This 3D printed protein model of Asparaginase identifies an engineered mutation that extends the protein's half-life. It is printed in full-color sandstone color green to blue by the protein's bFactor. In red is the site of the mutation responsible for prolonging the protein's half-life.
This 3D printed protein model of Asparaginase created from PDB ID: 5MQ5. Asparaginase exists as both a monomer (single Asparaginase) and dimer (two bound Asparaginase). The monomer is colored green by the protein’s bFactor, yellow-green the hottest and blue-green the coolest. Mutation N24S is colored orange-red.
Asparaginase is an enzyme from Escherichia coli involved in intracellular asparagine utilization. It’s also used within different industries as a medication and in food manufacturing. Asparaginase is administered subcutaneously, and it’s half-life is problematic for long-term storage. This 3D printed protein model of Asparaginase identifies an engineered mutation that extends the protein’s half-life.
“L-Asparaginases (ASNases) have been used as first-line drugs for pediatric Acute Lymphoblastic Leukaemia (ALL) treatment for more than 40 years. Both the Escherichia coli (EcAII) and Erwinia chrysanthemi (ErAII) type II ASNases currently used in the clinics are characterized by high in vivo instability, short half-life and the requirement of several administrations to obtain a pharmacologically active concentration. Moreover, they are sensitive to proteases (cathepsin B and asparagine endopeptidase) that are over-expressed by resistant leukemia lymphoblasts, thereby impairing drug activity and pharmacokinetics. Herein, we present the biochemical, structural and in vitro antiproliferative characterization of a new EcAII variant, N24S. The mutant shows completely preserved asparaginase and glutaminase activities, long-term storage stability, improved thermal parameters, and outstanding resistance to proteases derived from leukemia cells. The structural analysis demonstrates a modification of the hydrogen bond network related to residue 24, while Normal Mode-based geometric Simulation and Molecular Dynamics predict a general rigidification of the monomer as compared to wild-type. These improved features render N24S a potential alternative treatment to reduce the number of drug administrations in vivo and to successfully address one of the major current challenges of ALL treatment: spontaneous, protease-dependent and immunological inactivation of ASNase.”
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