Proposed model for the mechanism of WT l-ASP’s and Q59L lASP’s anticancer activity. The mechanism of anticancer activity depends on l-ASP glutaminase activity and ASNS expression, which is reflected by the color gradient of the background. For simplicity, glutamine synthesis pathways are not shown. (A) (Left panel) (1) Q59L l-ASP effectively depletes Asn but not Gln, which (2) is imported by the cancer cell for (3) synthesis of Asn by ASNS, thereby promoting cancer cell proliferation (4). Numbering is omitted from subsequent panels, but analogous interpretation illustrates that the added glutaminase activity of WT l-ASP decreases the extracellular supply of Gln, thereby limiting cancer cell proliferation (right panel). (B) Low-ASNS cancer cells are insensitive to Q59L l-ASP (left panel), but not to WT l-ASP (right panel). (C) ASNS-negative cancer cells are sensitive to both Q59L (left panel) and WT (right panel). Details of the model are provided in the text.