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@ARTICLE{Ritacco:872836,
      author       = {Ritacco, Ida and Spinello, Angelo and Ippoliti, Emiliano
                      and Magistrato, Alessandra},
      title        = {{P}ost-{T}ranslational {R}egulation of {CYP}450s
                      {M}etabolism {A}s {R}evealed by {A}ll-{A}toms {S}imulations
                      of the {A}romatase {E}nzyme},
      journal      = {Journal of chemical information and modeling},
      volume       = {59},
      number       = {6},
      issn         = {1549-960X},
      address      = {Washington, DC},
      publisher    = {American Chemical Society64160},
      reportid     = {FZJ-2020-00306},
      pages        = {2930 - 2940},
      year         = {2019},
      abstract     = {Phosphorylation by kinases enzymes is a widespread
                      regulatory mechanism able of rapidly altering the function
                      of target proteins. Among these are cytochrome P450s
                      (CYP450), a superfamily of enzymes performing the oxidation
                      of endogenous and exogenous substrates thanks to the
                      electron supply of a redox partner. In spite of its pivotal
                      role, the molecular mechanism by which phosphorylation
                      modulates CYP450s metabolism remains elusive. Here by
                      performing microsecond-long all-atom molecular dynamics
                      simulations, we disclose how phosphorylation regulates
                      estrogen biosynthesis, catalyzed by the Human Aromatase (HA)
                      enzyme. Namely, we unprecedentedly propose that HA
                      phosphorylation at Y361 markedly stabilizes its adduct with
                      the flavin mononucleotide domain of CYP450s reductase (CPR),
                      the redox partner of microsomal CYP450s, and a variety of
                      other proteins. With CPR present at physiological conditions
                      in a limiting ratio with respect to its multiple oxidative
                      partners, the enhanced stability of the CPR/HA adduct may
                      favor HA in the competition with the other proteins
                      requiring CPR’s electron supply, ultimately facilitating
                      the electron transfer and estrogen biosynthesis. As a
                      result, our work elucidates at atomic-level the
                      post-translational regulation of CYP450s catalysis. Given
                      the potential for rational clinical management of diseases
                      associated with steroid metabolism disorders, unraveling
                      this mechanism is of utmost importance, and raises the
                      intriguing perspective of exploiting this knowledge to
                      devise novel therapies.},
      cin          = {IAS-5 / INM-9 / JARA-HPC},
      ddc          = {540},
      cid          = {I:(DE-Juel1)IAS-5-20120330 / I:(DE-Juel1)INM-9-20140121 /
                      $I:(DE-82)080012_20140620$},
      pnm          = {574 - Theory, modelling and simulation (POF3-574) /
                      Post-Transcriptional regulation mechanism of Human Aromatase
                      investigated by molecular simulations $(jias5a_20190501)$},
      pid          = {G:(DE-HGF)POF3-574 / $G:(DE-Juel1)jias5a_20190501$},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:31033287},
      UT           = {WOS:000473116500039},
      doi          = {10.1021/acs.jcim.9b00157},
      url          = {https://juser.fz-juelich.de/record/872836},
}