Medical implications from the crystal structure of a copper-containing amine oxidase complexed with the antidepressant drug tranylcypromine

Carrie M Wilmot; Colin G. Saysell; Aidan Blessington; Danyl A. Conn; Christian R. Kurtis; Michael J. McPherson; Peter F. Knowles; Simon E.V. Phillips

doi:10.1016/j.febslet.2004.09.031

Medical implications from the crystal structure of a copper-containing amine oxidase complexed with the antidepressant drug tranylcypromine

Carrie M Wilmot, Colin G. Saysell, Aidan Blessington, Danyl A. Conn, Christian R. Kurtis, Michael J. McPherson, Peter F. Knowles, Simon E.V. Phillips

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Abstract

The X-ray crystal structure of the copper-containing quinoprotein amine oxidase from E. coli has been determined in complex with the antidepressant drug tranylcypromine to 2.4 Å resolution. The drug is a racemic mix of two enantiomers, but only one is seen bound to the enzyme. The other enantiomer is not acting as a substrate for the enzyme as no catalytic activity was detected when the enzyme was initially exposed to the drug. The inhibition of human copper amine oxidases could be a source of side-effects in its use as an antidepressant to inhibit the flavin-containing monoamine oxidases in the brain.

Original language	English (US)
Pages (from-to)	301-305
Number of pages	5
Journal	FEBS Letters
Volume	576
Issue number	3
DOIs	https://doi.org/10.1016/j.febslet.2004.09.031
State	Published - Oct 22 2004

Bibliographical note

Funding Information:
This work was supported by a Howard Hughes Medical Institute International Research Scholar award to SEVP, a grant from the UK Biotechnology and Biological Sciences Research Council (BBSRC) and the BBSRC Structural Biology Initiative. The authors thank Veronica Blakeley for preparing the protein, the staff at the Daresbury SRS, particularly Pierre Rizkallah, Brad Elmore for sequence alignments and Arwen Pearson for help with figures. The structure factors and model coordinates have been deposited with the Protein Data Bank, accession code 1LVN.

Keywords

Amine oxidase
Copper metalloprotein
Quinoprotein
Tranylcypromine
X-ray crystallography

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10.1016/j.febslet.2004.09.031

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title = "Medical implications from the crystal structure of a copper-containing amine oxidase complexed with the antidepressant drug tranylcypromine",

abstract = "The X-ray crystal structure of the copper-containing quinoprotein amine oxidase from E. coli has been determined in complex with the antidepressant drug tranylcypromine to 2.4 {\AA} resolution. The drug is a racemic mix of two enantiomers, but only one is seen bound to the enzyme. The other enantiomer is not acting as a substrate for the enzyme as no catalytic activity was detected when the enzyme was initially exposed to the drug. The inhibition of human copper amine oxidases could be a source of side-effects in its use as an antidepressant to inhibit the flavin-containing monoamine oxidases in the brain.",

keywords = "Amine oxidase, Copper metalloprotein, Quinoprotein, Tranylcypromine, X-ray crystallography",

author = "Wilmot, {Carrie M} and Saysell, {Colin G.} and Aidan Blessington and Conn, {Danyl A.} and Kurtis, {Christian R.} and McPherson, {Michael J.} and Knowles, {Peter F.} and Phillips, {Simon E.V.}",

note = "Funding Information: This work was supported by a Howard Hughes Medical Institute International Research Scholar award to SEVP, a grant from the UK Biotechnology and Biological Sciences Research Council (BBSRC) and the BBSRC Structural Biology Initiative. The authors thank Veronica Blakeley for preparing the protein, the staff at the Daresbury SRS, particularly Pierre Rizkallah, Brad Elmore for sequence alignments and Arwen Pearson for help with figures. The structure factors and model coordinates have been deposited with the Protein Data Bank, accession code 1LVN.",

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month = oct,

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doi = "10.1016/j.febslet.2004.09.031",

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AU - Wilmot, Carrie M

AU - Saysell, Colin G.

AU - Blessington, Aidan

AU - Conn, Danyl A.

AU - Kurtis, Christian R.

AU - McPherson, Michael J.

AU - Knowles, Peter F.

AU - Phillips, Simon E.V.

N1 - Funding Information: This work was supported by a Howard Hughes Medical Institute International Research Scholar award to SEVP, a grant from the UK Biotechnology and Biological Sciences Research Council (BBSRC) and the BBSRC Structural Biology Initiative. The authors thank Veronica Blakeley for preparing the protein, the staff at the Daresbury SRS, particularly Pierre Rizkallah, Brad Elmore for sequence alignments and Arwen Pearson for help with figures. The structure factors and model coordinates have been deposited with the Protein Data Bank, accession code 1LVN.

PY - 2004/10/22

Y1 - 2004/10/22

N2 - The X-ray crystal structure of the copper-containing quinoprotein amine oxidase from E. coli has been determined in complex with the antidepressant drug tranylcypromine to 2.4 Å resolution. The drug is a racemic mix of two enantiomers, but only one is seen bound to the enzyme. The other enantiomer is not acting as a substrate for the enzyme as no catalytic activity was detected when the enzyme was initially exposed to the drug. The inhibition of human copper amine oxidases could be a source of side-effects in its use as an antidepressant to inhibit the flavin-containing monoamine oxidases in the brain.

AB - The X-ray crystal structure of the copper-containing quinoprotein amine oxidase from E. coli has been determined in complex with the antidepressant drug tranylcypromine to 2.4 Å resolution. The drug is a racemic mix of two enantiomers, but only one is seen bound to the enzyme. The other enantiomer is not acting as a substrate for the enzyme as no catalytic activity was detected when the enzyme was initially exposed to the drug. The inhibition of human copper amine oxidases could be a source of side-effects in its use as an antidepressant to inhibit the flavin-containing monoamine oxidases in the brain.

KW - Amine oxidase

KW - Copper metalloprotein

KW - Quinoprotein

KW - Tranylcypromine

KW - X-ray crystallography

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SN - 0014-5793

VL - 576

SP - 301

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JO - FEBS Letters

JF - FEBS Letters

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ER -

Medical implications from the crystal structure of a copper-containing amine oxidase complexed with the antidepressant drug tranylcypromine

Abstract

Bibliographical note

Keywords

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