3TFU

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

Summary for 3TFU

• Entry DOI: 10.2210/pdb3tfu/pdb
• Related: 3TFT
• Descriptor: Adenosylmethionine-8-amino-7-oxononanoate aminotransferase, [5-hydroxy-4-({[6-(3-hydroxypropyl)-2-oxo-1,2-dihydropyridin-3-yl]amino}methyl)-6-methylpyridin-3-yl]methyl dihydrogen phosphate, DIMETHYL SULFOXIDE, ... (4 entities in total)
• Functional Keywords: transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Mycobacterium tuberculosis
• Cellular location: Cytoplasm (By similarity): P0A4X6
• Total number of polymer chains: 2
• Total formula weight: 97949.85

Authors

Geders, T.W.,Finzel, B.C. (deposition date: 2011-08-16, release date: 2011-10-19, Last modification date: 2023-09-13)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.94 Å)