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@PHDTHESIS{Haase:1047604,
      author       = {Haase, Mona},
      title        = {{A}pplication of {C}3-methyltransferases for natural
                      product synthesis},
      volume       = {52},
      school       = {Düsseldorf},
      type         = {Dissertation},
      address      = {Jülich},
      publisher    = {Forschungszentrum Jülich GmbH Zentralbibliothek, Verlag},
      reportid     = {FZJ-2025-04406},
      isbn         = {978-3-95806-862-9},
      series       = {Bioorganische Chemie an der Heinrich-Heine-Universität im
                      Forschungszentrum Jülich},
      pages        = {432},
      year         = {2025},
      note         = {Dissertation, Düsseldorf, 2025},
      abstract     = {Natural products play a vital role in drug development,
                      either directly as pharmaceuticals or as templates for
                      designing target-specific therapeutics. The chemical
                      synthesis of these compounds often presents significant
                      challenges, requiring multiple reaction steps and hazardous
                      reagents. One prominent structural motif found in numerous
                      bioactive natural products is the hexahydropyrrolo[2,3-
                      b]indole (HPI) framework. Its unique tricyclic structure and
                      diverse biological activities have driven significant
                      synthetic interest, yet traditional methods struggle to
                      achieve stereoselectivity efficiently. This thesis aims to
                      develop a biocatalytic route for synthesising the HPI motif
                      using methyltransferases (MTases), which catalyses
                      C3-methylation of tryptophan-based cyclic dipeptides (DKPs).
                      The MTase StspM1 from Streptomyces sp. HPH0547 was selected
                      as the starting point for these studies: Optimised reaction
                      conditions, enzyme immobilisation, and S-adenosyl methionine
                      (SAM) cofactor recycling were investigated to create a
                      scalable, efficient method. To broaden the understanding of
                      their catalytic functions, homologs of StspM1 were explored,
                      focusing on their structure and mechanism. This
                      investigation was supported by two crystal structures
                      obtained during the study. Computational docking and
                      mutagenesis confirmed key residues critical for activity.
                      Among these homologs, SgMT from Streptomyces griseoviridis
                      was successfully integrated into the total synthesis of the
                      natural product lansai B, demonstrating its synthetic
                      utility. The gene clusters linked to these C3-MTases involve
                      additional enzymes contributing to the biosynthesis of
                      lansai B, including a second MTase, a cyclodipeptide
                      synthase (CDPS) and a prenyltransferase (PTase). The second
                      MTase was confirmed to function as an N-MTase. The PTase was
                      found to prenylate the C5-position, representing the final
                      step in the biosynthesis of lansai B This work advances
                      biocatalytic strategies for synthesising complex natural
                      product frameworks, offering new methodologies for
                      pharmaceutical development.},
      cin          = {IBOC},
      cid          = {I:(DE-Juel1)IBOC-20090406},
      pnm          = {2172 - Utilization of renewable carbon and energy sources
                      and engineering of ecosystem functions (POF4-217)},
      pid          = {G:(DE-HGF)POF4-2172},
      typ          = {PUB:(DE-HGF)3 / PUB:(DE-HGF)11},
      url          = {https://juser.fz-juelich.de/record/1047604},
}