@article{EisenbergAlbertTeuffeletal.2022,
  author    = {Eisenberg, Philip and Albert, Leon and Teuffel, Jonathan and Zitzow, Eric and Michaelis, Claudia and Jarick, Jane and Sehlke, Clemens and Große, Lisa and Bader, Nicole and Nunes-Alves, Ariane and Kreikemeyer, Bernd and Schindelin, Hermann and Wade, Rebecca C. and Fiedler, Tomas},
  title     = {The Non-phosphorylating Glyceraldehyde-3-Phosphate Dehydrogenase GapN Is a Potential New Drug Target in Streptococcus pyogenes},
  series = {Frontiers in Microbiology},
  volume    = {13},
  journal   = {Frontiers in Microbiology},
  issn      = {1664-302X},
  doi       = {10.3389/fmicb.2022.802427},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-262869},
  year      = {2022},
  abstract  = {The strict human pathogen Streptococcus pyogenes causes infections of varying severity, ranging from self-limiting suppurative infections to life-threatening diseases like necrotizing fasciitis or streptococcal toxic shock syndrome. Here, we show that the non-phosphorylating glyceraldehyde-3-phosphate dehydrogenase GapN is an essential enzyme for S. pyogenes. GapN converts glyceraldehyde 3-phosphate into 3-phosphoglycerate coupled to the reduction of NADP to NADPH. The knock-down of gapN by antisense peptide nucleic acids (asPNA) significantly reduces viable bacterial counts of S. pyogenes laboratory and macrolide-resistant clinical strains in vitro. As S. pyogenes lacks the oxidative part of the pentose phosphate pathway, GapN appears to be the major NADPH source for the bacterium. Accordingly, other streptococci that carry a complete pentose phosphate pathway are not prone to asPNA-based gapN knock-down. Determination of the crystal structure of the S. pyogenes GapN apo-enzyme revealed an unusual cis-peptide in proximity to the catalytic binding site. Furthermore, using a structural modeling approach, we correctly predicted competitive inhibition of S. pyogenes GapN by erythrose 4-phosphate, indicating that our structural model can be used for in silico screening of specific GapN inhibitors. In conclusion, the data provided here reveal that GapN is a potential target for antimicrobial substances that selectively kill S. pyogenes and other streptococci that lack the oxidative part of the pentose phosphate pathway.},
  language  = {en}
}
@article{NishidaXavierdaSilvaSchulteNunesAlvesetal.2023,
  author    = {Nishida Xavier da Silva, Thamara and Schulte, Clemens and Nunes Alves, Ariane and Maric, Hans Michael and Friedmann Angeli, Jos{\´e} Pedro},
  title     = {Molecular characterization of AIFM2/FSP1 inhibition by iFSP1-like molecules},
  series = {Cell Death \& Disease},
  volume    = {14},
  journal   = {Cell Death \& Disease},
  doi       = {10.1038/s41419-023-05787-z},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357943},
  year      = {2023},
  abstract  = {Ferroptosis is a form of cell death characterized by phospholipid peroxidation, where numerous studies have suggested that the induction of ferroptosis is a therapeutic strategy to target therapy refractory cancer entities. Ferroptosis suppressor protein 1 (FSP1), an NAD(P)H-ubiquinone reductase, is a key determinant of ferroptosis vulnerability, and its pharmacological inhibition was shown to strongly sensitize cancer cells to ferroptosis. A first generation of FSP1 inhibitors, exemplified by the small molecule iFSP1, has been reported; however, the molecular mechanisms underlying inhibition have not been characterized in detail. In this study, we explore the species-specific inhibition of iFSP1 on the human isoform to gain insights into its mechanism of action. Using a combination of cellular, biochemical, and computational methods, we establish a critical contribution of a species-specific aromatic architecture that is essential for target engagement. The results described here provide valuable insights for the rational development of second-generation FSP1 inhibitors combined with a tracer for screening the druggable pocket. In addition, we pose a cautionary notice for using iFSP1 in animal models, specifically murine models.},
  language  = {en}
}