5UIH

structure of DHFR with bound phenformin and NADP

Summary for 5UIH

• Entry DOI: 10.2210/pdb5uih/pdb
• Related: 5UII 5UIO 5UIP
• Descriptor: Dihydrofolate reductase, N-(2-phenylethyl)imidodicarbonimidic diamide, SODIUM ION, ... (7 entities in total)
• Functional Keywords: dhfr, phenformin, nadp, oxidoreductase
• Biological source: Escherichia coli
• Total number of polymer chains: 1
• Total formula weight: 20188.28

Authors

Pedersen, L.C.,London, R.E. (deposition date: 2017-01-14, release date: 2017-11-22, Last modification date: 2023-10-04)

Primary citation

Gabel, 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

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

Experimental method

X-RAY DIFFRACTION (1.647 Å)