Glutathione transferase P1‐1 as an arsenic drug‐sequestering enzyme

Journal Article · 14 December 2016 · Protein Science

DOI: https://doi.org/10.1002/pro.3084 · OSTI ID:1401027

Parker, Lorien J.  ^[1]; Bocedi, Alessio ^[2]; Ascher, David B. ^[3]; Aitken, Jade B. ^[4]; Harris, Hugh H. ^[5]; Lo Bello, Mario ^[6]; Ricci, Giorgio ^[2]; Morton, Craig J. ^[3]; Parker, Michael W. ^[1]

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1. ACRF Rational Drug Discovery Centre St. Vincent's Institute of Medical Research Fitzroy Victoria 3065 Australia, Department of Biochemistry and Molecular Biology Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne Parkville Victoria 3010 Australia
2. Department of Chemical Sciences and Technologies University of Rome “Tor Vergata” Rome 00133 Italy
3. ACRF Rational Drug Discovery Centre St. Vincent's Institute of Medical Research Fitzroy Victoria 3065 Australia
4. School of Chemistry The University of Sydney Sydney New South Wales 2006 Australia
5. Department of Chemistry The University of Adelaide Adelaide South Australia 5005 Australia
6. Department of Biology University of Rome “Tor Vergata” Rome 00133 Italy

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.

• Sponsoring Organization: USDOE
• OSTI ID: 1401027
• Journal Information: Protein Science, Journal Name: Protein Science Journal Issue: 2 Vol. 26; ISSN 0961-8368
• Publisher: Wiley Blackwell (John Wiley & Sons)Copyright Statement
• Country of Publication: United Kingdom
• Language: English