Semnan University of Medical Sciences

Research and Technology Vice Chancellor

Aghaeepoor, Mojtaba and Akbarzadeh, Ali and Mirzaie, Sako and Hadian, Asieh and Jamshidi Aval, Sanaz and Dehnavi, Ehsan (2018) Selective reduction in glutaminase activity of L‑Asparaginase by asparagine 248 to serine mutation: A combined computational and experimental effort in blood cancer treatment. International Journal of Biological Macromolecules, 120. pp. 2448-2457. ISSN 01418130

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    Abstract

    Type II L‑asparaginase (L‑ASNase) is an FDA approved enzyme drug with extensive applications for treatment of certain blood cancers. However, the therapeutic efficiency of this enzyme is hampered by its undesirable glutaminase activity. Given the pivotal role of this enzyme against cancer, designing engineered mutants with diminished glutaminase activity would be of great therapeutic interest. To this end, N248S mutation was selected as the potential mutation with beneficial effects. Various in silico analyses including MD simulation, molecular docking and QMMM studies were performed to assess the effects of N248S mutation on the activity of the enzyme. Thereafter, this mutation along with N248A, N248V and N248T mutations as controls were exerted in L‑ASNase gene. The results from in silico analyses and experimental efforts indicated that N248S mutation is associated with the suitable L‑ASNase activity, while the glutaminase activity is disturbed due to impaired interactions. It has been shown that glutamine turnover was affected much more strongly than asparagine hydrolysis. The approach of exploiting in silico tools to design mutated enzymes lead to staggering time and cost reduction. Following this strategy, we have designed a mutant L‑ASNase with diminished glutaminase activity, which could be of interest for improved biomedical applications. © 2018

    Item Type: Article
    Subjects: R Medicine > R Medicine (General)
    Divisions: Faculty of Medical Sciences > School of Medicine
    Depositing User: Admin User
    Date Deposited: 31 Dec 2018 10:37
    Last Modified: 31 Dec 2018 10:37
    URI: http://eprints.semums.ac.ir/id/eprint/1448

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