Sampangine Inhibits Heme Biosynthesis in Both Yeast and Human

Eukaryot Cell. 2011 Nov;10(11):1536-44. doi: 10.1128/EC.05170-11. Epub 2011 Sep 9.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • ATP-Dependent Proteases / genetics
  • ATP-Dependent Proteases / metabolism
  • Alkaloids / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Heme / biosynthesis*
  • Heterocyclic Compounds, 4 or More Rings / pharmacology
  • Humans
  • Jurkat Cells
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • Mitochondrial Proton-Translocating ATPases / genetics
  • Mitochondrial Proton-Translocating ATPases / metabolism
  • Naphthyridines
  • Plant Extracts / pharmacology
  • Protoporphyrinogen Oxidase / genetics
  • Protoporphyrinogen Oxidase / metabolism
  • Reactive Oxygen Species / metabolism
  • Saccharomyces cerevisiae / drug effects*
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism
  • Uroporphyrinogen III Synthetase / biosynthesis
  • Uroporphyrinogen III Synthetase / metabolism
  • Uroporphyrinogens / metabolism

Substances

  • Alkaloids
  • Heterocyclic Compounds, 4 or More Rings
  • Mitochondrial Proteins
  • Naphthyridines
  • Plant Extracts
  • Reactive Oxygen Species
  • Saccharomyces cerevisiae Proteins
  • Uroporphyrinogens
  • Heme
  • HEM14 protein, S cerevisiae
  • Protoporphyrinogen Oxidase
  • ATP-Dependent Proteases
  • YME1 protein, S cerevisiae
  • Mitochondrial Proton-Translocating ATPases
  • Uroporphyrinogen III Synthetase
  • sampangine