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Blood. 2014 Jun 5;123(23):3596-606. doi: 10.1182/blood-2013-10-535112. Epub 2014 Mar 21.

The glutaminase activity of L-asparaginase is not required for anticancer activity against ASNS-negative cells.

Author information

  • 1Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX;
  • 2Center for Computational Proteomics, Huck Institute of Life Sciences, Pennsylvania State University, State College, PA;
  • 3Center for Biological and Materials Sciences, Sandia National Laboratories, Albuquerque, NM; and.
  • 4Department of Biology, University of Maryland, College Park, MD.


L-Asparaginase (L-ASP) is a key component of therapy for acute lymphoblastic leukemia. Its mechanism of action, however, is still poorly understood, in part because of its dual asparaginase and glutaminase activities. Here, we show that L-ASP's glutaminase activity is not always required for the enzyme's anticancer effect. We first used molecular dynamics simulations of the clinically standard Escherichia coli L-ASP to predict what mutated forms could be engineered to retain activity against asparagine but not glutamine. Dynamic mapping of enzyme substrate contacts identified Q59 as a promising mutagenesis target for that purpose. Saturation mutagenesis followed by enzymatic screening identified Q59L as a variant that retains asparaginase activity but shows undetectable glutaminase activity. Unlike wild-type L-ASP, Q59L is inactive against cancer cells that express measurable asparagine synthetase (ASNS). Q59L is potently active, however, against ASNS-negative cells. Those observations indicate that the glutaminase activity of L-ASP is necessary for anticancer activity against ASNS-positive cell types but not ASNS-negative cell types. Because the clinical toxicity of L-ASP is thought to stem from its glutaminase activity, these findings suggest the hypothesis that glutaminase-negative variants of L-ASP would provide larger therapeutic indices than wild-type L-ASP for ASNS-negative cancers.

© 2014 by The American Society of Hematology.

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