Inhibiting dihydrodipicolinate synthase across species: Towards specificity for pathogens?

Mitsakos, Voula; Dobson, Renwick C. J.; Pearce, F. Grant; Devenish, Sean R. A.; Evans, G.L.; Burgess, Benjamin R.; Perugini, Matthew A.; Gerrard, Juliet A.; Hutton, Craig A.

doi:10.1016/j.bmcl.2007.11.026

Cited by 42 publications

(39 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Here, relaxation of conformational strain in the Ile203 peptide bond may provide free energy to lower the activation-energy barrier to cyclization. However, inspection of the active site indicates that there is very little space, if any, to achieve cyclization of this intermediate species, consistent with observations that putative cyclic analogs (such as piperidine ester [Mitsakos et al 2008]) inhibit DHDPS very poorly. If cyclization occurs off-enzyme, then water is the likely nucleophile to break the pyruvyl-Lys161 Figure 6.…”

Section: Mechanistic Consequences Of This Distortionsupporting

confidence: 79%

Conserved main‐chain peptide distortions: A proposed role for Ile203 in catalysis by dihydrodipicolinate synthase

et al. 2008

Self Cite

View full text Add to dashboard Cite

In recent years, dihydrodipicolinate synthase (DHDPS, E.C. 4.2.1.52) has received considerable attention from a mechanistic and structural viewpoint. DHDPS catalyzes the reaction of (S)-aspartate-b-semialdehyde with pyruvate, which is bound via a Schiff base to a conserved active-site lysine (Lys161 in the enzyme from Escherichia coli). To probe the mechanism of DHDPS, we have studied the inhibition of E. coli DHDPS by the substrate analog, b-hydroxypyruvate. The K i was determined to be 0.21 (60.02) mM, similar to that of the allosteric inhibitor, (S)-lysine, and b-hydroxypyruvate was observed to cause timedependent inhibition. The inhibitory reaction with b-hydroxypyruvate could be qualitatively followed by mass spectrometry, which showed initial noncovalent adduct formation, followed by the slow formation of the covalent adduct. It is unclear whether b-hydroxypyruvate plays a role in regulating the biosynthesis of meso-diaminopimelate and (S)-lysine in E. coli, although we note that it is present in vivo. The crystal structure of DHDPS complexed with b-hydroxypyruvate was solved. The active site clearly showed the presence of the inhibitor covalently bound to the Lys161. Interestingly, the hydroxyl group of bhydroxypyruvate was hydrogen-bonded to the main-chain carbonyl of Ile203. This provides insight into the possible catalytic role played by this peptide unit, which has a highly strained torsion angle (v ;201°). A survey of the known DHDPS structures from other organisms shows this distortion to be a highly conserved feature of the DHDPS active site, and we propose that this peptide unit plays a critical role in catalysis.Keywords: dihydrodipicolinate synthase; lysine biosynthesis; conserved peptide distortion; X-ray crystallography Abbreviations: HTPA, (4S)-4-hydroxy-2,3,4,5-tetrahydro-(2S)-dipicolinic acid; DHDPS, dihydrodipicolinate synthase; DHDPR, dihydrodipicolinate reductase; (S)-ASA, (S)-aspartate-bsemialdehyde; DAP, meso-diaminopimelate; MS, mass spectrometry.Article and publication are at

show abstract

Section: Mechanistic Consequences Of This Distortionsupporting

confidence: 79%

Conserved main‐chain peptide distortions: A proposed role for Ile203 in catalysis by dihydrodipicolinate synthase

et al. 2008

Self Cite

View full text Add to dashboard Cite

show abstract

“…201 was generated using Cambridge Soft ChemOffice 2010 [25]. Additionally we also generated five experimentally known inhibitors i.e., dimethyl-1,4-dihydro-4-oxopyridine-2.6-dicarboxylate, piperidine-2,6-dicarboxylic acid, 1,4-dihydro-4-oxopyridine-2, 6-dicarboxylic acid, dimethylpiperidine-2,6-dicarboxylate, pyridine-2,6-dicarboxylic acid of MTb DHDPS, inhibiting the enzyme activity in the range of 24-84% [26] for validation purpose. The energy of the generated chemical structures was minimized using MM2 force field methods [27] and save as SYBL mol2 files.…”

Section: Generation Of Chemical Structuresmentioning

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

View full text Add to dashboard Cite

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.

show abstract

“…More success was achieved with inhibitors based on the acyclic enzyme-bound DHDPS intermediates, such as diethyl (E,E)-4-oxo-2,5-heptadienedioate ) and a bis-oxime ester (Boughton et al, 2008), which irreversibly inhibit DHDPS. Interestingly, several of these compounds have displayed clear differentiation in inhibition of DHDPS enzymes from different species (Mitsakos et al, 2008), suggesting the potential for targeting compounds to specific pathogens.…”

Section: Inhibition Of Dhdpsmentioning

confidence: 99%

“…1), yields the important metabolites meso-2,6-diaminopimelate (meso-DAP) and lysine. Lysine is utilised for protein synthesis in bacteria and forms part of the peptidoglycan cross-link structure in the cell wall of most Gram-positive species; whilst meso-DAP is the peptidoglycan cross-linking moiety in the cell wall of Gram-negative bacteria and also Gram-positive Bacillus species Mitsakos et al, 2008;Voss et al, 2010) (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

Enzymology of Bacterial Lysine Biosynthesis

Dogovski¹,

Atkinson²,

Dommaraju³

et al. 2012

Biochemistry

View full text Add to dashboard Cite

Inhibiting dihydrodipicolinate synthase across species: Towards specificity for pathogens?

Cited by 42 publications

References 20 publications

Conserved main‐chain peptide distortions: A proposed role for Ile203 in catalysis by dihydrodipicolinate synthase

Conserved main‐chain peptide distortions: A proposed role for Ile203 in catalysis by dihydrodipicolinate synthase

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

Enzymology of Bacterial Lysine Biosynthesis

Contact Info

Product

Resources

About