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

Qingjun Ma, Xin Zhao, Ali Nasser Eddine, Arie Geerlof, Xinping Li, John E. Cronan, Stefan H.E. Kaufmann, Matthias Wilmanns

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)8662-8667
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number23
StatePublished - Jun 6 2006


  • Catalytic dyad
  • Lipoic acid
  • Mass spectrometry
  • Thioester formation
  • X-ray structure

ASJC Scopus subject areas

  • General


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