Crystal structures of mycolic acid cyclopropane synthases from Mycobacterium tuberculosis

Chih Chin Huang, Clare V. Smith, Michael S. Glickman, William R. Jacobs, James C. Sacchettini

Research output: Contribution to journalArticle

141 Citations (Scopus)

Abstract

Mycolic acids are major components of the cell wall of Mycobacterium tuberculosis. Several studies indicate that functional groups in the acyl chain of mycotic acids are important for pathogenesis and persistence. There are at least three mycotic acid cyclopropane synthases (PcaA, CmaA1, and CmaA2) that are responsible for these site-specific modifications of mycotic acids. To derive information on the specificity and enzyme mechanism of the family of proteins, the crystal structures of CmaA1, CmaA2, and PcaA were solved to 2-, 2-, and 2.65-Å resolution, respectively. All three enzymes have a seven-stranded α/β fold similar to other methyltransferases with the location and interactions with the cofactor S-adenosyl-L-methionine conserved. The structures of the ternary complexes demonstrate the position of the mycolic acid substrate binding site. Close examination of the active site reveals electron density that we believe represents a bicarbonate ion. The structures support the hypothesis that these enzymes catalyze methyl transfer via a carbocation mechanism in which the bicarbonate ion acts as a general base. In addition, comparison of the enzyme structures reveals a possible mechanism for substrate specificity. These structures provide a foundation for rational-drug design, which may lead to the development of new inhibitors effective against persistent bacteria.

Original languageEnglish (US)
Pages (from-to)11559-11569
Number of pages11
JournalJournal of Biological Chemistry
Volume277
Issue number13
DOIs
StatePublished - Mar 29 2002
Externally publishedYes

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Mycolic Acids
Mycobacterium tuberculosis
Crystal structure
Enzymes
Bicarbonates
Acids
S-Adenosylmethionine
Drug Design
Methyltransferases
Substrates
Substrate Specificity
Cell Wall
Functional groups
Carrier concentration
Catalytic Domain
Bacteria
Binding Sites
Cells
Electrons
cyclopropane

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Crystal structures of mycolic acid cyclopropane synthases from Mycobacterium tuberculosis. / Huang, Chih Chin; Smith, Clare V.; Glickman, Michael S.; Jacobs, William R.; Sacchettini, James C.

In: Journal of Biological Chemistry, Vol. 277, No. 13, 29.03.2002, p. 11559-11569.

Research output: Contribution to journalArticle

Huang, Chih Chin ; Smith, Clare V. ; Glickman, Michael S. ; Jacobs, William R. ; Sacchettini, James C. / Crystal structures of mycolic acid cyclopropane synthases from Mycobacterium tuberculosis. In: Journal of Biological Chemistry. 2002 ; Vol. 277, No. 13. pp. 11559-11569.
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