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Intermediate analogue inhibitors of mandelate racemase: N-Hydroxyformanilide and cupferron

Jennifer R Bourque1, Rodney K M Burley, Stephen L Bearne

  • 1Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, Nova Scotia, Canada.

Bioorganic & Medicinal Chemistry Letters
|October 24, 2006
PubMed

Insights

Mandelate racemase (MR) enzyme inhibitors were identified. N-hydroxyformanilide and cupferron show potent competitive inhibition, with MR binding N-hydroxyformanilide more effectively in its deprotonated form.

Area of Science:

  • Biochemistry
  • Enzyme kinetics
  • Organic chemistry

Background:

  • Mandelate racemase (MR) is an enzyme crucial for interconverting mandelate enantiomers via 1,1-proton transfer.
  • Understanding enzyme inhibition mechanisms is vital for drug discovery and biochemical research.

Purpose of the Study:

  • To identify and characterize potent inhibitors of Mandelate Racemase (MR).
  • To investigate the binding characteristics of identified inhibitors with MR across different pH levels.

Main Methods:

  • Enzyme inhibition assays were performed to determine inhibitor constants (K(i)).
  • pH-dependent inhibition studies were conducted to analyze binding affinities.

Main Results:

  • N-hydroxyformanilide and cupferron were identified as potent competitive inhibitors of MR, with K(i) values in the microM range.
  • The pH-pK(i) profile revealed that MR exhibits a 10-fold greater affinity for the deprotonated form of N-hydroxyformanilide compared to its protonated form.

Conclusions:

  • N-hydroxyformanilide and cupferron are effective competitive inhibitors of Mandelate Racemase.
  • The pH-dependent binding affinity provides insights into the enzyme's active site characteristics and catalytic mechanism.

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