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325 a.a.
309 a.a.
 L-asparagine |
+ |
H(2)O |
= |
 L-aspartate |
+ |
NH(3) |
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Key reference
DOI no: 10.1111/j.1742-4658.2008.06574.x Febs J 275:4306-4316 (2008) PubMed id: 18647344
Structural and functional insights into Erwinia carotovora l-asparaginase. A.C.Papageorgiou, G.A.Posypanova, C.S.Andersson, N.N.Sokolov, J.Krasotkina. ABSTRACT
Bacterial l-asparaginases are enzymes that catalyze the hydrolysis of l-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 of l-Asp was determined at 2.5 A resolution and refined to an R(cryst) of 19.2 (R(free) = 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.
Literature references that cite this PDB file's key reference
PubMed id Reference
19966411 P.Dhavala, and A.C.Papageorgiou (2009).
Structure of Helicobacter pyloriL-asparaginase at 1.4 A resolution.Acta Crystallogr D Biol Crystallogr, 65, 1253-1261.
PDB code: 2wlt The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.
