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PDBsum entry 1m4d
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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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Aminoglycoside 2'-N-Acetyltransferase from mycobacterium tuberculosis in complex with coenzyme a and aminoglycoside substrates.
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Authors
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M.W.Vetting,
S.S.Hegde,
F.Javid-Majd,
J.S.Blanchard,
S.L.Roderick.
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Ref.
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Nat Struct Biol, 2002,
9,
653-658.
[DOI no: ]
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PubMed id
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Abstract
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AAC(2')-Ic catalyzes the coenzyme A (CoA)-dependent acetylation of the 2'
hydroxyl or amino group of a broad spectrum of aminoglycosides. The crystal
structure of the AAC(2')-Ic from Mycobacterium tuberculosis has been determined
in the apo enzyme form and in ternary complexes with CoA and either tobramycin,
kanamycin A or ribostamycin, representing the first structures of an
aminoglycoside acetyltransferase bound to a drug. The overall fold of AAC(2')-Ic
places it in the GCN5-related N-acetyltransferase (GNAT) superfamily. Although
the physiological function of AAC(2')-Ic is uncertain, a structural analysis of
these high-affinity aminoglycoside complexes suggests that the enzyme may
acetylate a key biosynthetic intermediate of mycothiol, the major reducing agent
in mycobacteria, and participate in the regulation of cellular redox potential.
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Figure 3.
Figure 3. Comparison of bound aminoglycosides and the chemical
mechanism of acyltransfer by AAC(2')-Ic. a, Stereo view of
the superposition of tobramycin (blue), kanamycin A (green), and
ribostamycin (red) in the aminoglycoside -AAC(2')-Ic complexes.
The five water molecules that are conserved in all three ternary
complexes are shown as red spheres. Protein coordinates are from
AAC(2')-Ic in complex with ribostamycin and CoA. b, Chemical
reaction mechanism of AAC(2')-Ic based on the AAC(2')-Ic ternary
complexes.
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Figure 4.
Figure 4. Potential physiological function of AAC(2')-Ic. a,
Proposed step in mycothiol biosynthesis that may be catalyzed by
AAC(2')-Ic. b, Model of GlcN-Ins bound to AAC(2')-Ic. The
differentiating hydroxyls of inositol compared with
2-deoxystreptamine are green, and their potential interactions
with AAC(2')-Ic are red.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nat Struct Biol
(2002,
9,
653-658)
copyright 2002.
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Secondary reference #1
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Title
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Overexpression and mechanistic analysis of chromosomally encoded aminoglycoside 2'-N-Acetyltransferase (aac(2')-Ic) from mycobacterium tuberculosis.
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Authors
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S.S.Hegde,
F.Javid-Majd,
J.S.Blanchard.
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Ref.
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J Biol Chem, 2001,
276,
45876-45881.
[DOI no: ]
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PubMed id
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Figure 1.
Fig. 1. Structures of 4,5-disubstituted (A) and
4,6-disubstituted (B) aminoglycosides used in the study. a and
b, hexopyranosyl and 2-deoxystreptamine residues, respectively.
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Figure 2.
Fig. 2. Double-reciprocal plots of initial velocities
versus [ribostamycin] obtained at a fixed, saturating
concentration (100 µM) of propionyl-CoA in H[2]O (  ) and 98%
D[2]O (  ). The
symbols are experimentally determined values, while the smooth
curve is a fit of the data to Equation 5.
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The above figures are
reproduced from the cited reference
with permission from the ASBMB
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