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PDBsum entry 1kpi
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Crystal structures of mycolic acid cyclopropane synthases from mycobacterium tuberculosis.
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Authors
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C.C.Huang,
C.V.Smith,
M.S.Glickman,
W.R.Jacobs,
J.C.Sacchettini.
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Ref.
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J Biol Chem, 2002,
277,
11559-11569.
[DOI no: ]
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PubMed id
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Abstract
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Mycolic acids are major components of the cell wall of Mycobacterium
tuberculosis. Several studies indicate that functional groups in the acyl chain
of mycolic acids are important for pathogenesis and persistence. There are at
least three mycolic acid cyclopropane synthases (PcaA, CmaA1, and CmaA2) that
are responsible for these site-specific modifications of mycolic 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-A resolution, respectively. All three enzymes have a seven-stranded
alpha/beta 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.
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Figure 3.
Fig. 3. Structure of apoCmaA1. a, superimposition of C[
 ]atoms
of structures of apoCmaA1 (gray) and CmaAl-SAH-DDDMAB (blue)
using residues 20-170. Residues 136-145 and residues 170-210 of
apoCmaA1 are colored in green. b, comparison of the active site
cavities in apoCmaA1 and CmaAl-SAH-DDDMAB.
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Figure 4.
Fig. 4. a, interactions between cofactor SAH and CmaA1.
The detailed interactions are also listed in Table II. The
figure was prepared using LIGPLOT(54). b, interactions between 7
amino acid insertions (residues 153-159) of CmaA2 (orange) and
the N terminus compared with CmaA1 (blue). c, active site
architecture. SAH and DDDMAB are shown in green. Residues
136-140 are shown in orange. DDDMAB in CmaA2-SAH-DDDMAB
structure is superimposed with CmaA1-SAH-DDDMAB structure and is
shown in gray. The bicarbonate ion in the active site is shown
interacting with His-167, Cys-35, and Glu-140. The carbocation
intermediate of the reaction mechanism may be stabilized by
cation-  interactions
during catalysis, specifically by the aromatic ring of the
Tyr-33.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2002,
277,
11559-11569)
copyright 2002.
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