Mechanistic Analysis Of Biguanide Induced Inhibition Of Oxidative Phosphorylation

1460 Words May 11th, 2016 6 Pages
Kevin Raible Advanced Molecular Biology Final Exam

TITLE
Mechanistic Analysis of Biguanide-Induced Inhibition of Oxidative Phosphorylation

ABSTRACT
Biguanide compounds are used clinically to treat a variety of conditions ranging from diabetes to malaria. Despite showing efficacy the underlying mechanisms of how these compounds work is still debated. It has be previously shown biguanides inhibit oxidative phosphorylation, specifically through inhibiting complexes in the electron transport chain. In the current study we tested five clinically relevant biguanides; metformin, phenformin, buformin, proguanil, cycloguanil and begin to elucidate mechanistically how they inhibit mitochondrial function. Our results suggest that all five compounds inhibit mammalian complex I in varying degrees based on hydrophobicity. We have identified two possible binding sites of these compounds; one which may lock an active subunit into an inactive confirmation inhibiting the oxidation of NADH, and the other a flavin binding site where NADH binding and electron donation is disrupted. We have also discovered that biguanides inhibit ATP hydrolysis, of which phenformin and buformin inhibit the F1 subunit of ATPase. The penetrance of the compounds into the mitochondria varies on hydrophobicity, in general anti-diabetic biguanides can passively diffuse while anti-malarial compounds cannot. These findings are a next step in trying to understand the biochemical interactions this family of…
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