereby, a required constitutional switch for cofactor activation is suppressed. Cobalamin dependant methione synthase (MetH) is important for DNA and RNA synthesis and inhibition could therefore yield a new class of anti-proliferating agents (i).In biological systems, chemical signals are efficiently converted into biochemical responses by signal transduction and amplification steps. Inspired by these principles, we intend to develop in the second project a catalytic system for cyanide detection in which cyanide (the primary signal) generates an active catalyst from an inactive precursor. The active catalyst triggers the formation of a visually detectable amplified signal. Imidazole-modified B12 derivatives will be applied for this purpose (ii). This could then be used for the detection of cyanide in water in developing countries.
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