Structure-reactivity relationships in the inactivation of elastase by β-sultams

Paul S. Hinchliffe, J. Matthew Wood, Andrew M. Davis, Rupert P. Austin, R. Paul Beckett, Michael I. Page

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

N-Acyl-β-sultams are time dependent irreversible active site directed inhibitors of elastase. The rate of inactivation is first order with respect to β-sultam concentration and the second order rate constants show a similar dependence on pH to that for the hydrolysis of a peptide substrate. Inactivation is due to the formation of a stable 1:1 enzyme inhibitor complex as a result of the active site serine being sulfonylated by the β-sultam. Ring opening of the β-sultam occurs by S-N fission in contrast to the C-N fission observed in the acylation of elastase by N-acylsulfonamides. Structure-activity effects are compared between sulfonylation of the enzyme and alkaline hydrolysis. Variation in 4-alkyl and N-substituted β-sultams causes differences in the rates of inactivation by 4 orders of magnitude.

Original languageEnglish
Pages (from-to)67-80
Number of pages14
JournalOrganic and Biomolecular Chemistry
Volume1
Issue number1
Early online date27 Nov 2002
DOIs
Publication statusPublished - 7 Jan 2003

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Pancreatic Elastase
deactivation
reactivity
fission
hydrolysis
enzyme inhibitors
acylation
Hydrolysis
Catalytic Domain
inhibitors
peptides
enzymes
Acylation
Enzyme Inhibitors
causes
rings
Serine
Rate constants
naphthosultone
Peptides

Cite this

Hinchliffe, P. S., Wood, J. M., Davis, A. M., Austin, R. P., Beckett, R. P., & Page, M. I. (2003). Structure-reactivity relationships in the inactivation of elastase by β-sultams. Organic and Biomolecular Chemistry, 1(1), 67-80. https://doi.org/10.1039/b208079f
Hinchliffe, Paul S. ; Wood, J. Matthew ; Davis, Andrew M. ; Austin, Rupert P. ; Beckett, R. Paul ; Page, Michael I. / Structure-reactivity relationships in the inactivation of elastase by β-sultams. In: Organic and Biomolecular Chemistry. 2003 ; Vol. 1, No. 1. pp. 67-80.
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Hinchliffe, PS, Wood, JM, Davis, AM, Austin, RP, Beckett, RP & Page, MI 2003, 'Structure-reactivity relationships in the inactivation of elastase by β-sultams', Organic and Biomolecular Chemistry, vol. 1, no. 1, pp. 67-80. https://doi.org/10.1039/b208079f

Structure-reactivity relationships in the inactivation of elastase by β-sultams. / Hinchliffe, Paul S.; Wood, J. Matthew; Davis, Andrew M.; Austin, Rupert P.; Beckett, R. Paul; Page, Michael I.

In: Organic and Biomolecular Chemistry, Vol. 1, No. 1, 07.01.2003, p. 67-80.

Research output: Contribution to journalArticle

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