5NNO

Structure of TbALDH3 complexed with NAD and AN3057 aldehyde

Summary for 5NNO

• Entry DOI: 10.2210/pdb5nno/pdb
• Related: 5MYP
• Descriptor: Aldehyde dehydrogenase, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, 4-[(1-oxidanyl-3~{H}-2,1-benzoxaborol-5-yl)oxy]benzaldehyde, ... (4 entities in total)
• Functional Keywords: aldehyde dehydrogenase, aldh, trypanosoma brucei, glycosomal, oxidoreductase, oxaborole, nad
• Biological source: Trypanosoma brucei
• Total number of polymer chains: 2
• Total formula weight: 121760.89

Authors

Zoltner, M.,Zhang, N.,Horn, D.,Field, M.C. (deposition date: 2017-04-10, release date: 2017-04-19, Last modification date: 2024-01-17)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.5 Å)