A suppressor of dioxygenase inhibition in a yeast model of SDH deficiency

William Beimers, Megan Braun, Kaleb Schwinefus, Keenan Pearson, Brandon Wilbanks, Louis James Maher

Research output: Contribution to journalArticlepeer-review

Abstract

A fascinating class of familial paraganglioma (PGL) neuroendocrine tumors is driven by the loss of the tricarboxylic acid (TCA) cycle enzyme succinate dehydrogenase (SDH) resulting in succinate accumulation as an oncometabolite and other metabolic derangements. Here, we exploit a Saccharomyces cerevisiae yeast model of SDH loss where accumulating succinate, and possibly reactive oxygen species, poison a dioxygenase enzyme required for sulfur scavenging. Using this model, we performed a chemical suppression screen for compounds that relieve dioxygenase inhibition. After testing 1280 pharmaceutically active compounds, we identified meclofenoxate HCl and its hydrolysis product, dimethylaminoethanol (DMAE), as suppressors of dioxygenase intoxication in SDH-loss yeast cells. We show that DMAE acts to alter metabolism so as to normalize the succinate:2-ketoglutarate ratio, improving dioxygenase function. This study raises the possibility that oncometabolite effects might be therapeutically suppressed by drugs that rewire metabolism to reduce the flux of carbon into pathological metabolic pathways.

Original languageEnglish (US)
Pages (from-to)345-358
Number of pages14
JournalEndocrine-Related Cancer
Volume29
Issue number6
DOIs
StatePublished - May 11 2022

Keywords

  • drug screen
  • paraganglioma
  • Saccharomyces cerevisiae
  • succinate dehydrogenase

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Oncology
  • Endocrinology
  • Cancer Research

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