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A few amino acid substitutions can convert deoxyribonucleoside kinase specificity from pyrimidines to purines

Knecht, Wolfgang LU ; Sandrini, Michael P B LU ; Johansson, Kenth ; Eklund, Hans ; Munch-Petersen, Birgitte LU and Piskur, Jure LU (2002) In EMBO Journal 21(7). p.1873-1880
Abstract

In mammals, the four native deoxyribonucleosides are phosphorylated to the corresponding monophosphates by four deoxyribonucleoside kinases, which have specialized substrate specificities. These four enzymes are likely to originate from a common progenitor kinase. Insects appear to have only one multisubstrate deoxyribonucleoside kinase (dNK, EC 2.7.1.145), which prefers pyrimidine nucleosides, but can also phosphorylate purine substrates. When the structures of the human deoxyguanosine kinase (dGK, EC 2.7.1.113) and the dNK from Drosophila melanogaster were compared, a limited number of amino acid residues were identified and proposed to be responsible for the substrate specificity. Three of these key residues in Drosophila dNK were... (More)

In mammals, the four native deoxyribonucleosides are phosphorylated to the corresponding monophosphates by four deoxyribonucleoside kinases, which have specialized substrate specificities. These four enzymes are likely to originate from a common progenitor kinase. Insects appear to have only one multisubstrate deoxyribonucleoside kinase (dNK, EC 2.7.1.145), which prefers pyrimidine nucleosides, but can also phosphorylate purine substrates. When the structures of the human deoxyguanosine kinase (dGK, EC 2.7.1.113) and the dNK from Drosophila melanogaster were compared, a limited number of amino acid residues were identified and proposed to be responsible for the substrate specificity. Three of these key residues in Drosophila dNK were then mutagenized and the mutant enzymes were characterized regarding their ability to phosphorylate native deoxyribonucleosides and nucleoside analogs. The mutations converted the dNK substrate specificity from predominantly pyrimidine specific into purine specific. A similar scenario could have been followed during the evolution of kinases. Upon gene duplication of the progenitor kinase, only a limited number of single amino acid changes has taken place in each copy and resulted in substrate-specialized enzymes.

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author
; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
keywords
Amino Acid Sequence, Amino Acid Substitution, Animals, Deoxyribonucleosides/metabolism, Humans, Mice, Molecular Sequence Data, Mutagenesis, Site-Directed, Phosphorylation, Phosphotransferases (Alcohol Group Acceptor)/genetics, Purines/metabolism, Pyrimidines/metabolism, Sequence Homology, Amino Acid, Substrate Specificity
in
EMBO Journal
volume
21
issue
7
pages
8 pages
publisher
Oxford University Press
external identifiers
  • scopus:0037007213
  • pmid:11927571
ISSN
0261-4189
DOI
10.1093/emboj/21.7.1873
language
English
LU publication?
no
id
148bdfec-5b3f-479f-ab19-75a30a3b6b46
date added to LUP
2020-07-22 14:24:09
date last changed
2024-04-17 13:57:58
@article{148bdfec-5b3f-479f-ab19-75a30a3b6b46,
  abstract     = {{<p>In mammals, the four native deoxyribonucleosides are phosphorylated to the corresponding monophosphates by four deoxyribonucleoside kinases, which have specialized substrate specificities. These four enzymes are likely to originate from a common progenitor kinase. Insects appear to have only one multisubstrate deoxyribonucleoside kinase (dNK, EC 2.7.1.145), which prefers pyrimidine nucleosides, but can also phosphorylate purine substrates. When the structures of the human deoxyguanosine kinase (dGK, EC 2.7.1.113) and the dNK from Drosophila melanogaster were compared, a limited number of amino acid residues were identified and proposed to be responsible for the substrate specificity. Three of these key residues in Drosophila dNK were then mutagenized and the mutant enzymes were characterized regarding their ability to phosphorylate native deoxyribonucleosides and nucleoside analogs. The mutations converted the dNK substrate specificity from predominantly pyrimidine specific into purine specific. A similar scenario could have been followed during the evolution of kinases. Upon gene duplication of the progenitor kinase, only a limited number of single amino acid changes has taken place in each copy and resulted in substrate-specialized enzymes.</p>}},
  author       = {{Knecht, Wolfgang and Sandrini, Michael P B and Johansson, Kenth and Eklund, Hans and Munch-Petersen, Birgitte and Piskur, Jure}},
  issn         = {{0261-4189}},
  keywords     = {{Amino Acid Sequence; Amino Acid Substitution; Animals; Deoxyribonucleosides/metabolism; Humans; Mice; Molecular Sequence Data; Mutagenesis, Site-Directed; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor)/genetics; Purines/metabolism; Pyrimidines/metabolism; Sequence Homology, Amino Acid; Substrate Specificity}},
  language     = {{eng}},
  month        = {{04}},
  number       = {{7}},
  pages        = {{1873--1880}},
  publisher    = {{Oxford University Press}},
  series       = {{EMBO Journal}},
  title        = {{A few amino acid substitutions can convert deoxyribonucleoside kinase specificity from pyrimidines to purines}},
  url          = {{http://dx.doi.org/10.1093/emboj/21.7.1873}},
  doi          = {{10.1093/emboj/21.7.1873}},
  volume       = {{21}},
  year         = {{2002}},
}