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Title: Sampangine inhibits heme biosynthesis in both yeast and human

Author
item HUANG, ZHIWEI - Baylor College Of Medicine
item CHEN, KAIFU - Baylor College Of Medicine
item XU, TAO - University Of Mississippi
item ZHANG, JIANHUAI - Baylor College Of Medicine
item LI, YONGXIANG - Baylor College Of Medicine
item LI, WEI - Baylor College Of Medicine
item AGARWAL, AMEETA - University Of Mississippi
item CLARK, ALICE - University Of Mississippi
item PHILLIPS, JOHN - University Of Utah
item PAN, XUEWEN - Baylor College Of Medicine

Submitted to: Eukaryotic Cell
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/31/2011
Publication Date: 9/29/2011
Citation: Huang, Z., Chen, K., Xu, T., Zhang, J., Li, Y., Li, W., Agarwal, A.K., Clark, A.M., Phillips, J.D., Pan, X. 2011. Sampangine inhibits heme biosynthesis in both yeast and human. Eukaryotic Cell. 10(11):1536-1544.

Interpretive Summary: This paper describes mechanism of action studies on the plant-derived compound sampangine. The studies show that sampangine directly inhibits heme biosynthesis in both yeast and human cells. The work described shows that the primary mechanism of action of sampangine is heme synthesis inhibition which consequently leads to oxidative stress. It also shows that sampangine treatment results in the accumulation of heme intermediates in yeast cells. This type of study is important in understanding how a candidate drug mediates it activity and also in predicting whether it will produce harmful side-effects in patients.

Technical 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.