Two new irreversible inhibitors of dihydrodipicolinate synthase: diethyl (E,E)-4-oxo-2,5-heptadienedioate and diethyl (E)-4-oxo-2-heptenedioate

Turner, Jennifer; Healy, Jackie P.; Dobson, Renwick C. J.; Gerrard, Juliet A.; Hutton, Craig A.

doi:10.1016/j.bmcl.2004.12.043

Cited by 36 publications

(16 citation statements)

References 10 publications

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“…We are also interested in designing inhibitors of enzymes in the l -lysine biosynthetic pathway [15], [16], [17], [18] based primarily on our knowledge of enzyme function and structure [19], [20], [21], [22], [23], [24]. Here we identify and characterize the first Type I l , l -DAP aminotransferase ortholog from an algae, Chalmydomonas reinhardtii , annotated by the locus tag CHLREDRAFT_129557.…”

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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“…[9,10] DHDPS catalyzes the condensation of pyruvate with l-aspartate-b-semialdehyde (ASA) to form dihydrodipicolinate (Scheme 1), and the enzyme has been well-studied, particularly in a recent series of structure-function studies by Gerrard and coworkers on the DHDPS from E. coli. [11][12][13][14][15][16][17] These studies indicate that DHDPS follows a ping-pong mechanism, in which…”

Section: Introductionmentioning

confidence: 99%

Structural, Functional and Calorimetric Investigation of MosA, a Dihydrodipicolinate Synthase from Sinorhizobium meliloti L5–30, does not Support Involvement in Rhizopine Biosynthesis

et al. 2008

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MosA is an enzyme from Sinorhizobium meliloti L5-30, a beneficial soil bacterium that forms a symbiotic relationship with leguminous plants. MosA was proposed to catalyze the conversion of scyllo-inosamine to 3-O-methyl-scyllo-inosamine (compounds known as rhizopines), despite the MosA sequence showing a strong resemblance to dihydrodipicolinate synthase (DHDPS) sequences rather than to methyltransferases. Our laboratory has already shown that MosA is an efficient catalyst of the DHDPS reaction. Here we report the structure of MosA, solved to 1.95 A resolution, which resembles previously reported DHDPS structures. In this structure Lys161 forms a Schiff base adduct with pyruvate, consistent with the DHDPS mechanism. We have synthesized both known rhizopines and investigated their ability to interact with MosA in the presence and absence of methyl donors. No MosA-catalyzed methyltransferase activity is observed in the presence of scyllo-inosamine and S-adenosylmethionine (SAM). 2-Oxobutyrate can form a Schiff base with MosA, acting as a competitive inhibitor of MosA-catalyzed dihydrodipicolinate synthesis. It can be trapped on the enzyme by reaction with sodium borohydride, but does not act as a methyl donor. The presence of rhizopines does not affect the kinetics of dihydrodipicolinate synthesis. Isothermal titration calorimetry (ITC) shows no apparent interaction of MosA with rhizopines and SAM. Similar experiments with pyruvate as titrant demonstrate that the reversible Schiff base formation is largely entropically driven. This is the first use of ITC to study Schiff base formation between an enzyme and its substrate.

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“…Both the identity, as well as the relative spatial orientation of these functional groups, is conserved among characterized DHDPS enzymes [13]. There have been reports of experimental procedures for designing of inhibitors against DHDPS but no potent inhibitors have been reported till date [22,23]. A few work on virtual screening of pyruvate analogs against DHDPS inhibitors has been reported recently [24], but the present work on molecular docking studies against DHDPS enzyme by 2-methylheptyl isonicotinate (2MHI) produced by Streptomyces sp.…”

Section: Introductionmentioning

confidence: 99%

Molecular Interaction of Novel Compound 2-Methylheptyl Isonicotinate Produced by Streptomyces sp. 201 with Dihydrodipicolinate Synthase (DHDPS) Enzyme of Mycobacterium tuberculosis for its Antibacterial Activity

2012

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Antibiotic resistance is a growing problem in multi-drug-resistant tuberculosis which is caused by Mycobacterium tuberculosis (MTB). Hence there is an urgent need for designing or developing a novel or potent anti-tubercular agent. The Lysine/DAP biosynthetic pathway is a promising target because of its role in cell wall and amino acid biosynthesis. In our study we performed a molecular docking analysis of a novel antibacterial isolated from Streptomyces sp. 201 at three different binding site of dihydrodipicolinate synthase (DHDPS) enzyme of MTB. The molecular docking studies suggest that the novel molecule shows favourable interaction at the three different binding sites as compared to five experimentally known inhibitors of DHDPS.

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Two new irreversible inhibitors of dihydrodipicolinate synthase: diethyl (E,E)-4-oxo-2,5-heptadienedioate and diethyl (E)-4-oxo-2-heptenedioate

Cited by 36 publications

References 10 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

Structural, Functional and Calorimetric Investigation of MosA, a Dihydrodipicolinate Synthase from Sinorhizobium meliloti L5–30, does not Support Involvement in Rhizopine Biosynthesis

Molecular Interaction of Novel Compound 2-Methylheptyl Isonicotinate Produced by Streptomyces sp. 201 with Dihydrodipicolinate Synthase (DHDPS) Enzyme of Mycobacterium tuberculosis for its Antibacterial Activity

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