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

Danielle Park, Joyce Chiu, Gabriel G. Perrone, Pierre J. Dilda, Philip J. Hogg

    Research output: Contribution to journalArticlepeer-review

    49 Citations (Scopus)

    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 Ã… apart in the crystal structures of ANT and the optimal spacing of cysteine thiolates for reaction with As (III) is 3-4 Ã…. 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.
    Original languageEnglish
    Pages (from-to)1-6
    Number of pages6
    JournalCancer Cell International
    Volume12
    Issue number11
    Publication statusPublished - 2012

    Keywords

    • adenine nucleotide translocase
    • cancer
    • mitochondria
    • tumors

    Fingerprint

    Dive into the research topics of 'The tumour metabolism inhibitors GSAO and PENAO react with cysteines 57 and 257 of mitochondrial adenine nucleotide translocase'. Together they form a unique fingerprint.

    Cite this