PMID- 29447943
OWN - NLM
STAT- MEDLINE
DCOM- 20180913
LR  - 20180913
IS  - 1532-2777 (Electronic)
IS  - 0306-9877 (Linking)
VI  - 112
DP  - 2018 Mar
TI  - Novel mutant of Escherichia coli asparaginase II to reduction of the glutaminase 
      activity in treatment of acute lymphocytic leukemia by molecular dynamics 
      simulations and QM-MM studies.
PG  - 7-17
LID - S0306-9877(17)31126-X [pii]
LID - 10.1016/j.mehy.2018.01.004 [doi]
AB  - L-Asparaginases (ASNase) belong to a family of amidohydrolases, have both 
      asparaginase and glutaminase activity. Acute lymphocytic leukemia (ALL) is an 
      outrageous disease worldwide. Bacterial ASNase has been used for the treatment of 
      ALL. Glutaminase activity of enzyme causes some side effect and it is not 
      essential for anticancer activity. The aim of this study was engineering of 
      Escherichia coli asparaginase II to find a mutant with reduced glutaminase 
      activity by molecular docking, molecular dynamics (MD) and QM-MM (Quantum 
      mechanics molecular dynamics) simulations. Residues with low free energy of 
      binding to Asn and high free binding energy to Gln were chosen for mutagenesis. 
      Then, a mutant with higher glutaminase free binding energy was selected for 
      further studies. Additionally, the MD simulation and QM-MM computation of wild 
      type (WT) were employed and the selected mutated ASNase were analyzed and 
      discussed. Our data showed that V27T is a good candidate to reduction the 
      glutaminase activity, while has no remarkable effect on asparaginase activity of 
      the enzyme. The simulation analysis revealed that V27T mutant is more stable than 
      WT and mutant simulation was successful completely. QM-MM results confirmed the 
      successfulness of our mutagenesis.
CI  - Copyright (c) 2018 Elsevier Ltd. All rights reserved.
FAU - Ardalan, Noeman
AU  - Ardalan N
AD  - Department of Microbiology, Science and Research Branch, Islamic Azad University, 
      Tehran, Iran.
FAU - Mirzaie, Sako
AU  - Mirzaie S
AD  - Department of Biochemistry, Sanandaj Branch, Islamic Azad University, Sanandaj, 
      Iran. Electronic address: sako.biochem@gmail.com.
FAU - Sepahi, Abbas Akhavan
AU  - Sepahi AA
AD  - Department of Microbiology, Faculty of Science, North Branch, Islamic Azad 
      University, Tehran, Iran. Electronic address: akhavansepahy@gmail.com.
FAU - Khavari-Nejad, Ramazan Ali
AU  - Khavari-Nejad RA
AD  - Department of Biology, Science and Research Branch, Islamic Azad University, 
      Tehran, Iran.
LA  - eng
PT  - Journal Article
DEP - 20180130
PL  - United States
TA  - Med Hypotheses
JT  - Medical hypotheses
JID - 7505668
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Escherichia coli Proteins)
RN  - 0RH81L854J (Glutamine)
RN  - 7006-34-0 (Asparagine)
RN  - EC 3.5.1.1 (Asparaginase)
SB  - IM
MH  - Antineoplastic Agents/chemistry
MH  - Asparaginase/chemistry/*genetics/metabolism
MH  - Asparagine/metabolism
MH  - Catalytic Domain
MH  - Drug Design
MH  - Escherichia coli Proteins/chemistry/*genetics/metabolism
MH  - Glutamine/metabolism
MH  - Humans
MH  - Models, Molecular
MH  - Molecular Docking Simulation
MH  - Molecular Dynamics Simulation
MH  - Mutagenesis, Site-Directed
MH  - *Mutation, Missense
MH  - *Point Mutation
MH  - Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
MH  - Protein Binding
MH  - Protein Conformation
MH  - Quantum Theory
MH  - Substrate Specificity
MH  - Thermodynamics
OTO - NOTNLM
OT  - Acute lymphocytic leukemia
OT  - Escherichia coli
OT  - Glutaminase activity
OT  - L-asparaginase
OT  - Molecular dynamics
OT  - QMMM studies
EDAT- 2018/02/16 06:00
MHDA- 2018/09/14 06:00
CRDT- 2018/02/16 06:00
PHST- 2017/10/27 00:00 [received]
PHST- 2017/12/29 00:00 [revised]
PHST- 2018/01/13 00:00 [accepted]
PHST- 2018/02/16 06:00 [entrez]
PHST- 2018/02/16 06:00 [pubmed]
PHST- 2018/09/14 06:00 [medline]
AID - S0306-9877(17)31126-X [pii]
AID - 10.1016/j.mehy.2018.01.004 [doi]
PST - ppublish
SO  - Med Hypotheses. 2018 Mar;112:7-17. doi: 10.1016/j.mehy.2018.01.004. Epub 2018 Jan 
      30.