Synthesis of Orotidine-5'-monophosphate modifications for the study of the catalytic activity of the enzyme Orotidine-5'-monophosphate decarboxylase

by Tobias Schmidt
Doctoral thesis
Date of Examination:2021-12-09
Date of issue:2022-01-27
Advisor:Prof. Dr. Ulf Diederichsen
Referee:Prof. Dr. Kai Tittmann
Referee:Prof. Dr. Lutz Ackermann
Referee:Prof. Dr. Ricardo Mata
Referee:Dr. Holm Frauendorf
Referee:Dr. Michael John
Persistent Address: http://dx.doi.org/10.53846/goediss-9068

 

 

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Abstract

English

In this thesis, the synthesis of OMPD substrate analogs was investigated to further elucidate the mechanism of the OMPD. As inhibiting molecules, 6-thioamido UMP, OMP methyl ester, reduced OMP, and nonpolar substituted UMPs (6-methyl, 6-ethyl, 6-isopropenyl) were synthesized. The synthesized substrate analogs were obtained in high purity after HPLC purification as bis(triethylammonium) salts which were soaked into pre-crystallized resting state crystals of the OMPD (human, wild type) and analyzed via x-ray crystallography. The obtained crystal structures of the synthesized ligands of OMPD were obtained in ultra-high resolution, which gave further information of the complex network of enzyme-substrate interactions. In addition, new synthetic approaches of the syntheses of several other inhibitors were attempted.
Keywords: organic chemistry; biochemistry; ompd; enzymatic catalysis; nucleotide
 
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