Submit Manuscript  

Article Details


Polyethylene Glycol Acts as a Mechanistic Stabilizer of L-asparaginase: A Computational Probing

Author(s):

R. Sindhu, H. Pradeep and H. K. Manonmani*   Pages 1 - 9 ( 9 )

Abstract:


L-asparaginase (L-ASN) is an anti-cancer enzyme therapeutic drug that exerts cytotoxicity via inhibition of protein synthesis through depletion of L-asparagine in the tumour microenvironment. The therapeutic performance of the native drug is partly due to the associated instability, reduced half-life and immunogenic complications. In this study, we report the modification of recombinant L-asparaginase with PEG and an integrated computational strategy to probe the PEGylation in the protein to understand the biological stability/activity imparted by PEG. PEGylation of L-asparaginase resulted in enhanced thermal and pH activities with extended serum half-life and resistance to proteases compared to the native enzyme. The molecular dynamics analysis revealed intricate interactions required in the coupling of PEG to L-asparaginase to bestow a stronger binding affinity of L-asparagine moiety towards L-asparaginase. PEG-asparagine complex ensured stable conformation over both the native protein and asparagine-protein complex thus elucidating the PEG-induced stable conformation in the protein. PEG mechanistically stabilized L-asparaginase through inducing pocket modification at the receptor to adapt to the cavity. Thus, the study provides the rationale of PEGylation in imparting the stability towards L-asparaginase which would expand the potential application of L-asparaginase enzyme for the effective treatment of cancer.

Keywords:

L-asparaginase, Polyethylene glycation, biological stability, computation.

Affiliation:

Food Protectants and Infestation Control Dept., CSIR-Central Food Technological Research Institute Mysore – 570 020, Food Protectants and Infestation Control Dept., CSIR-Central Food Technological Research Institute Mysore – 570 020, Food Protectants and Infestation Control Dept., CSIR-Central Food Technological Research Institute Mysore – 570 020



Read Full-Text article