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.

LanguageEnglish
Pages67-80
Number of pages14
JournalOrganic and Biomolecular Chemistry
Volume1
Issue number1
Early online date27 Nov 2002
DOIs
Publication statusPublished - 7 Jan 2003

Fingerprint

Pancreatic Elastase
deactivation
reactivity
fission
hydrolysis
enzyme inhibitors
acylation
Hydrolysis
Catalytic Domain
inhibitors
peptides
enzymes
Acylation
Enzyme Inhibitors
causes
rings
Serine
Rate constants
beta-sultam
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.
@article{dbbada8014f849adb7e77cf452066420,
title = "Structure-reactivity relationships in the inactivation of elastase by β-sultams",
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.",
author = "Hinchliffe, {Paul S.} and Wood, {J. Matthew} and Davis, {Andrew M.} and Austin, {Rupert P.} and Beckett, {R. Paul} and Page, {Michael I.}",
year = "2003",
month = "1",
day = "7",
doi = "10.1039/b208079f",
language = "English",
volume = "1",
pages = "67--80",
journal = "Organic and Biomolecular Chemistry",
issn = "1477-0520",
publisher = "Royal Society of Chemistry",
number = "1",

}

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

TY - JOUR

T1 - Structure-reactivity relationships in the inactivation of elastase by β-sultams

AU - Hinchliffe, Paul S.

AU - Wood, J. Matthew

AU - Davis, Andrew M.

AU - Austin, Rupert P.

AU - Beckett, R. Paul

AU - Page, Michael I.

PY - 2003/1/7

Y1 - 2003/1/7

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0043281507&partnerID=8YFLogxK

U2 - 10.1039/b208079f

DO - 10.1039/b208079f

M3 - Article

VL - 1

SP - 67

EP - 80

JO - Organic and Biomolecular Chemistry

T2 - Organic and Biomolecular Chemistry

JF - Organic and Biomolecular Chemistry

SN - 1477-0520

IS - 1

ER -