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 language | English (US) |
|---|---|
| Pages (from-to) | 181-186 |
| Number of pages | 6 |
| Journal | Toxicology and Applied Pharmacology |
| Volume | 176 |
| Issue number | 3 |
| DOIs | |
| State | Published - Nov 1 2001 |
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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 journal › Article
}
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.
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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
C2 - 11714250
AN - SCOPUS:0035517097
VL - 176
SP - 181
EP - 186
JO - Toxicology and Applied Pharmacology
JF - Toxicology and Applied Pharmacology
SN - 0041-008X
IS - 3
ER -