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5UII

structure of DHFR with bound buformin and NADP

Summary for 5UII
Entry DOI10.2210/pdb5uii/pdb
Related5UIH 5UIO 5UIP
DescriptorDihydrofolate reductase, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, CALCIUM ION, ... (6 entities in total)
Functional Keywordsdhfr, buformin, nadp, oxidoreductase
Biological sourceEscherichia coli
Total number of polymer chains1
Total formula weight19121.03
Authors
Pedersen, L.C.,London, R.E. (deposition date: 2017-01-14, release date: 2018-01-31, Last modification date: 2023-10-25)
Primary citationGabel, S.A.,Duff, M.R.,Pedersen, L.C.,DeRose, E.F.,Krahn, J.M.,Howell, E.E.,London, R.E.
A Structural Basis for Biguanide Activity.
Biochemistry, 56:4786-4798, 2017
Cited by
PubMed Abstract: 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 of structural data. Structural considerations along with a growing body of literature demonstrating its effects on one-carbon metabolism suggest the possibility of folate mimicry and anti-folate activity. Motivated by the growing recognition that anti-diabetic biguanides may act directly upon the gut microbiome, we have determined structures of the complexes formed between the anti-diabetic biguanides (phenformin, buformin, and metformin) and Escherichia coli dihydrofolate reductase (ecDHFR) based on nuclear magnetic resonance, crystallographic, and molecular modeling studies. Interligand Overhauser effects indicate that metformin can form ternary complexes with p-aminobenzoyl-l-glutamate (pABG) as well as other ligands that occupy the region of the folate-binding site that interacts with pABG; however, DHFR inhibition is not cooperative. The biguanides competitively inhibit the activity of ecDHFR, with the phenformin inhibition constant being 100-fold lower than that of metformin. This inhibition may be significant at concentrations present in the gut of treated individuals, and inhibition of DHFR in intestinal mucosal cells may also occur if accumulation levels are sufficient. Perturbation of folate homeostasis can alter the pyridine nucleotide redox ratios that are important regulators of cellular metabolism.
PubMed: 28766937
DOI: 10.1021/acs.biochem.7b00619
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.351 Å)
Structure validation

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