Li Xiyan, Wang Xin, Snyder Michael P
Department of Genetics, Stanford University, Stanford, CA 94305-5120.
Department of Genetics, Stanford University, Stanford, CA 94305-5120
G3 (Bethesda). 2019 Feb 7;9(2):513-522. doi: 10.1534/g3.118.200803.
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.
二甲双胍具有多种有益作用，可用于治疗糖尿病、特定癌症以及延缓衰老。尽管其作用重要，但目前仍缺乏一个令人信服且统一的机制来解释二甲双胍的作用方式。在此，我们描述了通过血红素和血红蛋白对二甲双胍作用机制的研究。二甲双胍可使酵母中的血红素生成量减少50%，这种抑制作用需要线粒体功能，而线粒体功能是血红素合成所必需的。在与临床使用浓度相当的高浓度下，二甲双胍还可使人类红细胞、造血细胞和肝细胞中的血红素生成量减少30% - 50%；靶向血红素的药物青蒿素的作用效力更强。值得注意的是，二甲双胍可防止三种蛋白质支架（细胞色素c、肌红蛋白和血红蛋白）中的血红素氧化，解离常数（Kd）值< 3 mM，这表明其在血红素氧化还原转变调节中具有双重氧化和还原作用。由于血红素和卟啉样基团在控制重要代谢过程的多种酶中发挥作用，我们认为二甲双胍至少部分是通过稳定血红素和其他含卟啉基团的适当氧化还原状态来控制细胞代谢的。
