4r8k
Crystal structure of the guinea pig L-asparaginase 1 catalytic domain
Structural highlights
FunctionPublication Abstract from PubMedThe 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 FDA approved 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 to 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. Identification and Structural Analysis of an L-asparaginase Enzyme from Guinea Pig with Putative Tumor Cell-killing Properties.,Schalk AM, Nguyen HA, Rigouin C, Lavie A J Biol Chem. 2014 Oct 15. pii: jbc.M114.609552. PMID:25320094[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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