Synthesis of rare nucleobases and artificial nucleotides for investigation of catalytic enzyme activity

by Matthias Krull
Doctoral thesis
Date of Examination:2019-09-25
Date of issue:2019-10-25
Advisor:Prof. Dr. Ulf Diederichsen
Referee:Prof. Dr. Ulf Diederichsen
Referee:Prof. Dr. Kai Tittmann
Referee:Prof. Dr. Manuel Alcarazo
Referee:Prof. Dr. Claudia Steinem
Referee:Dr. Sebastian Kruss
Referee:Dr. Michael John
Persistent Address: http://dx.doi.org/10.53846/goediss-7697

 

 

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Abstract

English

Enzymes are involved in replication, transcription and translation of DNA, as well as the synthesis of nucleobases. The roles and mechanisms for many of these enzymes stay broadly unknown until today. The herein presented projects are based on the research of the enzymatic activity of selected enzymes, which are important for the synthesis and modification of nucleobases. Chapter 1 describes the synthesis of uridine-derivatives for co-crystallization with orotidine-5’-monophosphatedecarboxylase (OMPD). This enzyme catalyzes the last step in the de novo biosynthesis of pyrimidine-nucleotides and shows an extreme high catalytic activity. Therefore, investigation of the natural enzyme-substrate complex is impossible with currently available methods. By decreasing the catalytic activity with suitable substrate-derivatives, a targeted investigation of the mechanism should be possible. Chapter 2 describes the development of a new synthetic route for the rare nucleobase queuine, with focus on its cyclopentadiene part. Via in vitro introduction of queuine into tRNA, the stimulation of S. pombe Dnmt2 activity by queuine should be demonstrated.
Keywords: orotidine-5’-monophosphatedecarboxylase, queuine, substrate modification
 
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