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PDBsum entry 2v35
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References listed in PDB file
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Key reference
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Title
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The efficiency of c-4 substituents in activating the beta-Lactam scaffold towards serine proteases and hydroxide ion.
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Authors
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J.Mulchande,
L.Martins,
R.Moreira,
M.Archer,
T.F.Oliveira,
J.Iley.
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Ref.
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Org Biomol Chem, 2007,
5,
2617-2626.
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PubMed id
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Abstract
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The presence of a leaving group at C-4 of monobactams is usually considered to
be a requirement for mechanism-based inhibition of human leukocyte elastase by
these acylating agents. We report that second-order rate constants for the
alkaline hydrolysis and elastase inactivation by N-carbamoyl monobactams are
independent of the pKa of the leaving group at C-4. Indeed, the effect exerted
by these substituents is purely inductive: electron-withdrawing substituents at
C-4 of N-carbamoyl-3,3-diethylmonobactams increase the rate of alkaline
hydrolysis and elastase inactivation, with Hammett pI values of 3.4 and 2.5,
respectively, which indicate the development of a negative charge in the
transition-states. The difference in magnitude between these pI values is
consistent with an earlier transition-state for the enzymatic reaction when
compared with that for the chemical process. These results suggest that the
rate-limiting step in elastase inactivation is the formation of the tetrahedral
intermediate, and that beta-lactam ring-opening is not concerted with the
departure of a leaving group from C-4. Monobactam sulfones emerged as potent
elastase inhibitors even when the ethyl groups at C-3, required for interaction
with the primary recognition site, are absent. For one such compound, a 1 : 1
enzyme-inhibitor complex involving porcine pancreatic elastase has been examined
by X-ray crystallography and shown to result from serine acylation and sulfinate
departure from the beta-lactam C-4.
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Secondary reference #1
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Title
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Crystallization and preliminary diffraction studies of porcine pancreatic elastase in complex with a novel inhibitor.
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Authors
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T.F.Oliveira,
J.Mulchande,
R.Moreira,
J.Iley,
M.Archer.
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Ref.
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Protein Pept Lett, 2007,
14,
93-95.
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PubMed id
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