3TFT

Crystal structure of 7,8-diaminopelargonic acid synthase (BioA) from Mycobacterium tuberculosis, pre-reaction complex with a 3,6-dihydropyrid-2-one heterocycle inhibitor

3TFT の概要

• エントリーDOI: 10.2210/pdb3tft/pdb
• 関連するPDBエントリー: 3TFU
• 分子名称: Adenosylmethionine-8-amino-7-oxononanoate aminotransferase, PYRIDOXAL-5'-PHOSPHATE, DIMETHYL SULFOXIDE, ... (4 entities in total)
• 機能のキーワード: transferase, plp
• 由来する生物種: Mycobacterium tuberculosis
• 細胞内の位置: Cytoplasm (By similarity): P0A4X6
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 97645.46

構造登録者

Geders, T.W.,Finzel, B.C. (登録日: 2011-08-16, 公開日: 2011-10-19, 最終更新日: 2023-09-13)

主引用文献

Shi, C.,Geders, T.W.,Park, S.W.,Wilson, D.J.,Boshoff, H.I.,Abayomi, O.,Barry, C.E.,Schnappinger, D.,Finzel, B.C.,Aldrich, C.C.
Mechanism-based Inactivation by Aromatization of the Transaminase BioA Involved in Biotin Biosynthesis in Mycobaterium tuberculosis.
J.Am.Chem.Soc., 133:18194-18201, 2011

PubMed Abstract: BioA catalyzes the second step of biotin biosynthesis, and this enzyme represents a potential target to develop new antitubercular agents. Herein we report the design, synthesis, and biochemical characterization of a mechanism-based inhibitor (1) featuring a 3,6-dihydropyrid-2-one heterocycle that covalently modifies the pyridoxal 5'-phosphate (PLP) cofactor of BioA through aromatization. The structure of the PLP adduct was confirmed by MS/MS and X-ray crystallography at 1.94 Å resolution. Inactivation of BioA by 1 was time- and concentration-dependent and protected by substrate. We used a conditional knock-down mutant of M. tuberculosis to demonstrate the antitubercular activity of 1 correlated with BioA expression, and these results provide support for the designed mechanism of action.

PubMed: 21988601
DOI: 10.1021/ja204036t

実験手法

X-RAY DIFFRACTION (1.95 Å)