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Bisphosphonates Are Incorporated into Adenine Nucleotides by Human Aminoacyl-tRNA Synthetase Enzymes

https://doi.org/10.1006/bbrc.1996.1113Get rights and content

Abstract

Bisphosphonates are synthetic pyrophosphate analogues and are therapeutic inhibitors of bone resorption, although their exact mechanisms of action are unclear. Some bisphosphonates can be metabolised into non-hydrolysable ATP analogues byDictyostelium discoideumamoebae, in a back-reaction catalysed by several Class II aminoacyl-tRNA synthetases. We have found that the same enzymes in cell-free extracts of several human cell lines are also capable of metabolisingin vitrothe same bisphosphonates that are metabolised byDictyostelium.These results indicate that human cells, following drug internalisation, should be capable of metabolising certain bisphosphonates. The toxic effects of these bisphosphonates towards bone-resorbing osteoclasts may therefore be due to accumulation of non-hydrolysable ATP analogues or inhibition of aminoacyl-tRNA synthetase enzymes.

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