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.
The authors declare that they have no competing interests.
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.
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.
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.
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.
Don AS, Kisker O, Dilda P, Donoghue N, Zhao X, Decollogne S, Creighton B, Flynn E, Folkman J, Hogg PJ: A peptide trivalent arsenical inhibits tumor angiogenesis by perturbing mitochondrial function in angiogenic endothelial cells. Cancer Cell. 2003, 3 (5): 497-509. 10.1016/S1535-6108(03)00109-0. CrossRefPubMed
Adams E, Jeter D, Cordes AW, Kolis JW: Chemistry of organometalloid complexes with potential antidotes: structure of an organoarsenic(III) dithiolate ring. Inorg Chem. 1990, 29: 1500-1503. 10.1021/ic00333a012. CrossRef
Abramoff MD, Magalhaes PJ, Ram SJ: Image Processing with ImageJ. Biophotonics International. 2004, 11 (7): 36-42.
Daum G, Bohni PC, Schatz G: Import of proteins into mitochondria. Cytochrome b2 and cytochrome c peroxidase are located in the intermembrane space of yeast mitochondria. J Biol Chem. 1982, 257 (21): 13028-13033. PubMed
DeLano WL: The PyMOL Molecular Graphics System. 2002, DeLano Scientific, San Carlos, CA, USA
- The tumour metabolism inhibitors GSAO and PENAO react with cysteines 57 and 257 of mitochondrial adenine nucleotide translocase
Gabriel G Perrone
Pierre J Dilda
Philip J Hogg
- BioMed Central
Neu im Fachgebiet Onkologie
e.Med Kampagnen-Visual, Mail Icon II