6DDW

Mycobacterium tuberculosis Dihydrofolate Reductase complexed with beta-NADPH and N-(4-{[(2-amino-4-oxo-3,4-dihydropteridin-6-yl)methyl]amino}-2-hydroxybenzene-1-carbonyl)-L-glutamic acid

6DDW の概要

• エントリーDOI: 10.2210/pdb6ddw/pdb
• 分子名称: Dihydrofolate reductase, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, N-(4-{[(2-amino-4-oxo-3,4-dihydropteridin-6-yl)methyl]amino}-2-hydroxybenzene-1-carbonyl)-L-glutamic acid, ... (6 entities in total)
• 機能のキーワード: dhfr, antifolate, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 19560.55

構造登録者

Hajian, B.,Scocchera, E.,Wright, D. (登録日: 2018-05-10, 公開日: 2018-05-23, 最終更新日: 2023-10-11)

主引用文献

Hajian, B.,Scocchera, E.,Shoen, C.,Krucinska, J.,Viswanathan, K.,G-Dayanandan, N.,Erlandsen, H.,Estrada, A.,Mikusova, K.,Kordulakova, J.,Cynamon, M.,Wright, D.
Drugging the Folate Pathway in Mycobacterium tuberculosis: The Role of Multi-targeting Agents.
Cell Chem Biol, 26:781-791.e6, 2019

PubMed Abstract: The folate biosynthetic pathway offers many druggable targets that have yet to be exploited in tuberculosis therapy. Herein, we have identified a series of small molecules that interrupt Mycobacterium tuberculosis (Mtb) folate metabolism by dual targeting of dihydrofolate reductase (DHFR), a key enzyme in the folate pathway, and its functional analog, Rv2671. We have also compared the antifolate activity of these compounds with that of para-aminosalicylic acid (PAS). We found that the bioactive metabolite of PAS, in addition to previously reported activity against DHFR, inhibits flavin-dependent thymidylate synthase in Mtb, suggesting a multi-targeted mechanism of action for this drug. Finally, we have shown that antifolate treatment in Mtb decreases the production of mycolic acids, most likely due to perturbation of the activated methyl cycle. We conclude that multi-targeting of the folate pathway in Mtb is associated with highly potent anti-mycobacterial activity.

PubMed: 30930162
DOI: 10.1016/j.chembiol.2019.02.013

実験手法

X-RAY DIFFRACTION (1.4 Å)