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Crystal Structure and Substrate Specificity of the 8-oxo-dGTP Hydrolase NUDT1 from Arabidopsis thaliana

Jemth, Ann Sofie ; Scaletti, Emma LU ; Carter, Megan ; Helleday, Thomas and Stenmark, Pål LU orcid (2019) In Biochemistry 58(7). p.887-899
Abstract

Arabidopsis thaliana NUDT1 (AtNUDT1) belongs to the Nudix family of proteins, which have a diverse range of substrates, including oxidized nucleotides such as 8-oxo-dGTP. The hydrolysis of oxidized dNTPs is highly important as it prevents their incorporation into DNA, thus preventing mutations and DNA damage. AtNUDT1 is the sole Nudix enzyme from A. thaliana shown to have activity against 8-oxo-dGTP. We present the structure of AtNUDT1 in complex with 8-oxo-dGTP. Structural comparison with bacterial and human homologues reveals a conserved overall fold. Analysis of the 8-oxo-dGTP binding mode shows that the residues Asn76 and Ser89 interact with the O8 atom of the substrate, a feature not observed in structures of protein homologues... (More)

Arabidopsis thaliana NUDT1 (AtNUDT1) belongs to the Nudix family of proteins, which have a diverse range of substrates, including oxidized nucleotides such as 8-oxo-dGTP. The hydrolysis of oxidized dNTPs is highly important as it prevents their incorporation into DNA, thus preventing mutations and DNA damage. AtNUDT1 is the sole Nudix enzyme from A. thaliana shown to have activity against 8-oxo-dGTP. We present the structure of AtNUDT1 in complex with 8-oxo-dGTP. Structural comparison with bacterial and human homologues reveals a conserved overall fold. Analysis of the 8-oxo-dGTP binding mode shows that the residues Asn76 and Ser89 interact with the O8 atom of the substrate, a feature not observed in structures of protein homologues solved to date. Kinetic analysis of wild-type and mutant AtNUDT1 confirmed that these active site residues influence 8-oxo-dGTP hydrolysis. A recent study showed that AtNUDT1 is also able to hydrolyze terpene compounds. The diversity of reactions catalyzed by AtNUDT1 suggests that this Nudix enzyme from higher plants has evolved in a manner distinct to those from other organisms.

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author
; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Biochemistry
volume
58
issue
7
pages
13 pages
publisher
The American Chemical Society (ACS)
external identifiers
  • scopus:85061868866
  • pmid:30614695
ISSN
0006-2960
DOI
10.1021/acs.biochem.8b00950
language
English
LU publication?
yes
id
d9f4d2ab-923b-4a0b-8dd5-6579a81c096e
date added to LUP
2019-03-01 13:11:07
date last changed
2024-04-01 21:05:53
@article{d9f4d2ab-923b-4a0b-8dd5-6579a81c096e,
  abstract     = {{<p>Arabidopsis thaliana NUDT1 (AtNUDT1) belongs to the Nudix family of proteins, which have a diverse range of substrates, including oxidized nucleotides such as 8-oxo-dGTP. The hydrolysis of oxidized dNTPs is highly important as it prevents their incorporation into DNA, thus preventing mutations and DNA damage. AtNUDT1 is the sole Nudix enzyme from A. thaliana shown to have activity against 8-oxo-dGTP. We present the structure of AtNUDT1 in complex with 8-oxo-dGTP. Structural comparison with bacterial and human homologues reveals a conserved overall fold. Analysis of the 8-oxo-dGTP binding mode shows that the residues Asn76 and Ser89 interact with the O8 atom of the substrate, a feature not observed in structures of protein homologues solved to date. Kinetic analysis of wild-type and mutant AtNUDT1 confirmed that these active site residues influence 8-oxo-dGTP hydrolysis. A recent study showed that AtNUDT1 is also able to hydrolyze terpene compounds. The diversity of reactions catalyzed by AtNUDT1 suggests that this Nudix enzyme from higher plants has evolved in a manner distinct to those from other organisms.</p>}},
  author       = {{Jemth, Ann Sofie and Scaletti, Emma and Carter, Megan and Helleday, Thomas and Stenmark, Pål}},
  issn         = {{0006-2960}},
  language     = {{eng}},
  number       = {{7}},
  pages        = {{887--899}},
  publisher    = {{The American Chemical Society (ACS)}},
  series       = {{Biochemistry}},
  title        = {{Crystal Structure and Substrate Specificity of the 8-oxo-dGTP Hydrolase NUDT1 from Arabidopsis thaliana}},
  url          = {{http://dx.doi.org/10.1021/acs.biochem.8b00950}},
  doi          = {{10.1021/acs.biochem.8b00950}},
  volume       = {{58}},
  year         = {{2019}},
}