Acylation versus sulfonylation in the inhibition of elastase by 3-oxo-β-sultams

W.Y. Tsang, N. Ahmed, L.P. Harding, K. Hemming, A.P. Laws, M.I. Page

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

β-Sultams are the sulfonyl analogues of β-lactams, and 3-oxo-β-sultams are both β-lactams and β-sultams and, therefore, susceptible to nucleophilic attack at either the acyl or the sulfonyl center. They are novel inactivators of serine enzymes. The second-order rate constant for the inactivation of elastase at pH 6 by N-benzyl-4,4-dimethyl-3-oxo-β-sultam is 768 M-1 s-1, which is 103-fold greater than that with N-benzoyl β-sultam. However, in contrast to N-acyl β-sultams, which sulfonylate the active site serine residue to form a sulfonate ester, 3-oxo-β-sultams inhibit the enzyme by acylation followed by slow deacylation to regenerate the active enzyme.
Original languageEnglish
Pages (from-to)8946-8947
Number of pages2
JournalJournal of the American Chemical Society
Volume127
Issue number25
DOIs
Publication statusPublished - 1 Jun 2005

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Acylation
Pancreatic Elastase
Enzymes
Lactams
Rate constants
Esters
Serine
naphthosultone
Catalytic Domain

Cite this

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title = "Acylation versus sulfonylation in the inhibition of elastase by 3-oxo-β-sultams",
abstract = "β-Sultams are the sulfonyl analogues of β-lactams, and 3-oxo-β-sultams are both β-lactams and β-sultams and, therefore, susceptible to nucleophilic attack at either the acyl or the sulfonyl center. They are novel inactivators of serine enzymes. The second-order rate constant for the inactivation of elastase at pH 6 by N-benzyl-4,4-dimethyl-3-oxo-β-sultam is 768 M-1 s-1, which is 103-fold greater than that with N-benzoyl β-sultam. However, in contrast to N-acyl β-sultams, which sulfonylate the active site serine residue to form a sulfonate ester, 3-oxo-β-sultams inhibit the enzyme by acylation followed by slow deacylation to regenerate the active enzyme.",
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Acylation versus sulfonylation in the inhibition of elastase by 3-oxo-β-sultams. / Tsang, W.Y.; Ahmed, N.; Harding, L.P.; Hemming, K.; Laws, A.P.; Page, M.I.

In: Journal of the American Chemical Society, Vol. 127, No. 25, 01.06.2005, p. 8946-8947.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Acylation versus sulfonylation in the inhibition of elastase by 3-oxo-β-sultams

AU - Tsang, W.Y.

AU - Ahmed, N.

AU - Harding, L.P.

AU - Hemming, K.

AU - Laws, A.P.

AU - Page, M.I.

N1 - cited By 33

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AB - β-Sultams are the sulfonyl analogues of β-lactams, and 3-oxo-β-sultams are both β-lactams and β-sultams and, therefore, susceptible to nucleophilic attack at either the acyl or the sulfonyl center. They are novel inactivators of serine enzymes. The second-order rate constant for the inactivation of elastase at pH 6 by N-benzyl-4,4-dimethyl-3-oxo-β-sultam is 768 M-1 s-1, which is 103-fold greater than that with N-benzoyl β-sultam. However, in contrast to N-acyl β-sultams, which sulfonylate the active site serine residue to form a sulfonate ester, 3-oxo-β-sultams inhibit the enzyme by acylation followed by slow deacylation to regenerate the active enzyme.

U2 - 10.1021/ja050787z

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