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Predicting the Effects of GSTPπ Polymorphism on Resistance to Ezatiostat
Author(s) -
Risbud Kajal S.,
Muwonge Alecia N.,
Frey Kathleen M.
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.lb97
Subject(s) - glutathione , enzyme , single nucleotide polymorphism , wild type , snp , genetics , mutation , chemistry , biochemistry , microbiology and biotechnology , biology , computational biology , gene , mutant , genotype
Glutathione S‐transferases (GSTs) are a family of phase II metabolic enzymes. These enzymes catalyze the conjugation of glutathione (GSH) to xenobiotic substrates for detoxification. There is evidence that supports the role of GSTπ in cancer development. Ezatiostat (EZT) has received orphan drug status for Myelodysplastic Syndrome (MDS). A single nucleotide polymorphism (SNP) Ile105Val (I105V) near the Glutathione binding site of GSTπ affects its structure, and this may cause chemotherapeutic resistance. We hypothesize that this mutation expressed in some individuals may cause resistance to EZT. This study incorporates computational analysis of the binding mode for EZT with wild‐type and I105V. We used residue scanning and molecular dynamics (MD) to compare the interactions for EZT. Results from MD show differences in the EZT binding mode in wildtype and I105V GST. GST with the I105V mutation makes less interactions with EZT. Future work involves inhibition assays and x‐ray crystallography to validate the computational results. Support or Funding Information Dean's Internal Research Support Grant This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .