title: Sampangine inhibits heme biosynthesis in both yeast and human.
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.
authors: Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors: Zhiwei
authors: Z
authors: Huang
authors: Kaifu
authors: K
authors: Chen
authors: Tao
authors: T
authors: Xu
authors: Jianhuai
authors: J
authors: Zhang
authors: Yongxiang
authors: Y
authors: Li
authors: Wei
authors: W
authors: Li
authors: Ameeta K
authors: AK
authors: Agarwal
authors: Alice M
authors: AM
authors: Clark
authors: John D
authors: JD
authors: Phillips
authors: Xuewen
authors: X
authors: Pan
mesh_terms: D049069:ATP-Dependent Proteases / Q000235:genetics / Q000378:metabolism; D000470:Alkaloids / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006418:Heme / Q000096:biosynthesis*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D006801:Humans; D019169:Jurkat Cells; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D025261:Mitochondrial Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism; D009287:Naphthyridines; D010936:Plant Extracts / Q000494:pharmacology; D050768:Protoporphyrinogen Oxidase / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D014576:Uroporphyrinogen III Synthetase / Q000096:biosynthesis / Q000378:metabolism; D014577:Uroporphyrinogens / Q000378:metabolism
chemical_list: D000470:Alkaloids; D006576:Heterocyclic Compounds, 4 or More Rings; D024101:Mitochondrial Proteins; D009287:Naphthyridines; D010936:Plant Extracts; D017382:Reactive Oxygen Species; D029701:Saccharomyces cerevisiae Proteins; D014577:Uroporphyrinogens; D006418:Heme; C493976:HEM14 protein, S cerevisiae; D050768:Protoporphyrinogen Oxidase; D049069:ATP-Dependent Proteases; C082702:YME1 protein, S cerevisiae; D025261:Mitochondrial Proton-Translocating ATPases; D014576:Uroporphyrinogen III Synthetase; C121572:sampangine