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- Title
Structural and functional insights into Erwinia carotovora l-asparaginase.
- Authors
Papageorgiou, Anastassios C.; Posypanova, Galina A.; Andersson, Charlotta S.; Sokolov, Nikolay N.; Krasotkina, Julya
- Abstract
Bacteriall-asparaginases are enzymes that catalyze the hydrolysis ofl-asparagine to aspartic acid. For the past 30 years, these enzymes have been used as therapeutic agents in the treatment of acute childhood lymphoblastic leukemia. Their intrinsic low-rate glutaminase activity, however, causes serious side-effects, including neurotoxicity, hepatitis, coagulopathy, and other dysfunctions. Erwinia carotovora asparaginase shows decreased glutaminase activity, so it is believed to have fewer side-effects in leukemia therapy. To gain detailed insights into the properties of E. carotovora asparaginase, combined crystallographic, thermal stability and cytotoxic experiments were performed. The crystal structure of E. carotovoral-asparaginase in the presence ofl-Asp was determined at 2.5 Å resolution and refined to an Rcryst of 19.2 ( Rfree = 26.6%) with good stereochemistry. Cytotoxicity measurements revealed that E. carotovora asparaginase is 30 times less toxic than the Escherichia coli enzyme against human leukemia cell lines. Moreover, denaturing experiments showed that E. carotovora asparaginase has decreased thermodynamic stability as compared to the E. coli enzyme and is rapidly inactivated in the presence of urea. On the basis of these results, we propose that E. carotovora asparaginase has limited potential as an antileukemic drug, despite its promising low glutaminase activity. Our analysis may be applicable to the therapeutic evaluation of other asparaginases as well.
- Subjects
ASPARAGINASE; HYDROLYSIS; LYMPHOBLASTIC leukemia; NEUROTOXICOLOGY; CELL-mediated cytotoxicity; ENZYMES
- Publication
FEBS Journal, 2008, Vol 275, Issue 17, p4306
- ISSN
1742-464X
- Publication type
Article
- DOI
10.1111/j.1742-4658.2008.06574.x