Richard Hall - Tight Binding Inhibitors of N-Acyl Amino Sugar and N-Acyl Amino Acid Deacetylases

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      Publication Details (including relevant citation   information):

      Xu, Chengfu; Hall, Richard; Cummings, Jennifer; Raushel, Frank   M..  Tight Binding Inhibitors of N-Acyl Amino Sugar and   N-Acyl Amino Acid Deacetylases.    Journal of the   American Chemical Society  (2006),  128(13),    4244-4245.  CODEN: JACSAT  ISSN:0002-7863.  CAN   144:427877  AN 2006:208354    CAPLUS

      Abstract:

      Very potent inhibitors were synthesized for the enzymatic   deacetylation of N-acetyl-d-glucosamine-6-phosphate   (NagA) and N-acetyl-d-glutamate (DGD). The methyl   phosphonamidate derivative of d-glucosamine-6-phosphate bound to   N-acetyl-d-glucosamine-6-phosphate deacetylase with an   equilibrium dissociation constant of 34 ± 5 nM at pH 7.5 and an   association rate constant of 6.1 × 103 M-1  s-1. The inhibition constant is 4000-fold lower than   the Michaelis constant for the substrate   N-acetyl-D-glucosamine-6-phosphate.   N-Acetyl-D-glutamate deacetylase was inhibited by the   methyl phosphonamidate derivative of D-glutamate with an   inhibition constant of 460 ± 70 pM at pH 7.6. The inhibitor bound   to the enzyme 500 000-fold tighter than the Michaelis constant   for N-formyl-D-glutamate. These compounds mimic the   putative tetrahedral intermediate formed upon nucleophilic attack   of an activated water molecule on the amide bond of the target   substrate. These inhibitors should prove useful in the   elucidation of the enzyme−substrate interactions for enzymes   within the amidohydrolase superfamily.

      Address (URL): http://pubs.acs.org/cgi-bin/abstract.cgi/jacsat/2006/128/i13/abs/ja0600680.html