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Synthesis of mono-dithiolene molybdenum complexes and their evaluation as potential drugs for the treatment of human isolated sulfite oxidase deficiency

Objective

Two rare but usually fatal diseases are caused by a failure at different levels of the multistep biosynthetic generation of the three human molybdenum dependent enzymes involved in metabolic processes. In contrast to the more general Moco deficiency (MocoD) affecting all three enzymes, isolated sulfite oxidase deficiency (iSOD) cannot be treated yet. The proposed project is primarily aimed at synthesising a large variety of molybdenum complexes that mimic the natural molybdenum cofactor of the respective enzymes. These compounds will be prepared with a focus on distinct aspects of the biomolecules (first coordination sphere, different functional groups of the complex molybdopterin ligand, hydrogen bonding sites); their stability and ability to catalyse oxygen atom transfer (in particular the oxidation of sulfite) will be assessed and their suitability to bind in the active site pocket of the protein and restore activity will be tested. In addition alternative metals will be investigated with respect to possible benefits regarding stability and activity.
The ultimate aim is to combine all the different synthetic approaches and information about properties to build a compound containing all indispensable functional groups while being stable, active and made with the least possible effort. Consequently this project addresses the human iSOD by developing synthetic structural models for the molybdenum cofactor active site of sulfite oxidase, testing their potential for incorporation into the biotechnologically generated apo-enzyme and evaluating the activity of the resulting semi-synthetic enzymes thereby assessing their suitability as future iSOD treatments. This work will have impact on the way iSOD and MocoD patients will be treated in the future and deepen the understanding of fundamentally important chemical, structural and catalytic aspects of the Moco dependent enzymes.

Call for proposal

ERC-2011-StG_20101109
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Host institution

UNIVERSITAET GREIFSWALD
Address
Domstrasse 11
17489 Greifswald
Germany
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 1 402 860,91
Principal investigator
Carola Schulzke (Prof.)
Administrative Contact
Diana Lode (Ms.)

Beneficiaries (3)

UNIVERSITAET GREIFSWALD
Germany
EU contribution
€ 1 402 860,91
Address
Domstrasse 11
17489 Greifswald
Activity type
Higher or Secondary Education Establishments
Principal investigator
Carola Schulzke (Prof.)
Administrative Contact
Diana Lode (Ms.)
UNIVERSITAET POTSDAM
Germany
EU contribution
€ 48 000
Address
Am Neuen Palais 10
14469 Potsdam
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Adriana Wipperling (Dr.)
THE PROVOST, FELLOWS, FOUNDATION SCHOLARS & THE OTHER MEMBERS OF BOARD, OF THE COLLEGE OF THE HOLY & UNDIVIDED TRINITY OF QUEEN ELIZABETH NEAR DUBLIN

Participation ended

Ireland
EU contribution
€ 49 009,09
Address
College Green
2 Dublin
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Deirdre Savage (Ms.)