Cited by 70Metal-Catalyzed Oxygenation MechanismsInflammatory mediators and NSAID effectsEicosanoids and Hypertension Pharmacology

The Environment of the Lipoxygenase Iron Binding Site Explored with Novel Hydroxypyridinone Iron Chelators

Open access
Abeysinghe, Rajeewa D., Roberts, Pamela J., Cooper, Chris E., MacLean, Kirsteen H., Hider, Robert C., Porter, John B.·1996·Journal of Biological Chemistry

Abstract

The mechanisms of lipoxygenase inhibition by iron chelators have been investigated in human neutrophils and in isolated soybean lipoxygenase. Their Fe(III)-containing active sites have been targeted by synthesizing novel bidentate chelators from the hydroxypyridinone family sufficiently small to gain access through the hydrophobic channels of lipoxygenase. In stimulated human neutrophils, release of [3H]arachidonate-labeled eicosanoids is dependent on the lipid solubility of hydroxypyridinones, but larger hexadentate chelators have no effect on this or on total cellular leukotriene B4 production. Lipophilic hydroxypyridinones inhibit 5-lipoxygenase at equivalent concentrations to the established inhibitor, piriprost, and show additional but minor anti-phospholipase A2 activity. Soybean 15-lipoxygenase inhibition is also dependent on the lipid solubility and coordination structure of chelators. Inhibition is associated with the formation of chelate-iron complexes, which are removed by dialysis without restoration of enzyme activity. Only after adding back iron is activity restored. Electron paramagnetic resonance studies show the removal of the iron center signal (g = 6) is concomitant with formation of Fe(III)-chelator complexes, identical in spectral shape and g value to 3:1 hydroxypyridinone Fe(III) complexes. Removal of iron is not the only mechanism by which hydroxypyridinones can inhibit lipoxygenase in intact cells, however, as a lipophilic non-iron-binding hydroxypyridinone, which shows no inhibition of the soybean lipoxygenase activity, partially inhibits 5-lipoxygenase in intact neutrophils without inhibiting neutrophil phospholipase A2.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1074/jbc.271.14.7965

Cites

38 of 38 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Harrison, P. M., Clegg, G. A., and May, K. (1980) in Iron in Biochemistry and Medicine II (Jacobs, A., and Worwood, M., eds) pp. 131-171, Academic Press, London

Cited by

Sorted by citations

Authors
Abeysinghe, R. D., Roberts, P. J., Cooper, C. E., MacLean, K. H., Hider, R. C., & Porter, J. B.
Affiliations
  • University College London (GB)
  • King's College London (GB)
Corresponding author
Porter, John B.
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
1996-04
Volume
271
Issue
14
Pages
7965-7972
ISSN
0021-9258 (ISSN-L)
OpenAlex
W2031699532
Cited by
70
References
38
Citations by year
2026: 4 · 2025: 2 · 2023: 3 · 2022: 1 · 2021: 1 · 2020: 1 · 2019: 2 · 2018: 3 · 2017: 2 · 2016: 2 · 2014: 1 · 2013: 3 · 2012: 4
FWCI
2.15
Type
journal article
Language
en
Open access
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
Funders
  • University College London
  • National Institutes of Health (5r01hl042800-03)
  • Medical Research Council
  • Menzies Centre for Australian Studies, King's College London, University of London
  • National Heart, Lung, and Blood Institute (R01-HL-42800-01)
Topics
  • Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
  • Health Sciences › Medicine › Pharmacology › Inflammatory mediators and NSAID effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Eicosanoids and Hypertension Pharmacology
Keywords
lipoxygenase inhibition, 5-lipoxygenase, 15-lipoxygenase, human neutrophils, soybean lipoxygenase, iron binding sites, eicosanoid release, leukotriene B4, phospholipase A2, electron spin resonance, lipid solubility, anti-inflammatory agents
MeSH terms
Electron Spin Resonance Spectroscopy, Humans, Iron, Iron Chelating Agents, Ligands, Lipoxygenase, Neutrophils, Phospholipases A, Pyridones, Solubility, Glycine max, Superoxides, Lipoxygenase Inhibitors, Phospholipases A2

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review