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The Mycobacterium tuberculosis LipB enzyme functions as a cysteine/lysine dyad acyltransferase

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http://pubman.mpdl.mpg.de/cone/persons/resource/persons81861

Nasser Eddine,  Ali
Department of Immunology, Max Planck Institute for Infection Biology, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons81969

Kaufmann,  Stefan H. E.
Department of Immunology, Max Planck Institute for Infection Biology, Max Planck Society;

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Citation

Ma, Q., Zhao, X., Nasser Eddine, A., Geerlof, A., Li, X., Cronan, J. E., et al. (2006). The Mycobacterium tuberculosis LipB enzyme functions as a cysteine/lysine dyad acyltransferase. Proceedings of the National Academy of Sciences of the United States of America, 103(23), 8662-8667.


Cite as: http://hdl.handle.net/11858/00-001M-0000-000E-C382-8
Abstract
Lipoic acid is essential for the activation of a number of protein complexes involved in key metabolic processes. Growth of Mycobacterium tuberculosis relies on a pathway in which the lipoate attachment group is synthesized from an endogenously produced octanoic acid moiety. In patients with multiple-drug-resistant M. tuberculosis, expression of one gene from this pathway, lipB, encoding for octanoyl-[acyl carrier protein]-protein acyltransferase is considerably up-regulated, thus making it a potential target in the search for novel antiinfectives against tuberculosis. Here we present the crystal structure of the M. tuberculosis LipB protein at atomic resolution, showing an unexpected thioether-linked active-site complex with decanoic acid. We provide evidence that the transferase functions as a cysteine/lysine dyad acyltransferase, in which two invariant residues (Lys-142 and Cys-176) are likely to function as acid/base catalysts. Analysis by MS reveals that the LipB catalytic reaction proceeds by means of an internal thioesteracyl intermediate. Structural comparison of LipB with lipoate protein ligase A indicates that, despite conserved structural and sequence active-site features in the two enzymes, 4'-phosphopantetheine-bound octanoic acid recognition is a specific property of LipB.