Mechanism of inhibition of lysyl hydroxylase activity by the organophosphates malathion and malaoxon

Ana Samimi, Jerold A Last

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Direct inhibition of lysyl hydroxylase by malathion and malaoxon was observed in an in vitro enzyme assay with recombinant lysyl hydroxylase expressed via a baculoviral system. The IC50 values for malathion and malaoxon were estimated to be approximately 60 and 45 mM, respectively. Additional kinetic studies showed this inhibition to be competitive or partially competitive with respect to the synthetic (collagen) peptide, partially uncompetitive with respect to Fe2+, and partially noncompetitive with respect to ascorbic acid. The calculated values for the Ki were consistent with the IC50 values. Allosteric effects were not found for any of the cofactors tested, the peptide substrate, or the inhibitors. Interactions were found to be unimolecular for lysyl hydroxylase and its substrate and cofactors as well as for the inhibitors malathion and malaoxon. A computer search of a protein structure database showed an unexpected region of partial homology between the active site sequence of acetylcholinesterase and a segment of lysyl hydroxylase, suggesting a possible molecular basis for these observations. These results suggest the possibility of a novel and hitherto unexpected class of inhibitors of lysyl hydroxylase, based on the organophosphate structure, that might be of value for testing as antifibrotic drugs.

Original languageEnglish (US)
Pages (from-to)181-186
Number of pages6
JournalToxicology and Applied Pharmacology
Volume176
Issue number3
DOIs
StatePublished - Nov 1 2001

Fingerprint

2-Oxoglutarate 5-Dioxygenase Procollagen-Lysine
Malathion
Organophosphates
Inhibitory Concentration 50
Protein Databases
Peptides
Enzyme Assays
Substrates
Acetylcholinesterase
Ascorbic Acid
Assays
Catalytic Domain
Collagen
malaoxon
Kinetics
Testing
Enzymes
Pharmaceutical Preparations
Proteins

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Mechanism of inhibition of lysyl hydroxylase activity by the organophosphates malathion and malaoxon. / Samimi, Ana; Last, Jerold A.

In: Toxicology and Applied Pharmacology, Vol. 176, No. 3, 01.11.2001, p. 181-186.

Research output: Contribution to journalArticle

@article{79b5456b59884606954b4fa7d36c45db,
title = "Mechanism of inhibition of lysyl hydroxylase activity by the organophosphates malathion and malaoxon",
abstract = "Direct inhibition of lysyl hydroxylase by malathion and malaoxon was observed in an in vitro enzyme assay with recombinant lysyl hydroxylase expressed via a baculoviral system. The IC50 values for malathion and malaoxon were estimated to be approximately 60 and 45 mM, respectively. Additional kinetic studies showed this inhibition to be competitive or partially competitive with respect to the synthetic (collagen) peptide, partially uncompetitive with respect to Fe2+, and partially noncompetitive with respect to ascorbic acid. The calculated values for the Ki were consistent with the IC50 values. Allosteric effects were not found for any of the cofactors tested, the peptide substrate, or the inhibitors. Interactions were found to be unimolecular for lysyl hydroxylase and its substrate and cofactors as well as for the inhibitors malathion and malaoxon. A computer search of a protein structure database showed an unexpected region of partial homology between the active site sequence of acetylcholinesterase and a segment of lysyl hydroxylase, suggesting a possible molecular basis for these observations. These results suggest the possibility of a novel and hitherto unexpected class of inhibitors of lysyl hydroxylase, based on the organophosphate structure, that might be of value for testing as antifibrotic drugs.",
author = "Ana Samimi and Last, {Jerold A}",
year = "2001",
month = "11",
day = "1",
doi = "10.1006/taap.2001.9275",
language = "English (US)",
volume = "176",
pages = "181--186",
journal = "Toxicology and Applied Pharmacology",
issn = "0041-008X",
publisher = "Academic Press Inc.",
number = "3",

}

TY - JOUR

T1 - Mechanism of inhibition of lysyl hydroxylase activity by the organophosphates malathion and malaoxon

AU - Samimi, Ana

AU - Last, Jerold A

PY - 2001/11/1

Y1 - 2001/11/1

N2 - Direct inhibition of lysyl hydroxylase by malathion and malaoxon was observed in an in vitro enzyme assay with recombinant lysyl hydroxylase expressed via a baculoviral system. The IC50 values for malathion and malaoxon were estimated to be approximately 60 and 45 mM, respectively. Additional kinetic studies showed this inhibition to be competitive or partially competitive with respect to the synthetic (collagen) peptide, partially uncompetitive with respect to Fe2+, and partially noncompetitive with respect to ascorbic acid. The calculated values for the Ki were consistent with the IC50 values. Allosteric effects were not found for any of the cofactors tested, the peptide substrate, or the inhibitors. Interactions were found to be unimolecular for lysyl hydroxylase and its substrate and cofactors as well as for the inhibitors malathion and malaoxon. A computer search of a protein structure database showed an unexpected region of partial homology between the active site sequence of acetylcholinesterase and a segment of lysyl hydroxylase, suggesting a possible molecular basis for these observations. These results suggest the possibility of a novel and hitherto unexpected class of inhibitors of lysyl hydroxylase, based on the organophosphate structure, that might be of value for testing as antifibrotic drugs.

AB - Direct inhibition of lysyl hydroxylase by malathion and malaoxon was observed in an in vitro enzyme assay with recombinant lysyl hydroxylase expressed via a baculoviral system. The IC50 values for malathion and malaoxon were estimated to be approximately 60 and 45 mM, respectively. Additional kinetic studies showed this inhibition to be competitive or partially competitive with respect to the synthetic (collagen) peptide, partially uncompetitive with respect to Fe2+, and partially noncompetitive with respect to ascorbic acid. The calculated values for the Ki were consistent with the IC50 values. Allosteric effects were not found for any of the cofactors tested, the peptide substrate, or the inhibitors. Interactions were found to be unimolecular for lysyl hydroxylase and its substrate and cofactors as well as for the inhibitors malathion and malaoxon. A computer search of a protein structure database showed an unexpected region of partial homology between the active site sequence of acetylcholinesterase and a segment of lysyl hydroxylase, suggesting a possible molecular basis for these observations. These results suggest the possibility of a novel and hitherto unexpected class of inhibitors of lysyl hydroxylase, based on the organophosphate structure, that might be of value for testing as antifibrotic drugs.

UR - http://www.scopus.com/inward/record.url?scp=0035517097&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035517097&partnerID=8YFLogxK

U2 - 10.1006/taap.2001.9275

DO - 10.1006/taap.2001.9275

M3 - Article

VL - 176

SP - 181

EP - 186

JO - Toxicology and Applied Pharmacology

JF - Toxicology and Applied Pharmacology

SN - 0041-008X

IS - 3

ER -