Crystal structure of mycobacterium tuberculosis diaminopimelate decarboxylase, an essential enzyme in bacterial lysine biosynthesis | Academic Article individual record
abstract

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.

author list (cited authors)
Gokulan, K., Rupp, B., Pavelka, M. S., Jacobs, W. R., & Sacchettini, J. C.
publication date
2003
keywords
  • Models, Molecular
  • Animals
  • Protein Structure, Secondary
  • Vitamin B 6
  • Mutation
  • Sequence Homology, Amino Acid
  • Ligands
  • Cloning, Molecular
  • Escherichia Coli
  • Molecular Sequence Data
  • Mice, SCID
  • Protein Binding
  • Amino Acid Sequence
  • Mice
  • Crystallography, X-Ray
  • Female
  • Protein Conformation
  • Binding Sites
  • Carboxy-Lyases
  • Models, Chemical
  • Mycobacterium Tuberculosis
  • Lysine
  • Time Factors
  • Bacterial Proteins
altmetric score

6.0

citation count

52