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National Academy of Sciences, Proceedings of the National Academy of Sciences, 23(103), p. 8662-8667, 2006

DOI: 10.1073/pnas.0510436103

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

Journal article published in 2006 by Qingjun Ma, Qingjun, Xin Zhao, Ali Nasser Eddine, Ali Nasser Eddine, Arie Geerlof, Xinping Li, John E. Cronan, Stefan H. E. Kaufmann, Matthias Wilmanns ORCID
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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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.