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Synthesis of 2'-Deoxyuridine 5'-(α,β-Imido)triphosphate: A Substrate Analogue and Potent Inhibitor of dUTPase

Persson, Tina LU ; Larsson, Gunilla and Nyman, Per-Olof LU (1996) In Bioorganic & Medicinal Chemistry 4(4). p.553-556
Abstract
The dUDP analogue, 2'-deoxyuridine 5'-(α,β-imido)diphosphate (dUPNP) was synthesized. The corresponding triphosphate analogue (dUPNPP) was prepared by enzymic phosphorylation of dUPNP using the enzyme pyruvate kinase and phosphoenolpyruvate as the phosphate donor. This method was successful in phosphorylating the imidodiphosphate analogue of 2'-deoxythymidine (dTPNP) to 2'-deoxythymidine 5'-(α,β-imido)triphosphate (dTPNPP), in contradiction to a previous report. The properties of dUPNPP have been tested using the enzyme dUTPase from Escherichia coli. This enzyme, having a crucial role in nucleotide metabolism, is strictly specific for its substrate (dUTP) and catalyzes the hydrolysis of the α,β-bridge, resulting in dUMP and pyrophosphate.... (More)
The dUDP analogue, 2'-deoxyuridine 5'-(α,β-imido)diphosphate (dUPNP) was synthesized. The corresponding triphosphate analogue (dUPNPP) was prepared by enzymic phosphorylation of dUPNP using the enzyme pyruvate kinase and phosphoenolpyruvate as the phosphate donor. This method was successful in phosphorylating the imidodiphosphate analogue of 2'-deoxythymidine (dTPNP) to 2'-deoxythymidine 5'-(α,β-imido)triphosphate (dTPNPP), in contradiction to a previous report. The properties of dUPNPP have been tested using the enzyme dUTPase from Escherichia coli. This enzyme, having a crucial role in nucleotide metabolism, is strictly specific for its substrate (dUTP) and catalyzes the hydrolysis of the α,β-bridge, resulting in dUMP and pyrophosphate. Replacement of the α,β-bridging oxygen in dUTP with an imido group resulted in a nonhydrolyzable substrate analogue and a potent competitive inhibitor of dUTPase (Ki=5μM). The analogue prepared (dUPNPP) may be utilized in crystallographic studies of the active site of dUTPase to provide knowledge about specific interactions involved in substrate binding and as a parental compound in design of dUTPase inhibition for medical purposes. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Bioorganic & Medicinal Chemistry
volume
4
issue
4
pages
553 - 556
publisher
Elsevier
external identifiers
  • scopus:0029931195
ISSN
0968-0896
DOI
10.1016/0968-0896(96)00044-2
language
English
LU publication?
yes
id
6f6ad594-6004-4234-979c-cc98f0c3fe87 (old id 126324)
date added to LUP
2007-07-06 13:19:11
date last changed
2017-01-01 04:47:03
@article{6f6ad594-6004-4234-979c-cc98f0c3fe87,
  abstract     = {The dUDP analogue, 2'-deoxyuridine 5'-(α,β-imido)diphosphate (dUPNP) was synthesized. The corresponding triphosphate analogue (dUPNPP) was prepared by enzymic phosphorylation of dUPNP using the enzyme pyruvate kinase and phosphoenolpyruvate as the phosphate donor. This method was successful in phosphorylating the imidodiphosphate analogue of 2'-deoxythymidine (dTPNP) to 2'-deoxythymidine 5'-(α,β-imido)triphosphate (dTPNPP), in contradiction to a previous report. The properties of dUPNPP have been tested using the enzyme dUTPase from Escherichia coli. This enzyme, having a crucial role in nucleotide metabolism, is strictly specific for its substrate (dUTP) and catalyzes the hydrolysis of the α,β-bridge, resulting in dUMP and pyrophosphate. Replacement of the α,β-bridging oxygen in dUTP with an imido group resulted in a nonhydrolyzable substrate analogue and a potent competitive inhibitor of dUTPase (Ki=5μM). The analogue prepared (dUPNPP) may be utilized in crystallographic studies of the active site of dUTPase to provide knowledge about specific interactions involved in substrate binding and as a parental compound in design of dUTPase inhibition for medical purposes.},
  author       = {Persson, Tina and Larsson, Gunilla and Nyman, Per-Olof},
  issn         = {0968-0896},
  language     = {eng},
  number       = {4},
  pages        = {553--556},
  publisher    = {Elsevier},
  series       = {Bioorganic & Medicinal Chemistry},
  title        = {Synthesis of 2'-Deoxyuridine 5'-(α,β-Imido)triphosphate: A Substrate Analogue and Potent Inhibitor of dUTPase},
  url          = {http://dx.doi.org/10.1016/0968-0896(96)00044-2},
  volume       = {4},
  year         = {1996},
}