2JK0

Structural and functional insights into Erwinia carotovora L- asparaginase

2JK0 の概要

• エントリーDOI: 10.2210/pdb2jk0/pdb
• 関連するPDBエントリー: 2VM7
• 分子名称: L-ASPARAGINASE, ASPARTIC ACID (3 entities in total)
• 機能のキーワード: erwinia, hydrolase, enzyme therapy, protein stability, leukemia treatment
• 由来する生物種: PECTOBACTERIUM CAROTOVORUM
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 275689.42

構造登録者

Papageorgiou, A.C.,Posypanova, G.A.,Andersson, C.S.,Sokolov, N.N.,Krasotkina, J. (登録日: 2008-05-23, 公開日: 2008-08-05, 最終更新日: 2023-12-13)

主引用文献

Papageorgiou, A.C.,Posypanova, G.A.,Andersson, C.S.,Sokolov, N.N.,Krasotkina, J.
Structural and Functional Insights Into Erwinia Carotovora L-Asparaginase.
FEBS J., 275:4306-, 2008

PubMed 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.

PubMed: 18647344
DOI: 10.1111/J.1742-4658.2008.06574.X

実験手法

X-RAY DIFFRACTION (2.5 Å)