5UIP

structure of DHFR with bound DAP, p-ABG and NADP

5UIP の概要

• エントリーDOI: 10.2210/pdb5uip/pdb
• 関連するPDBエントリー: 5UIH 5UII 5UIO
• 分子名称: Dihydrofolate reductase, N-(4-aminobenzene-1-carbonyl)-L-glutamic acid, PYRIMIDINE-2,4-DIAMINE, ... (6 entities in total)
• 機能のキーワード: dhfr, nadp, 2, 4 diaminopyridine, n-(4aminobenzoyl)-l-glutamate, oxidoreductase
• 由来する生物種: Escherichia coli
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 38600.20

構造登録者

Pedersen, L.C.,London, R.E. (登録日: 2017-01-14, 公開日: 2017-11-22, 最終更新日: 2023-10-04)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.9 Å)