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PDBsum entry 1hkv
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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 structure of mycobacterium tuberculosis diaminopimelate decarboxylase, An essential enzyme in bacterial lysine biosynthesis.
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Authors
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K.Gokulan,
B.Rupp,
M.S.Pavelka,
W.R.Jacobs,
J.C.Sacchettini.
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Ref.
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J Biol Chem, 2003,
278,
18588-18596.
[DOI no: ]
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PubMed id
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Abstract
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The Mycobacterium tuberculosis lysA gene encodes the enzyme meso-diaminopimelate
decarboxylase (DAPDC), a pyridoxal-5'-phosphate (PLP)-dependent enzyme. The
enzyme catalyzes the final step in the lysine biosynthetic pathway converting
meso-diaminopimelic acid (DAP) to l-lysine. The lysA gene of M. tuberculosis
H37Rv has been established as essential for bacterial survival in
immunocompromised mice, demonstrating that de novo biosynthesis of lysine is
essential for in vivo viability. Drugs targeted against DAPDC could be efficient
anti-tuberculosis drugs, and the three-dimensional structure of DAPDC from M.
tuberculosis complexed with reaction product lysine and the ternary complex with
PLP and lysine in the active site has been determined. The first structure of a
DAPDC confirms its classification as a fold type III PLP-dependent enzyme. The
structure shows a stable 2-fold dimer in head-to-tail arrangement of a
triose-phosphate isomerase (TIM) barrel-like alpha/beta domain and a C-terminal
beta sheet domain, similar to the ornithine decarboxylase (ODC) fold family. PLP
is covalently bound via an internal aldimine, and residues from both domains and
both subunits contribute to the binding pocket. Comparison of the structure with
eukaryotic ODCs, in particular with a di-fluoromethyl ornithine (DMFO)-bound ODC
from Trypanosoma bruceii, indicates that corresponding DAP-analogues might be
potential inhibitors for mycobacterial DAPDCs.
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Figure 3.
Fig. 3. Multiple sequence alignment of PLP-dependent
enzymes. Top line indicates regions of partially conserved or
important binding motives or residues. Alignment carried out
with ClustalW 1.8.2 (40). Color key: green, polar residues; red,
hydrophobic residues; blue, negatively charged; and magenta,
positively charged.
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Figure 6.
Fig. 6. Schematic representation of ligand binding
interactions in active site pocket of DAPDC. Residues of both
homodimer subunits contribute to PLP and to lysine binding. This
figure was created by LIGPLOT (43).
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2003,
278,
18588-18596)
copyright 2003.
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