title: The tumour metabolism inhibitors GSAO and PENAO react with cysteines 57 and 257 of mitochondrial adenine nucleotide translocase.
abstract: BACKGROUND
  GSAO (4-(N-(S-glutathionylacetyl)amino) phenylarsonous acid) and PENAO (4-(N-(S-penicillaminylacetyl)amino) phenylarsonous acid) are tumour metabolism inhibitors that target adenine nucleotide translocase (ANT) of the inner-mitochondrial membrane. Both compounds are currently being trialled in patients with solid tumours. The trivalent arsenical moiety of GSAO and PENAO reacts with two matrix facing cysteine residues of ANT, inactivating the transporter. This leads to proliferation arrest and death of tumour and tumour-supporting cells.
  
  
  RESULTS
  The two reactive ANT cysteine residues have been identified in this study by expressing cysteine mutants of human ANT1 in Saccharomyces cerevisiae and measuring interaction with the arsenical moiety of GSAO and PENAO. The arsenic atom of both compounds cross-links cysteine residues 57 and 257 of human ANT1.
  
  
  CONCLUSIONS
  The sulphur atoms of these two cysteines are 20 Å apart in the crystal structures of ANT and the optimal spacing of cysteine thiolates for reaction with As (III) is 3-4 Å. This implies that a significant conformational change in ANT is required for the organoarsenicals to react with cysteines 57 and 257. This conformational change may relate to the selectivity of the compounds for proliferating cells.
authors.affiliation: Lowy Cancer Research Centre & Prince of Wales Clinical School, University of New South Wales, Sydney 2052, Australia.
authors.forename: Danielle
authors.initials: D
authors.lastname: Park
authors.affiliation: Lowy Cancer Research Centre & Prince of Wales Clinical School, University of New South Wales, Sydney 2052, Australia.
authors.forename: Joyce
authors.initials: J
authors.lastname: Chiu
authors.affiliation: Ramaciotti Centre for Gene Function Analysis, School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney 2052, Australia.
authors.forename: Gabriel G
authors.initials: GG
authors.lastname: Perrone
authors.affiliation: Lowy Cancer Research Centre & Prince of Wales Clinical School, University of New South Wales, Sydney 2052, Australia.
authors.forename: Pierre J
authors.initials: PJ
authors.lastname: Dilda
authors.affiliation: Lowy Cancer Research Centre & Prince of Wales Clinical School, University of New South Wales, Sydney 2052, Australia.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Hogg