Sampangine inhibits heme biosynthesis in both yeast and human

Zhiwei Huang, Kaifu Chen, Tao Xu, Jianhuai Zhang, Yongxiang Li, Wei Li, Ameeta K. Agarwal, Alice M. Clark, John D. Phillips, Xuewen Pan

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

The azaoxoaporphine alkaloid sampangine exhibits strong antiproliferation activity in various organisms. Previous studies suggested that it somehow affects heme metabolism and stimulates production of reactive oxygen species (ROS). In this study, we show that inhibition of heme biosynthesis is the primary mechanism of action by sampangine and that increases in the levels of reactive oxygen species are secondary to heme deficiency. We directly demonstrate that sampangine inhibits heme synthesis in the yeast Saccharomyces cerevisiae. It also causes accumulation of uroporphyrinogen and its decarboxylated derivatives, intermediate products of the heme biosynthesis pathway. Our results also suggest that sampangine likely works through an unusual mechanism-by hyperactivating uroporhyrinogen III synthase-to inhibit heme biosynthesis. We also show that the inhibitory effect of sampangine on heme synthesis is conserved in human cells. This study also reveals a surprising essential role for the interaction between the mitochondrial ATP synthase and the electron transport chain.

Original languageEnglish (US)
Pages (from-to)1536-1544
Number of pages9
JournalEukaryotic Cell
Volume10
Issue number11
DOIs
StatePublished - Nov 2011

ASJC Scopus subject areas

  • Microbiology
  • Molecular Biology

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