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@ARTICLE{Pavlin:820510,
      author       = {Pavlin, Matic and Rossetti, Giulia and De Vivo, Marco and
                      Carloni, Paolo},
      title        = {{C}arnosine and {H}omocarnosine {D}egradation {M}echanisms
                      by the {H}uman {C}arnosinase {E}nzyme {CN}1: {I}nsights from
                      {M}ultiscale {S}imulations},
      journal      = {Biochemistry},
      volume       = {55},
      number       = {19},
      issn         = {1520-4995},
      address      = {Columbus, Ohio},
      publisher    = {American Chemical Society},
      reportid     = {FZJ-2016-05803},
      pages        = {2772 - 2784},
      year         = {2016},
      abstract     = {The endogenous dipeptide l-carnosine, and its derivative
                      homocarnosine, prevent and reduce several pathologies like
                      amytrophic lateral sclerosis (ALS), Alzheimer’s disease,
                      and Parkinson’s disease. Their beneficial action is
                      severely hampered because of the hydrolysis by carnosinase
                      enzymes, in particular the human carnosinase, hCN1. This
                      belongs to the metallopeptidase M20 family, where a
                      cocatalytic active site is formed by two Zn2+ ions, bridged
                      by a hydroxide anion. The protein may exist as a monomer and
                      as a dimer in vivo. Here we used hybrid quantum
                      mechanics/molecular mechanics simulations based on the
                      dimeric apoenzyme’s structural information to predict the
                      Michaelis complexes with l-carnosine and its derivative
                      homocarnosine. On the basis of our calculations, we suggest
                      that (i) l-carnosine degradation occurs through a
                      nucleophilic attack of a Zn2+-coordinated bridging moiety
                      for both monomer and dimer. This mechanistic hypothesis for
                      hCN1 catalysis differs from previous proposals, while it is
                      in agreement with available experimental data. (ii) The
                      experimentally measured higher affinity of homocarnosine for
                      the enzyme relative to l-carnosine might be explained, at
                      least in part, by more extensive interactions inside the
                      monomeric and dimeric hCN1’s active site. (iii) Hydrogen
                      bonds at the binding site, present in the dimer but absent
                      in the monomer, might play a role in the experimentally
                      observed higher activity of the dimeric form. Investigations
                      of the enzymatic reaction are required to establish or
                      disprove this hypothesis. Our results may serve as a basis
                      for the design of potent hCN1 inhibitors.},
      cin          = {IAS-5 / INM-9 / JSC},
      ddc          = {570},
      cid          = {I:(DE-Juel1)IAS-5-20120330 / I:(DE-Juel1)INM-9-20140121 /
                      I:(DE-Juel1)JSC-20090406},
      pnm          = {572 - (Dys-)function and Plasticity (POF3-572) / 511 -
                      Computational Science and Mathematical Methods (POF3-511)},
      pid          = {G:(DE-HGF)POF3-572 / G:(DE-HGF)POF3-511},
      typ          = {PUB:(DE-HGF)16},
      UT           = {WOS:000376224000010},
      pubmed       = {pmid:27105448},
      doi          = {10.1021/acs.biochem.5b01263},
      url          = {https://juser.fz-juelich.de/record/820510},
}