5NNO

Structure of TbALDH3 complexed with NAD and AN3057 aldehyde

5NNO の概要

• エントリーDOI: 10.2210/pdb5nno/pdb
• 関連するPDBエントリー: 5MYP
• 分子名称: Aldehyde dehydrogenase, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, 4-[(1-oxidanyl-3~{H}-2,1-benzoxaborol-5-yl)oxy]benzaldehyde, ... (4 entities in total)
• 機能のキーワード: aldehyde dehydrogenase, aldh, trypanosoma brucei, glycosomal, oxidoreductase, oxaborole, nad
• 由来する生物種: Trypanosoma brucei
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 121760.89

構造登録者

Zoltner, M.,Zhang, N.,Horn, D.,Field, M.C. (登録日: 2017-04-10, 公開日: 2017-04-19, 最終更新日: 2024-01-17)

主引用文献

Zhang, N.,Zoltner, M.,Leung, K.F.,Scullion, P.,Hutchinson, S.,Del Pino, R.C.,Vincent, I.M.,Zhang, Y.K.,Freund, Y.R.,Alley, M.R.K.,Jacobs, R.T.,Read, K.D.,Barrett, M.P.,Horn, D.,Field, M.C.
Host-parasite co-metabolic activation of antitrypanosomal aminomethyl-benzoxaboroles.
PLoS Pathog., 14:e1006850-e1006850, 2018

PubMed Abstract: Recent development of benzoxaborole-based chemistry gave rise to a collection of compounds with great potential in targeting diverse infectious diseases, including human African Trypanosomiasis (HAT), a devastating neglected tropical disease. However, further medicinal development is largely restricted by a lack of insight into mechanism of action (MoA) in pathogenic kinetoplastids. We adopted a multidisciplinary approach, combining a high-throughput forward genetic screen with functional group focused chemical biological, structural biology and biochemical analyses, to tackle the complex MoAs of benzoxaboroles in Trypanosoma brucei. We describe an oxidative enzymatic pathway composed of host semicarbazide-sensitive amine oxidase and a trypanosomal aldehyde dehydrogenase TbALDH3. Two sequential reactions through this pathway serve as the key underlying mechanism for activating a series of 4-aminomethylphenoxy-benzoxaboroles as potent trypanocides; the methylamine parental compounds as pro-drugs are transformed first into intermediate aldehyde metabolites, and further into the carboxylate metabolites as effective forms. Moreover, comparative biochemical and crystallographic analyses elucidated the catalytic specificity of TbALDH3 towards the benzaldehyde benzoxaborole metabolites as xenogeneic substrates. Overall, this work proposes a novel drug activation mechanism dependent on both host and parasite metabolism of primary amine containing molecules, which contributes a new perspective to our understanding of the benzoxaborole MoA, and could be further exploited to improve the therapeutic index of antimicrobial compounds.

PubMed: 29425238
DOI: 10.1371/journal.ppat.1006850

実験手法

X-RAY DIFFRACTION (2.5 Å)