Mechanistic and structural characterization of human L-asparaginases

by Nora Eulig
Doctoral thesis
Date of Examination:2022-04-05
Date of issue:2024-04-04
Advisor:Prof. Dr. Kai Tittmann
Referee:Prof. Dr. Kai Tittmann
Referee:Prof. Dr. Dirk Görlich
Persistent Address: http://dx.doi.org/10.53846/goediss-10409

 

 

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Abstract

English

L-asparaginases are therapeutic proteins against acute lymphoblastic leukaemia (ALL), especially in children. As lymphoblastic cells depend on L-asparagine in the blood serum, its depletion by L-asparaginases leads to starvation and ultimately the death of leukemic cells. However, currently available drugs derive from bacterial L-asparaginases causing severe side effects and immune response against the foreign enzymes. Though treatment with a human enzyme could remedy these issues, the human L-asparaginase has a significantly lower affinity for the substrate L-asparagine than bacterial homologs and therefore cannot be used in the therapy of ALL. In this thesis the human asparaginase 1 was biochemically and structurally analysed. This work presents a novel crystal structure for the previously not structurally characterized human protein. Based on this, structural variants were engineered that possess significantly improved kinetic properties compared to the wild type enzyme. Thereby, they constitute a new foundation for the development of a therapeutically active human l-asparaginase enzyme for the treatment of ALL.
Keywords: L-asparaginase enzyme; acute lymphoblastic leukaemia (ALL); therapeutic protein; drug development
 
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