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01.12.2012 | Primary research | Ausgabe 1/2012 Open Access

Cancer Cell International 1/2012

The tumour metabolism inhibitors GSAO and PENAO react with cysteines 57 and 257 of mitochondrial adenine nucleotide translocase

Zeitschrift:
Cancer Cell International > Ausgabe 1/2012
Autoren:
Danielle Park, Joyce Chiu, Gabriel G Perrone, Pierre J Dilda, Philip J Hogg
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1475-2867-12-11) contains supplementary material, which is available to authorized users.
Danielle Park, Joyce Chiu contributed equally to this work.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

DP and JC performed the experiments and analysed the data. GGP assisted with the design of the yeast studies and performed some experiments. PJD and PJH conceived the study and wrote the manuscript. All authors approved the final manuscript.

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.
Zusatzmaterial
Authors’ original file for figure 1
12935_2011_333_MOESM1_ESM.tiff
Authors’ original file for figure 2
12935_2011_333_MOESM2_ESM.tiff
Authors’ original file for figure 3
12935_2011_333_MOESM3_ESM.tiff
Literatur
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