A Structural Basis for Biguanide Activity.

摘要: Metformin is the most commonly prescribed treatment for type II diabetes and related disorders; however, molecular insights into its mode(s) of action have been limited by an absence structural data. Structural considerations along with a growing body literature demonstrating effects on one-carbon metabolism suggest possibility folate mimicry anti-folate activity. Motivated recognition that anti-diabetic biguanides may act directly upon gut microbiome, we determined structures complexes formed between (phenformin, buformin, metformin) Escherichia coli dihydrofolate reductase (ecDHFR) based nuclear magnetic resonance, crystallographic, modeling studies. Interligand Overhauser indicate metformin can form ternary p-aminobenzoyl-l-glutamate (pABG) as well other ligands occupy region folate-binding site interacts pABG; DHFR inhibition not cooperative. The competitively inhibit activity ecDHFR, phenformin constant being 100-fold lower than metformin. This be significant at concentrations present in treated individuals, intestinal mucosal cells also occur if accumulation levels are sufficient. Perturbation homeostasis alter pyridine nucleotide redox ratios important regulators cellular metabolism.