4R8K

Crystal structure of the guinea pig L-asparaginase 1 catalytic domain

4R8K の概要

• エントリーDOI: 10.2210/pdb4r8k/pdb
• 関連するPDBエントリー: 4R8L
• 分子名称: Uncharacterized protein, 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID (3 entities in total)
• 機能のキーワード: l-asparaginase, hydrolase
• 由来する生物種: Cavia porcellus (guinea pig)
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 337725.78

構造登録者

Schalk, A.M.,Lavie, A. (登録日: 2014-09-02, 公開日: 2014-10-22, 最終更新日: 2023-09-20)

主引用文献

Schalk, A.M.,Nguyen, H.A.,Rigouin, C.,Lavie, A.
Identification and Structural Analysis of an l-Asparaginase Enzyme from Guinea Pig with Putative Tumor Cell Killing Properties.
J.Biol.Chem., 289:33175-33186, 2014

PubMed Abstract: The initial observation that guinea pig serum kills lymphoma cells marks the serendipitous discovery of a new class of anti-cancer agents. The serum cell killing factor was shown to be an enzyme with L-asparaginase (ASNase) activity. As a direct result of this observation, several bacterial L-asparaginases were developed and are currently approved by the Food and Drug Administration for the treatment of the subset of hematological malignancies that are dependent on the extracellular pool of the amino acid asparagine. As drugs, these enzymes act to hydrolyze asparagine to aspartate, thereby starving the cancer cells of this amino acid. Prior to the work presented here, the precise identity of this guinea pig enzyme has not been reported in the peer-reviewed literature. We discovered that the guinea pig enzyme annotated as H0W0T5_CAVPO, which we refer to as gpASNase1, has the required low Km property consistent with that possessed by the cell-killing guinea pig serum enzyme. Elucidation of the ligand-free and aspartate complex gpASNase1 crystal structures allows a direct comparison with the bacterial enzymes and serves to explain the lack of L-glutaminase activity in the guinea pig enzyme. The structures were also used to generate a homology model for the human homolog hASNase1 and to help explain its vastly different kinetic properties compared with gpASNase1, despite a 70% sequence identity. Given that the bacterial enzymes frequently present immunogenic and other toxic side effects, this work suggests that gpASNase1 could be a promising alternative to these bacterial enzymes.

PubMed: 25320094
DOI: 10.1074/jbc.M114.609552

実験手法

X-RAY DIFFRACTION (2.2 Å)