Glutathione transferase P1‐1 as an arsenic drug‐sequestering enzyme. (14th December 2016)

• Record Type: Journal Article
• Authors: Parker, Lorien J.; Bocedi, Alessio; Ascher, David B.; Aitken, Jade B.; Harris, Hugh H.; Lo Bello, Mario; Ricci, Giorgio; Morton, Craig J.; Parker, Michael W.
• Is Part Of: Protein science. Volume 26:Number 2(2017)
• Page Start: 317
• Page End: 326
• Publication Date: 2016-12-14
• Subjects: arsenic -- glutathione transferases -- inhibitors -- resistance -- X‐ray crystallography; Proteins -- Periodicals; 572.6
• DOI: 10.1002/pro.3084
• Languages: English
• ISSNs: 0961-8368

Abstract

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 ( K i = 90 n M ) 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. Abstract : PDB Code(s):5DCG ;5DAL ;5DAK ;5DDL