title: Alkynol natural products target ALDH2 in cancer cells by irreversible binding to the active site.
abstract: Falcarinol and stipudiol are natural products with potent anti-cancer activity found in several vegetables. Here, we use a chemical proteomic strategy to identify ALDH2 as a molecular target of falcarinol in cancer cells and confirm enzyme inhibition via covalent alkylation of the active site. Furthermore, the synthesis of stipudiol led to the observation that ALDH2 exhibits preference for alkynol-based binders. Inhibition of ALDH2 impairs detoxification of reactive aldehydes and limits oxidative stress response, two crucial pathways for cellular viability.
authors.affiliation: Department of Chemistry, Center for Integrated Protein Science Munich (CIPSM), Technische Universität München, Garching, Germany. stephan.sieber@tum.de.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Heydenreuter
authors.affiliation: Department of Chemistry, Center for Integrated Protein Science Munich (CIPSM), Technische Universität München, Garching, Germany. stephan.sieber@tum.de.
authors.forename: Elena
authors.initials: E
authors.lastname: Kunold
authors.affiliation: Department of Chemistry, Center for Integrated Protein Science Munich (CIPSM), Technische Universität München, Garching, Germany. stephan.sieber@tum.de.
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Sieber
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000480:Alkynes / Q000138:chemical synthesis / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D020134:Catalytic Domain; D057930:Click Chemistry; D003545:Cysteine / Q000737:chemistry; D053280:Diynes / Q000138:chemical synthesis / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D005233:Fatty Alcohols / Q000138:chemical synthesis / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D007700:Kinetics; D011994:Recombinant Proteins / Q000737:chemistry
chemical_list: D000480:Alkynes; D000970:Antineoplastic Agents; D053280:Diynes; D004791:Enzyme Inhibitors; D005233:Fatty Alcohols; D011994:Recombinant Proteins; C000610404:stipudiol; C018541:falcarinol; C096127:ALDH2 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D003545:Cysteine