Metformin Affects Heme Function as a Possible Mechanism of Action

G3: Genes, Genomes, Genetics

article

Xiyan Li¹  Xin Wang¹  Michael P. Snyder¹ 

[1] Department of Genetics, Stanford University, Stanford, CA 94305-5120

关键词: metformin;    heme;    hemoprotein;    diabetes;    porphyrin;    mechanism of action;    redox;   

DOI  :  10.1534/g3.118.200803

学科分类：社会科学、人文和艺术（综合）

来源: Genetics Society of America

【 摘 要 】

Metformin elicits pleiotropic effects that are beneficial for treating diabetes, as well as particular cancers and aging. In spite of its importance, a convincing and unifying mechanism to explain how metformin operates is lacking. Here we describe investigations into the mechanism of metformin action through heme and hemoprotein(s). Metformin suppresses heme production by 50% in yeast, and this suppression requires mitochondria function, which is necessary for heme synthesis. At high concentrations comparable to those in the clinic, metformin also suppresses heme production in human erythrocytes, erythropoietic cells and hepatocytes by 30–50%; the heme-targeting drug artemisinin operates at a greater potency. Significantly, metformin prevents oxidation of heme in three protein scaffolds, cytochrome c, myoglobin and hemoglobin, with Kd values < 3 mM suggesting a dual oxidation and reduction role in the regulation of heme redox transition. Since heme- and porphyrin-like groups operate in diverse enzymes that control important metabolic processes, we suggest that metformin acts, at least in part, through stabilizing appropriate redox states in heme and other porphyrin-containing groups to control cellular metabolism.

【 授权许可】

CC BY|CC BY-NC