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@ARTICLE{Dick:818274,
      author       = {Dick, Markus and Hartmann, Rudolf and Weiergräber, Oliver
                      H. and Bisterfeld, Carolin and Classen, Thomas and
                      Schwarten, Melanie and Neudecker, Philipp and Willbold,
                      Dieter and Pietruszka, Jörg},
      title        = {{M}echanism-based inhibition of an aldolase at high
                      concentrations of its natural substrate acetaldehyde:
                      structural insights and protective strategies},
      journal      = {Chemical science},
      volume       = {7},
      number       = {7},
      issn         = {2041-6539},
      address      = {Cambridge},
      publisher    = {RSC},
      reportid     = {FZJ-2016-04748},
      pages        = {4492 - 4502},
      year         = {2016},
      abstract     = {2-Deoxy-D-ribose-5-phosphate aldolase (DERA) is used in
                      organic synthesis for the enantioselective reaction between
                      acetaldehyde and a broad range of other aldehydes as
                      acceptor molecules. Nevertheless, its application is
                      hampered by a poor tolerance towards high concentrations of
                      acetaldehyde, its natural substrate. While numerous studies
                      have been performed searching for new, more
                      acetaldehyde-resistant DERAs, the mechanism underlying this
                      deactivation process has remained elusive. By using NMR
                      spectroscopy on both the protein and the small-molecule
                      scale, we could show that a reaction product binds to the
                      inner part of the enzyme, and that this effect can be partly
                      reversed via heating. The crystal structure of DERA before
                      and after acetaldehyde incubation was determined at high
                      resolution, revealing a covalently bound reaction product
                      bridging the catalytically active lysine (K167) to a nearby
                      cysteine (C47) in the deactivated enzyme. A reaction
                      mechanism is proposed where crotonaldehyde as the aldol
                      product of two acetaldehyde molecules after water
                      elimination forms a Schiff base with the lysine side chain,
                      followed by Michael addition of the cysteine thiol group to
                      the Cβ atom of the inhibitor. In support of this mechanism,
                      direct incubation of DERA with crotonaldehyde results in a
                      more than 100-fold stronger inhibition, compared to
                      acetaldehyde, whereas mutation of C47 gives rise to a fully
                      acetaldehyde-resistant DERA. Thus this variant appears
                      perfectly suited for synthetic applications. A similar
                      diagnostic and preventive strategy should be applicable to
                      other biocatalysts suffering from mechanism-based inhibition
                      by a reactive substrate, a condition that may be more common
                      than currently appreciated in biotechnology.},
      cin          = {ICS-6 / IBOC / IBG-1},
      ddc          = {540},
      cid          = {I:(DE-Juel1)ICS-6-20110106 / I:(DE-Juel1)IBOC-20090406 /
                      I:(DE-Juel1)IBG-1-20101118},
      pnm          = {553 - Physical Basis of Diseases (POF3-553) / 581 -
                      Biotechnology (POF3-581)},
      pid          = {G:(DE-HGF)POF3-553 / G:(DE-HGF)POF3-581},
      typ          = {PUB:(DE-HGF)16},
      UT           = {WOS:000378715000066},
      pubmed       = {pmid:30155096},
      doi          = {10.1039/C5SC04574F},
      url          = {https://juser.fz-juelich.de/record/818274},
}