Structural and Kinetics Studies of the Enzyme Dihydropteroate Synthase and the Implications for Antibiotic Resistance

@inproceedings{Ayers2009StructuralAK,
  title={Structural and Kinetics Studies of the Enzyme Dihydropteroate Synthase and the Implications for Antibiotic Resistance},
  author={Katherine A. Ayers},
  year={2009}
}
1 Citations
Substituted N-(Pyrazin-2-yl)benzenesulfonamides; Synthesis, Anti-Infective Evaluation, Cytotoxicity, and In Silico Studies
We prepared a series of substituted N-(pyrazin-2-yl)benzenesulfonamides as an attempt to investigate the effect of different linkers connecting pyrazine to benzene cores on antimicrobial activity

References

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TLDR
The results show that binding of DHPPP and pABA are separate distinguishable events in the reaction cycle, and that mutations which confer resistance to sulfonamide drugs act exclusively on the second step in the binding process.
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TLDR
The Mtb DHPS structure hints at a mechanism in which both loops 1 and 2 play important roles in catalysis by shielding the active site from bulk solvent and allowing pyrophosphoryl transfer to occur and a highly conserved pterin binding pocket that may be exploited for the design of novel antimycobacterial agents.
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TLDR
Remarkably, the corresponding DHPS enzymes show pronounced insensitivity to sulfonamides but normal binding to the p -aminobenzoic acid substrate, despite the close structural similarity between substrate and inhibitor.
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TLDR
Steady-state kinetic parameters for dihydropteroate synthases from both M. tuberculosis and M. leprae were determined, and the antimycobacterial agent p-aminosalicylate, a putative dihydrocarbon synthase inhibitor, was a poor inhibitor of the enzymes.
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TLDR
The crystal structure of E.coli DHPS at 2.0 Å resolution refined to an R-factor of 0.185 is reported, finding the 7,8-dihydropterin pyrophosphate substrate binds in a deep cleft in the barrel, whilst sulfanilamide binds closer to the surface.
Reductive alkylation of lysine residues to alter crystallization properties of proteins.
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