Nucleotide pyrophosphatase/phosphodiesterase 1 is responsible for degradation of antisense phosphorothioate oligonucleotides.
The rapid degradation of unmodified phosphodiester oligodeoxynucleotides (PO-oligos) by exo -and endonucleases limits their application as antisense constructs and requires the synthesis and use of modified oligonucleotides. Phosphorothioate analogs of oligonucleotides (PS-oligos) are much more stable against nucleolytic degradation than their unmodified counterparts, and this is one of the reasons for which they are a promising class of antisense oligonucleotides. However, PS-oligos also undergo slow hydrolysis by enzymes present in plasma. The oligonucleotide degradation proceeds mainly from the 3' -end, resulting in the formation of a typical ladder of shorter products and the release of the mononucleoside 5' -phosphorothioates. So far, little has been known concerning the molecular identity of the enzymes involved in the degradation of PS-oligos. We now identify the human plasma 3' -exonuclease responsible for their degradation as a soluble form of nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1) (EC 3.1.4.1/EC 3.6.1.9), also known as the plasma cell differentiation antigen PC-1. We also show that adenosine or deoxyadenosine (alpha-thio)triphosphates can act as potent inhibitors of NPPs.
Wójcik
Marzena
M
Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Łódź, Poland.
Cieślak
Marcin
M
Stec
Wojciech J
WJ
Goding
James W
JW
Koziołkiewicz
Maria
M
D004791:Enzyme Inhibitors / Q000494:pharmacology; D005092:Exonucleases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D016376:Oligonucleotides, Antisense / Q000737:chemistry*; D010727:Phosphoric Diester Hydrolases / Q000097:blood / Q000737:chemistry*; D011755:Pyrophosphatases / Q000037:antagonists & inhibitors / Q000097:blood / Q000737:chemistry*; D013379:Substrate Specificity; D013873:Thionucleotides / Q000737:chemistry*
D004791:Enzyme Inhibitors; D016376:Oligonucleotides, Antisense; D013873:Thionucleotides; D005092:Exonucleases; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases; C405782:nucleotide pyrophosphatase - phosphodiesterase I