8GIL

L-threonine 3-Dehydrogenase from Trypanosoma cruzi (apo form)

8GIL の概要

• エントリーDOI: 10.2210/pdb8gil/pdb
• 分子名称: L-threonine 3-dehydrogenase, POTASSIUM ION (3 entities in total)
• 機能のキーワード: threonine, dehydrogenase, trypanossoma, apo, oxidoreductase
• 由来する生物種: Trypanosoma cruzi
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 81085.24

構造登録者

Faria, J.N.,Mercaldi, G.F.,Fagundes, M.,Bezerra, E.H.S.,Cordeiro, A.T. (登録日: 2023-03-14, 公開日: 2024-03-20, 最終更新日: 2025-04-09)

主引用文献

Faria, J.D.N.,Eufrasio, A.G.,Fagundes, M.,Lobo-Rojas, A.,Marchese, L.,de Lima Silva, C.C.,Bezerra, E.H.S.,Mercaldi, G.F.,Alborghetti, M.R.,Sforca, M.L.,Cordeiro, A.T.
Inhibition of L-threonine dehydrogenase from Trypanosoma cruzi reduces glycine and acetate production and interferes with parasite growth and viability.
J.Biol.Chem., 301:108080-108080, 2025

PubMed Abstract: Trypanosoma cruzi is a flagellated protozoan and the etiological agent of Chagas disease, a neglected tropical disease described by Carlos Chagas in 1909 that remains without appropriate diagnostics and treatment. Throughout its life cycle, T. cruzi undergoes through many different environments, requiring adaptation of its metabolism to different nutrition sources. Recent studies have confirmed the adaptability of T. cruzi metabolism to different carbon sources and encouraged a deeper investigation of related metabolic pathways. In the present study, we investigated the catabolism of threonine in T. cruzi epimastigotes cultivated in LIT medium and following 24h of starvation in PBS. In LIT medium, threonine, serine, and histidine were rapidly consumed concomitantly with carbohydrates during parasite exponential growth. When threonine was provided as the only carbon source to starved parasites, they excreted acetate and glycine, corroborating the activity of a mitochondrial threonine degradation pathway. Subsequently, we used a recombinant T. cruzi L-threonine dehydrogrenase (TcTDH) to screen the Chagas Box, an open-source collection of phenotypic hits, and identified compound TCMDC-143160 as a low micromolar TcTDH inhibitor (IC50 = 3.5 μM). When TCMDC-143160 was administrated to starved parasites, it inhibited the threonine degradation pathway. Finally, we report the crystal structure of TcTDH and characterize its allosteric activation by potassium. Collectively, these data demonstrate the relevance of threonine catabolism in T. cruzi metabolism and provide a set of tools to further investigate TcTDH as a potential drug target for Chagas disease.

PubMed: 39675710
DOI: 10.1016/j.jbc.2024.108080

実験手法

X-RAY DIFFRACTION (2.1 Å)