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The crystal structures of dihydropyrimidinases reaffirm the close relationship between cyclic amidohydrolases and explain their substrate specificity

Lohkamp, B ; Andersen, Birgit LU ; Piskur, Jure LU and Dobritzsch, D (2006) In Journal of Biological Chemistry 281(19). p.13762-13776
Abstract
In eukaryotes, dihydropyrimidinase catalyzes the second step of the reductive pyrimidine degradation, the reversible hydrolytic ring opening of dihydropyrimidines. Here we describe the three- dimensional structures of dihydropyrimidinase from two eukaryotes, the yeast Saccharomyces kluyveri and the slime mold Dictyostelium discoideum, determined and refined to 2.4 and 2.05 angstrom, respectively. Both enzymes have a ( beta/ alpha)(8)- barrel structural core embedding the catalytic di- zinc center, which is accompanied by a smaller beta- sandwich domain. Despite loop- forming insertions in the sequence of the yeast enzyme, the overall structures and architectures of the active sites of the dihydropyrimidinases are strikingly similar to each... (More)
In eukaryotes, dihydropyrimidinase catalyzes the second step of the reductive pyrimidine degradation, the reversible hydrolytic ring opening of dihydropyrimidines. Here we describe the three- dimensional structures of dihydropyrimidinase from two eukaryotes, the yeast Saccharomyces kluyveri and the slime mold Dictyostelium discoideum, determined and refined to 2.4 and 2.05 angstrom, respectively. Both enzymes have a ( beta/ alpha)(8)- barrel structural core embedding the catalytic di- zinc center, which is accompanied by a smaller beta- sandwich domain. Despite loop- forming insertions in the sequence of the yeast enzyme, the overall structures and architectures of the active sites of the dihydropyrimidinases are strikingly similar to each other, as well as to those of hydantoinases, dihydroorotases, and other members of the amidohydrolase superfamily of enzymes. However, formation of the physiologically relevant tetramer shows subtle but nonetheless significant differences. The extension of one of the sheets of the beta- sandwich domain across a subunit- subunit interface in yeast dihydropyrimidinase underlines its closer evolutionary relationship to hydantoinases, whereas the slime mold enzyme shows higher similarity to the noncatalytic collapsin- response mediator proteins involved in neuron development. Catalysis is expected to follow a dihydroorotase- like mechanism but in the opposite direction and with a different substrate. Complexes with dihydrouracil and N- carbamyl- beta- alanine obtained for the yeast dihydropyrimidinase reveal the mode of substrate and product binding and allow conclusions about what determines substrate specificity, stereoselectivity, and the reaction direction among cyclic amidohydrolases. (Less)
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author
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Biological Chemistry
volume
281
issue
19
pages
13762 - 13776
publisher
ASBMB
external identifiers
  • wos:000237336600087
  • scopus:33744961438
  • pmid:16517602
ISSN
1083-351X
DOI
10.1074/jbc.M513266200
language
English
LU publication?
yes
id
7c932096-40dd-4e0f-be37-4723dfcac040 (old id 410076)
date added to LUP
2016-04-01 12:36:35
date last changed
2021-09-22 04:11:24
@article{7c932096-40dd-4e0f-be37-4723dfcac040,
  abstract     = {In eukaryotes, dihydropyrimidinase catalyzes the second step of the reductive pyrimidine degradation, the reversible hydrolytic ring opening of dihydropyrimidines. Here we describe the three- dimensional structures of dihydropyrimidinase from two eukaryotes, the yeast Saccharomyces kluyveri and the slime mold Dictyostelium discoideum, determined and refined to 2.4 and 2.05 angstrom, respectively. Both enzymes have a ( beta/ alpha)(8)- barrel structural core embedding the catalytic di- zinc center, which is accompanied by a smaller beta- sandwich domain. Despite loop- forming insertions in the sequence of the yeast enzyme, the overall structures and architectures of the active sites of the dihydropyrimidinases are strikingly similar to each other, as well as to those of hydantoinases, dihydroorotases, and other members of the amidohydrolase superfamily of enzymes. However, formation of the physiologically relevant tetramer shows subtle but nonetheless significant differences. The extension of one of the sheets of the beta- sandwich domain across a subunit- subunit interface in yeast dihydropyrimidinase underlines its closer evolutionary relationship to hydantoinases, whereas the slime mold enzyme shows higher similarity to the noncatalytic collapsin- response mediator proteins involved in neuron development. Catalysis is expected to follow a dihydroorotase- like mechanism but in the opposite direction and with a different substrate. Complexes with dihydrouracil and N- carbamyl- beta- alanine obtained for the yeast dihydropyrimidinase reveal the mode of substrate and product binding and allow conclusions about what determines substrate specificity, stereoselectivity, and the reaction direction among cyclic amidohydrolases.},
  author       = {Lohkamp, B and Andersen, Birgit and Piskur, Jure and Dobritzsch, D},
  issn         = {1083-351X},
  language     = {eng},
  number       = {19},
  pages        = {13762--13776},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {The crystal structures of dihydropyrimidinases reaffirm the close relationship between cyclic amidohydrolases and explain their substrate specificity},
  url          = {http://dx.doi.org/10.1074/jbc.M513266200},
  doi          = {10.1074/jbc.M513266200},
  volume       = {281},
  year         = {2006},
}