Exploration of inhibitors for diaminopimelate aminotransferase

Fan, Chenguang; Clay, Matthew D.; Deyholos, Michael K.; Vederas, John C.

doi:10.1016/j.bmc.2010.02.001

Cited by 31 publications

(20 citation statements)

References 31 publications

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“…Based on ligand bound structures, the binding modes for the substrates have been detailed and such structural detail will be useful for inhibitor design [13]. Indeed, inhibitors for the A. thaliana enzyme have already been reported [14].…”

Section: Introductionmentioning

confidence: 99%

L,L-Diaminopimelate Aminotransferase from Chlamydomonas reinhardtii: A Target for Algaecide Development

2011

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In some bacterial species and photosynthetic cohorts, including algae, the enzyme l,l-diaminopimelate aminotransferase (DapL) (E.C. 2.6.1.83) is involved in the anabolism of the essential amino acid L-lysine. DapL catalyzes the conversion of tetrahydrodipicolinate (THDPA) to l,l-diaminopimelate (l,l-DAP), in one step bypassing the DapD, DapC and DapE enzymatic reactions present in the acyl DAP pathways. Here we present an in vivo and in vitro characterization of the DapL ortholog from the alga Chlamydomonas reinhardtii (Cr-DapL). The in vivo analysis illustrated that the enzyme is able to functionally complement the E. coli dap auxotrophs and was essential for plant development in Arabidopsis. In vitro, the enzyme was able to inter-convert THDPA and l,l-DAP, showing strong substrate specificity. Cr-DapL was dimeric in both solution and when crystallized. The structure of Cr-DapL was solved in its apo form, showing an overall architecture of a α/β protein with each monomer in the dimer adopting a pyridoxal phosphate-dependent transferase-like fold in a V-shaped conformation. The active site comprises residues from both monomers in the dimer and shows some rearrangement when compared to the apo-DapL structure from Arabidopsis. Since animals do not possess the enzymatic machinery necessary for the de novo synthesis of the amino acid l-lysine, enzymes involved in this pathway are attractive targets for the development of antibiotics, herbicides and algaecides.

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Section: Introductionmentioning

confidence: 99%

L,L-Diaminopimelate Aminotransferase from Chlamydomonas reinhardtii: A Target for Algaecide Development

2011

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Section: Inhibitor Studies Of Daplmentioning

confidence: 99%

“…To that end, 29,201 drug-like compounds were screened against the Arabidopsis ortholog (Fan et al, 2010). The IC 50 values of 46 of the compounds were determined based on the fact that they were able to inhibit enzyme activity of at least 13% (Fan et al, 2010). In addition, aryl hydrazide and rhodanine modifications were used for the generation of 20 additional analogs in an attempt to elucidate structure-activity relationship (SAR), which are useful in guiding the development of drugs that could be potential biocides (Fan et al, 2010).…”

Section: Inhibitor Studies Of Daplmentioning

confidence: 99%

“…The IC 50 values of 46 of the compounds were determined based on the fact that they were able to inhibit enzyme activity of at least 13% (Fan et al, 2010). In addition, aryl hydrazide and rhodanine modifications were used for the generation of 20 additional analogs in an attempt to elucidate structure-activity relationship (SAR), which are useful in guiding the development of drugs that could be potential biocides (Fan et al, 2010). One of the compounds identified in the initial screen was an o -sulfonamido-arylhydrazide, which is a reversible inhibitor with an IC 50 ~ 5 μM.…”

Section: Inhibitor Studies Of Daplmentioning

confidence: 99%

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

et al. 2014

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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.

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“…Accordingly, we have been engaged in study of the structure and function of enzymes of lysine biosynthesis from a variety of pathogens (Dobson et al, 2004(Dobson et al, , 2005 Recently, the macromolecular structure of DapL from Arabidopsis was solved via X-ray crystallography (Watanabe et al, 2007(Watanabe et al, , 2008. These structures underpinned the rational design of a range of inhibitors of the DapL enzyme, which have been developed to bind the active site (Fan et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Crystallization and preliminary X-ray diffraction analysis ofL,L-diaminopimelate aminotransferase (DapL) fromChlamydomonas reinhardtii

2010

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In the anabolic synthesis of diaminopimelate and lysine in plants and in some bacteria, the enzyme l,l-diaminopimelate aminotransferase (DapL; EC 2.6.1.83) catalyzes the conversion of tetrahydrodipicolinic acid (THDPA) to l,l-diaminopimelate, bypassing the DapD, DapC and DapE enzymatic steps in the bacterial acyl pathways. Here, the cloning, expression, purification, crystallization and preliminary X-ray diffraction analysis of DapL from the alga Chlamydomonas reinhardtii are presented. Protein crystals were grown in conditions containing 25%(w/v) PEG 3350 and 200 mM lithium sulfate and initially diffracted to $1.35 Å resolution. They belonged to space group P2 1 2 1 2 1 , with unit-cell parameters a = 58.9, b = 91.8, c = 162.9 Å . The data were processed to 1.55 Å resolution with an R merge of 0.081, an R p.i.m. of 0.044, an R r.i.m of 0.093 and a V M of 2.28 Å 3 Da À1.

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Exploration of inhibitors for diaminopimelate aminotransferase

Cited by 31 publications

References 31 publications

L,L-Diaminopimelate Aminotransferase from Chlamydomonas reinhardtii: A Target for Algaecide Development

L,L-Diaminopimelate Aminotransferase from Chlamydomonas reinhardtii: A Target for Algaecide Development

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

Crystallization and preliminary X-ray diffraction analysis ofL,L-diaminopimelate aminotransferase (DapL) fromChlamydomonas reinhardtii

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