Heme Binding Biguanides Target Cytochrome P450-Dependent Cancer Cell Mitochondria

Guo, Zhijun; Sevrioukova, Irina F.; Denisov, Ilia G.; Zhang, Xia; Chiu, Ting Lan; Thomas, Dafydd G.; Hanse, Eric A.; Cuellar, Rebecca A. D.; Grinkova, Yelena V.; Langenfeld, Vanessa Wankhede; Swedien, Daniel; Stamschror, Justin; Álvarez, Juan A. García; Luna, Fernando; Galván, Adela; Bae, Young Kyung; Wulfkuhle, Julia; Gallagher, Rosa I.; Petricoin, Emanuel F.; Flory, Craig M.; Schumacher, Robert J.; O’Sullivan, M. Gerard; Cao, Qing; Chu, Haitao; Lipscomb, John D.; Atkins, William M.; Gupta, Kalpna; Kelekar, Ameeta; Blair, Ian A.; Capdevila, Jorge H.; Falck, John R.; Sligar, Stephen G.; Poulos, T.L.; Georg, Gunda I.; Ambrose, Elizabeth; Potter, David A.

doi:10.1016/j.chembiol.2017.09.012

Cited by 12 publications

(9 citation statements)

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“…The observation of effective concentrations of metformin in millimolar ranges in this study is consistent with functional studies (Guo et al 2017b). Metformin inhibits breast tumor growth with an IC50 at 5 mM and a cytochrome P450 enzyme activity with Kd50 at 1.5-4.5 mM.…”

Section: Discussionsupporting

confidence: 92%

“…Metformin inhibits breast tumor growth with an IC50 at 5 mM and a cytochrome P450 enzyme activity with Kd50 at 1.5-4.5 mM. Co-crystallization of metformin and the truncated heme-containing enzyme places metformin on the same side of heme with oxygen in hemoglobin (Guo et al 2017b; Terrell et al 2018). These results support a pharmacological model of metformin where the administrated levels (μM) are far below its optimal kinetic levels (mM), which might be consistent with the extraordinary safety profile of metformin for long-term use (Diabetes Prevention Program Research Group 2012).…”

Section: Discussionmentioning

confidence: 99%

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Metformin Affects Heme Function as a Possible Mechanism of Action

Wang

2019

G3 Genes|Genomes|Genetics

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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.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Metformin Affects Heme Function as a Possible Mechanism of Action

Wang

2019

G3 Genes|Genomes|Genetics

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“…The inhibition of mitochondrial respiratory-chain complex 1 by metformin leads to a mild decrease in ATP generation by mitochondrial OXPHOS and a concomitant moderate increase in the AMP:ATP ratio in hepatocytes 38,39 . During the last 20 years, the selective inhibition of mitochondrial respiratory-chain complex 1 by metformin has been further confirmed in multiple biological models and species 41,42 , including human primary hepatocytes 43 and various cancer cell lines [44][45][46][47][48][49][50][51][52][53] . Furthermore, this effect was usually associated with significant decrease in mitochondrial NADH oxidation, a decrease in the proton gradient across the inner mitochondrial membrane and decreases in cellular oxygen consumption rate 42 , when these aspects have been studied in the models (Figure 1).…”

