Bisphosphonates are incorporated into adenine nucleotides by human aminoacyl-tRNA synthetase enzymes.
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 by Dictyostelium discoideum amoebae, 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 metabolising in vitro the same bisphosphonates that are metabolised by Dictyostelium. 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.
Rogers
M J
MJ
Department of Human Metabolism and Clinical Biochemistry, University of Sheffield Medical School, United Kingdom.
Brown
R J
RJ
Hodkin
V
V
Blackburn
G M
GM
Russell
R G
RG
Watts
D J
DJ
D000227:Adenine Nucleotides / Q000378:metabolism*; D000604:Amino Acyl-tRNA Synthetases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002457:Cell Extracts; D002474:Cell-Free System; D004164:Diphosphonates / Q000378:metabolism* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D014407:Tumor Cells, Cultured
D000227:Adenine Nucleotides; D002457:Cell Extracts; D004164:Diphosphonates; D004791:Enzyme Inhibitors; D000604:Amino Acyl-tRNA Synthetases