L,L-diaminopimelate aminotransferase (DapL): a putative target for the development of narrow-spectrum antibacterial compounds

Abstract

Despite the urgent need for sustained development of novel antibacterial compounds to combat the drastic rise in antibiotic resistant and emerging bacterial infections, only a few clinically relevant antibacterial drugs have been recently developed. One of the bottlenecks impeding the development of novel antibacterial compounds is the identification of new enzymatic targets. The nutritionally essential amino acid anabolic pathways, for example lysine biosynthesis, provide an opportunity to explore the development of antibacterial compounds, since human genomes do not possess the genes necessary to synthesize these amino acids de novo. The diaminopimelate (DAP)/lysine (lys) anabolic pathways are attractive targets for antibacterial development since the penultimate lys precursor meso-DAP (m-DAP) is a cross-linking amino acid in the peptidoglycan (PG) cell wall of most Gram-negative bacteria and lys plays a similar role in the PG of most Gram-positive bacteria, in addition to its role as one of the 20 proteogenic amino acids. The L,L-diaminopimelate aminotransferase (DapL) pathway was recently identified as a novel variant of the DAP/lys anabolic pathways. The DapL pathway has been identified in the pathogenic bacteria belonging to the genus; Chlamydia, Leptospira, and Treponema. The dapL gene has been identified in the genomes of 381 or approximately 13% of the 2771 bacteria that have been sequenced, annotated and reposited in the NCBI database, as of May 23, 2014. The narrow distribution of the DapL pathway in the bacterial domain provides an opportunity for the development and or discovery of narrow spectrum antibacterial compounds.

The Arabidopsis thaliana gene annotated by the locus tag At3g08860 encodes alanine aminotransferase

“…Areas lacking secondary structural elements (i.e., disordered regions or loops) were areas with lower local quality scores (Figure c). The dimeric structural nature of At3g08860 is similar to that of other aminotransferases that have been solved by X‐ray crystallography including L,L‐diaminopimelate aminotransferase (DapL) and N ‐acetylornithine aminotransferase (Rajaram, Ratna Prasuna, Savithri, & Murthy, ; Triassi et al, ).…”

Identification of potential drugs targeting L,L‐diaminopimelate aminotransferase of Chlamydia trachomatis: An integrative pharmacoinformatics approach

“…Worldwide it is estimated that every year, more than 90 million people are affected by chlamydia, and this organism was also found to gain antibiotic resistance to many of the drugs. The increase in drug resistance among this species indicates an urgent need for alternate and potential antibacterial targets to help combat the infections . Molecular modeling and structural bioinformatics serves as powerful tool for studying intermolecular interactions and dynamic behavior of molecules in in silico simulated conditions .…”

“…This enzymatic reaction is also common to all four DAP/lys anabolic variants, 24 for the overall detailed enzymatic reaction, refer to Hudson et al 13,21 and Alexander et al (2014). 25 Hence, this L-Lysine biosynthetic pathways in bacteria and plants have been widely investigated by many groups for drug targeting because of their crucial role in synthesis of PG cell wall in most bacteria [26][27][28][29] and host nonhomology. 5 In this study, L,L-diaminopimelate aminotransferase of C.t (CtDAP-AT) was considered for drug targeting study, as this organism is solely dependent on this pathway for L-lysine synthesis.…”

“…The third and final step is the conversion of m‐DAP to l ‐lysine reaction which is catalyzed by the enzyme m‐DAP decarboxylase (LysA EC: 4.1.1.20) in DAP/lys pathways. This enzymatic reaction is also common to all four DAP/lys anabolic variants, for the overall detailed enzymatic reaction, refer to Hudson et al and Alexander et al (2014) . Hence, this l ‐Lysine biosynthetic pathways in bacteria and plants have been widely investigated by many groups for drug targeting because of their crucial role in synthesis of PG cell wall in most bacteria and host nonhomology .…”

Cloning, expression, purification, crystallization and X-ray diffraction analysis of dihydrodipicolinate synthase from the human pathogenic bacteriumBartonella henselaestrain Houston-1 at 2.1 Å resolution

“…Therefore, since Lys and DAP are necessary for both PG and protein synthesis, the inhibition of enzymes associated with this pathway will lead to cell death via lysis as a result of the osmotic pressure from the lack of PG (Cox, 1996;Baizman et al, 2000). The lack of protein synthesis would also lead to a bactericidal or bacteriostatic effect since Lys is one of the 20 ubiquitous proteogenic amino acids (Triassi et al, 2014). Therefore, enzymes associated with the DAP/Lys pathway are attractive targets for the development of antibiotics, herbicides and algaecides.…”