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@ARTICLE{Wittern:273914,
      author       = {Wittern, Carla Isabel and Schröder, Sophie and Jensen, Ole
                      and Brockmöller, Jürgen and Gebauer, Lukas},
      title        = {{C}omprehensive characterization of the {OCT}1
                      phenylalanine-244-alanine substitution reveals highly
                      substrate-dependent effects on transporter function.},
      journal      = {The journal of biological chemistry},
      volume       = {300},
      number       = {11},
      issn         = {0021-9258},
      address      = {Bethesda, Md.},
      publisher    = {Soc.},
      reportid     = {DZNE-2024-01388},
      pages        = {107835},
      year         = {2024},
      note         = {ISSN 0021-9258 not unique: **2 hits**.},
      abstract     = {Organic cation transporters (OCTs) can transport
                      structurally highly diverse substrates. The molecular basis
                      of this extensive polyspecificity has been further
                      elucidated by cryo-EM. Apparently, in addition to negatively
                      charged amino acids, aromatic residues may contribute to
                      substrate binding and substrate selectivity. In this study,
                      we provide a comprehensive characterization of phenylalanine
                      244 in OCT1 function. We analyzed the uptake of 144 OCT1
                      substrates for the phenylalanine 244 to alanine substitution
                      compared to WTOCT1. This substitution had highly
                      substrate-specific effects ranging from transport reduced to
                      $10\%$ of WT activity up to 8-fold increased transport
                      rates. Four percent of substrates showed strongly increased
                      uptake $(>200\%$ of WT) whereas $39\%$ showed strongly
                      reduced transport $(<50\%$ of WT). Particularly with larger,
                      more hydrophobic, and more aromatic substrates, the
                      Phe244Ala substitution resulted in higher transport rates
                      and lower inhibition of the transporter. In contrast,
                      substrates with a lower molecular weight and less aromatic
                      rings showed generally decreased uptake rates. A comparison
                      of our data to available transport kinetic data demonstrates
                      that generally, high-affinity low-capacity substrates show
                      increased uptake by the Phe244Ala substitution, whereas
                      low-affinity high-capacity substrates are characterized by
                      reduced transport rates. Altogether, our study provides the
                      first comprehensive characterization of the functional role
                      of an aromatic amino acid within the substrate translocation
                      pathway of OCT1. The pleiotropic function further highlights
                      that phenylalanine 244 interacts in a highly specific manner
                      with OCT1 substrates and inhibitors.},
      keywords     = {Humans / Phenylalanine: metabolism / Phenylalanine:
                      chemistry / Amino Acid Substitution / Substrate Specificity
                      / HEK293 Cells / Alanine: metabolism / Alanine: chemistry /
                      Kinetics / Biological Transport / Organic Cation Transporter
                      1: metabolism / Organic Cation Transporter 1: genetics /
                      Organic Cation Transporter 1: chemistry / alanine
                      mutagenesis (Other) / binding pocket (Other) / inhibition
                      (Other) / organic cation transporter 1 (Other) /
                      polyspecificity (Other) / site-directed mutagenesis (Other)
                      / transport (Other) / Phenylalanine (NLM Chemicals) /
                      Alanine (NLM Chemicals) / Organic Cation Transporter 1 (NLM
                      Chemicals)},
      cin          = {Clinical Dementia Research (Göttingen)},
      ddc          = {540},
      cid          = {I:(DE-2719)1440015},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:39342994},
      pmc          = {pmc:PMC11602988},
      doi          = {10.1016/j.jbc.2024.107835},
      url          = {https://pub.dzne.de/record/273914},
}