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  3. The Amaryllidaceae Alkaloid Haemanthamine Binds the Eukaryotic Ribosome to Repress Cancer Cell Growth

The Amaryllidaceae Alkaloid Haemanthamine Binds the Eukaryotic Ribosome to Repress Cancer Cell Growth

  • Structure. 2018 Mar 6;26(3):416-425.e4. doi: 10.1016/j.str.2018.01.009.
Simone Pellegrino 1,  Mélanie Meyer 1,  Christiane Zorbas 2,  Soumaya A Bouchta 2,  Kritika Saraf 2,  Stephen C Pelly 3,  Gulnara Yusupova 1,  Antonio Evidente 4,  Véronique Mathieu 5,  Alexander Kornienko 6,  Denis L J Lafontaine 7,  Marat Yusupov 8
Affiliations

Affiliations

  • 1 Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR7104, Université de Strasbourg, 67404 Illkirch, France.
  • 2 RNA Molecular Biology and Center for Microscopy and Molecular Imaging (CMMI), Fonds National de la Recherche (F.R.S./FNRS) and Université Libre de Bruxelles (ULB), BioPark Campus, 6041 Gosselies, Belgium.
  • 3 Department of Chemistry and Polymer Science, Stellenbosch University, Stellenbosch, Matieland 7602, South Africa.
  • 4 Dipartimento di Scienze Chimiche, Università di Napoli Federico II, Complesso Universitario Monte Sant'Angelo, Via Cintia 4, 80126 Napoli, Italy.
  • 5 Laboratoire de Cancérologie et de Toxicologie Expérimentale, Faculté de Pharmacie, Université Libre de Bruxelles, 1050 Brussels, Belgium.
  • 6 Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX 78666, USA.
  • 7 RNA Molecular Biology and Center for Microscopy and Molecular Imaging (CMMI), Fonds National de la Recherche (F.R.S./FNRS) and Université Libre de Bruxelles (ULB), BioPark Campus, 6041 Gosselies, Belgium. Electronic address: [email protected].
  • 8 Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR7104, Université de Strasbourg, 67404 Illkirch, France. Electronic address: [email protected].
PMID: 29429877 DOI: 10.1016/j.str.2018.01.009
Abstract

Alkaloids isolated from the Amaryllidaceae plants have potential as therapeutics for treating human diseases. Haemanthamine has been studied as a novel Anticancer agent due to its ability to overcome Cancer cell resistance to Apoptosis. Biochemical experiments have suggested that hemanthamine targets the ribosome. However, a structural characterization of its mechanism has been missing. Here we present the 3.1 Å resolution X-ray structure of haemanthamine bound to the Saccharomyces cerevisiae 80S ribosome. This structure reveals that haemanthamine targets the A-site cleft on the large ribosomal subunit rearranging rRNA to halt the elongation phase of translation. Furthermore, we provide evidence that haemanthamine and other Amaryllidaceae alkaloids also inhibit specifically ribosome biogenesis, triggering nucleolar stress response and leading to p53 stabilization in Cancer cells. Together with a computer-aided interpretation of existing structure-activity relationships of Amaryllidaceae alkaloids congeners, we provide a rationale for designing molecules with enhanced potencies and reduced toxicities.

Keywords

Amaryllidaceae alkaloids; X-ray crystallography; cancer; haemanthamine; nucleolar stress response; p53; peptidyl transferase center; ribosome; ribosome biogenesis; translation elongation.

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