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Glutathione transferase P1-1 as an arsenic drug-sequestering enzyme.


ABSTRACT: Arsenic-based compounds are paradoxically both poisons and drugs. Glutathione transferase (GSTP1-1) is a major factor in resistance to such drugs. Here we describe using crystallography, X-ray absorption spectroscopy, mutagenesis, mass spectrometry, and kinetic studies how GSTP1-1 recognizes the drug phenylarsine oxide (PAO). In conditions of cellular stress where glutathione (GSH) levels are low, PAO crosslinks C47 to C101 of the opposing monomer, a distance of 19.9 Å, and causes a dramatic widening of the dimer interface by approximately 10 Å. The GSH conjugate of PAO, which forms rapidly in cancerous cells, is a potent inhibitor (Ki ?=?90 nM) and binds as a di-GSH complex in the active site forming part of a continuous network of interactions from one active site to the other. In summary, GSTP1-1 can detoxify arsenic-based drugs by sequestration at the active site and at the dimer interface, in situations where there is a plentiful supply of GSH, and at the reactive cysteines in conditions of low GSH.

SUBMITTER: Parker LJ 

PROVIDER: S-EPMC5275733 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Glutathione transferase P1-1 as an arsenic drug-sequestering enzyme.

Parker Lorien J LJ   Bocedi Alessio A   Ascher David B DB   Aitken Jade B JB   Harris Hugh H HH   Lo Bello Mario M   Ricci Giorgio G   Morton Craig J CJ   Parker Michael W MW  

Protein science : a publication of the Protein Society 20161214 2


Arsenic-based compounds are paradoxically both poisons and drugs. Glutathione transferase (GSTP1-1) is a major factor in resistance to such drugs. Here we describe using crystallography, X-ray absorption spectroscopy, mutagenesis, mass spectrometry, and kinetic studies how GSTP1-1 recognizes the drug phenylarsine oxide (PAO). In conditions of cellular stress where glutathione (GSH) levels are low, PAO crosslinks C47 to C101 of the opposing monomer, a distance of 19.9 Å, and causes a dramatic wid  ...[more]

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