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Crystal structures of yeast beta-alanine synthase complexes reveal the mode of substrate binding and large scale domain closure movements

Lundgren, Stina; Andersen, Birgit LU ; Piskur, Jure LU and Dobritzsch, Doreen (2007) In Journal of Biological Chemistry 282(49). p.36037-36047
Abstract
β-Alanine synthase is the final enzyme of the reductive pyrimidine catabolic pathway, which is responsible for the breakdown of uracil and thymine in higher organisms. The fold of the homodimeric enzyme from the yeast Saccharomyces kluyveri identifies it as a member of the AcyI/M20 family of metallopeptidases. Its subunit consists of a catalytic domain harboring a di-zinc center and a smaller dimerization domain. The present site-directed mutagenesis studies identify Glu159 and Arg322 as crucial for catalysis and His262 and His397 as functionally important but not essential. We determined the crystal structures of wild-type β-alanine synthase in complex with the reaction product β-alanine, and of the mutant E159A with the substrate... (More)
β-Alanine synthase is the final enzyme of the reductive pyrimidine catabolic pathway, which is responsible for the breakdown of uracil and thymine in higher organisms. The fold of the homodimeric enzyme from the yeast Saccharomyces kluyveri identifies it as a member of the AcyI/M20 family of metallopeptidases. Its subunit consists of a catalytic domain harboring a di-zinc center and a smaller dimerization domain. The present site-directed mutagenesis studies identify Glu159 and Arg322 as crucial for catalysis and His262 and His397 as functionally important but not essential. We determined the crystal structures of wild-type β-alanine synthase in complex with the reaction product β-alanine, and of the mutant E159A with the substrate N-carbamyl-β-alanine, revealing the closed state of a dimeric AcyI/M20 metallopeptidase-like enzyme. Subunit closure is achieved by a 30° rigid body domain rotation, which completes the active site by integration of substrate binding residues that belong to the dimerization domain of the same or the partner subunit. Substrate binding is achieved via a salt bridge, a number of hydrogen bonds, and coordination to one of the zinc ions of the di-metal center. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
nucleic acid precursors, structure-function, catabolism
in
Journal of Biological Chemistry
volume
282
issue
49
pages
36037 - 36047
publisher
ASBMB
external identifiers
  • wos:000251458100063
  • scopus:37249009047
ISSN
1083-351X
DOI
10.1074/jbc.M705517200
language
English
LU publication?
yes
id
aec4e694-156d-4812-9e36-70f8f4d04c79 (old id 745317)
date added to LUP
2008-01-09 13:39:28
date last changed
2017-08-27 04:14:38
@article{aec4e694-156d-4812-9e36-70f8f4d04c79,
  abstract     = {β-Alanine synthase is the final enzyme of the reductive pyrimidine catabolic pathway, which is responsible for the breakdown of uracil and thymine in higher organisms. The fold of the homodimeric enzyme from the yeast Saccharomyces kluyveri identifies it as a member of the AcyI/M20 family of metallopeptidases. Its subunit consists of a catalytic domain harboring a di-zinc center and a smaller dimerization domain. The present site-directed mutagenesis studies identify Glu159 and Arg322 as crucial for catalysis and His262 and His397 as functionally important but not essential. We determined the crystal structures of wild-type β-alanine synthase in complex with the reaction product β-alanine, and of the mutant E159A with the substrate N-carbamyl-β-alanine, revealing the closed state of a dimeric AcyI/M20 metallopeptidase-like enzyme. Subunit closure is achieved by a 30° rigid body domain rotation, which completes the active site by integration of substrate binding residues that belong to the dimerization domain of the same or the partner subunit. Substrate binding is achieved via a salt bridge, a number of hydrogen bonds, and coordination to one of the zinc ions of the di-metal center.},
  author       = {Lundgren, Stina and Andersen, Birgit and Piskur, Jure and Dobritzsch, Doreen},
  issn         = {1083-351X},
  keyword      = {nucleic acid precursors,structure-function,catabolism},
  language     = {eng},
  number       = {49},
  pages        = {36037--36047},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {Crystal structures of yeast beta-alanine synthase complexes reveal the mode of substrate binding and large scale domain closure movements},
  url          = {http://dx.doi.org/10.1074/jbc.M705517200},
  volume       = {282},
  year         = {2007},
}