Section: Targeting Mitochondriamentioning

confidence: 94%

Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus

2019

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Despite its position as the first-line treatment for type 2 diabetes mellitus, the mechanisms underlying the plasma glucose level-lowering effects of metformin (1,1dimethylbiguanide) still remain incompletely understood. Metformin is thought to exert its primary antidiabetic action through the suppression of hepatic glucose production. Furthermore, the discovery that metformin inhibits the mitochondrial respiratory-chain complex 1 has placed energy metabolism and activation of AMP-activated protein kinase (AMPK) at the center of its mechanism of action. However, the role of AMPK has been challenged and might only account for indirect changes in hepatic insulin sensitivity. Various mechanisms involving alterations of cellular energy charge, AMP-mediated inhibition of adenylate cyclase or fructose-1,6-bisphosphatase-1 (FBP1) and modulation of the cellular redox state through direct inhibition of mitochondrial glycerol-3phosphate dehydrogenase (mG3PDH) are proposed for the acute inhibition of gluconeogenesis by metformin. Emerging evidence suggests that metformin could improve obesity-induced meta-inflammation via direct and indirect effects on tissueresident immune cells in metabolic organs (that is, adipose tissue, the gastrointestinal tract and the liver). Furthermore, the gastrointestinal tract also has a major role in metformin action through modulation of glucose-lowering hormone glucagon-like peptide-1 (GLP-1) and intestinal bile acid pool and alterations in gut microbiota composition. 3 Key points • Metformin is the first-line drug for treatment of type 2 diabetes mellitus, with an excellent safety profile, high efficacy on glycaemic control and clear but incompletely understood cardioprotective benefits. • The pleiotropic properties of metformin suggest that the drug acts on multiple tissues through various underlying mechanisms rather than on a single organ via an unifying mode of action. • The mitochondrial respiratory-chain complex 1 is a key cellular target of metformin and its mild and transient inhibition is involved in the AMPK-independent regulation of hepatic gluconeogenesis by triggering alterations in the cellular energy charge and redox state. • Metformin might contribute to improvements in obesity-associated metainflammation and tissue-specific insulin sensitivity through direct and indirect effects on various resident immune cells in metabolic organs. • The gastrointestinal tract has an important role in the action of metformin, which modulates bile acid recirculation and enhances the secretion of the glucose-lowering gut incretin hormone glucagon-like peptide-1 (GLP1). • The gut microbiota represents a novel target in the mechanisms of metformin action and is involved in both the therapeutic and adverse effects of the drug.

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“…This movement could facilitate proton transfer by the adjacent Thr309 residue in the I-helix, which is essential to oxygen activation by the heme. 25,[54][55][56][57] In addition to the F-helix, the C-helix also becomes very flexible in all of the activated bioconjugate enzymes, but not in the antagonist system. Noticeably, the Chelix is located below the entrance of the putative product egress channel 2e and is also involved in binding of the redox partner.…”

Section: Discussionmentioning

confidence: 99%

Combining small-molecule bioconjugation and hydrogen-deuterium exchange mass spectrometry (HDX-MS) to expose allostery: the case of human cytochrome P450 3A4

Ducharme

Thibodeaux

Auclair

2020

Preprint

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We report herein a novel approach to study allostery which combines the use of carefully selected bioconjugates and hydrogen-deuterium exchange mass spectrometry (HDX-MS). The utility of our method is demonstrated using human cytochrome P450 3A4 (CYP3A4). CYP3A4 is arguably the most important drug-metabolizing enzyme, and as such, is involved in numerous drug interactions. Diverse allosteric ligand effects have been reported for this enzyme, yet the structural mechanism of these phenomena remain poorly understood. We have described different CYP3A4-effector bioconjugates, some of which mimic the allosteric effect of positive effectors on CYP3A4, while others show activity enhancement even though the label does not occupy the allosteric pocket (agonistic), or do not show activation while still blocking the allosteric site (antagonistic). These bioonjugates were studied here by HDX-MS, which enabled us to better define the position of the allosteric site, and to identify important regions involved in CYP3A4 activation.

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Heme Binding Biguanides Target Cytochrome P450-Dependent Cancer Cell Mitochondria

Cited by 12 publications

References 0 publications

Metformin Affects Heme Function as a Possible Mechanism of Action

Metformin Affects Heme Function as a Possible Mechanism of Action

Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus

Combining small-molecule bioconjugation and hydrogen-deuterium exchange mass spectrometry (HDX-MS) to expose allostery: the case of human cytochrome P450 3A4

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