Pharmacological analysis of sterol Δ8=Δ7 isomerase proteins with [3H]fenprodil

Fabian F. Moebius, Raphael J. Reiter, Katrin Bermoser, Hartmut Glossmann, Sang Yun Cho, Young-Ki Paik

Research output: Contribution to journalArticle

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Abstract

Sterol Δ8-Δ7 isomerases (SIs) catalyze the shift of the double bondfrom C8-9 to C7-8 in the B-ring of sterols. Surprisingly, the isoenzymes in fungi (ERG2p) and vertebrates [emopamil binding protein (EBP)] are structurally completely unrelated, whereas the σ1 receptor, a mammalian protein of unknown function, bears significantly similarity with the yeast ERG2p. Here, we compare the drug binding properties of SIs and related proteins with [3H]ifenprodil as a common high affinity radioligand (K(d) = 1.4-19 nM), demonstrating an intimate pharmacological relationship among ERG2p, σ1 receptor, and EBP. This renders SIs a remarkable example for structurally diverse enzymes with similar pharmacological profiles and the propensity to bind drugs from different chemical groups with high affinity. We identified a variety of experimental drugs with nanomolar affinity for the human EBP (K(i) = 0.5-14 nM) such as MDL28815, AY9944, triparanol, and U18666A. These compounds, as well as the fungicide tridemorph and the clinically used drugs tamoxifen, clomiphene, amiodarone, and opipramol, inhibit the in vitro activity of the recombinant human EBP (IC50 = 0.015- 54 μM). The high affinity of the human EBP for 3H-tamoxifen (K(d) = 3 ± 2 nM) implies that the EBP carries the previously described microsomal antiestrogen binding site. Interactions of the EBP with structurally diverse lipophilic amines suggest that novel compounds of related structure should be counterscreened for inhibition of the enzyme to avoid interference with sterol Δ8-Δ7 isomerization.

Original languageEnglish
Pages (from-to)591-598
Number of pages8
JournalMolecular Pharmacology
Volume54
Issue number3
DOIs
Publication statusPublished - 1998 Jan 1

Fingerprint

human EBP protein
Carrier Proteins
Pharmacology
Sterols
Tamoxifen
Pharmaceutical Preparations
trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride
Opipramol
Triparanol
Proteins
Clomiphene
Estrogen Receptor Modulators
Amiodarone
Enzymes
Isoenzymes
Inhibitory Concentration 50
Amines
Vertebrates
Fungi
Yeasts

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

Moebius, Fabian F. ; Reiter, Raphael J. ; Bermoser, Katrin ; Glossmann, Hartmut ; Cho, Sang Yun ; Paik, Young-Ki. / Pharmacological analysis of sterol Δ8=Δ7 isomerase proteins with [3H]fenprodil. In: Molecular Pharmacology. 1998 ; Vol. 54, No. 3. pp. 591-598.
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Moebius, FF, Reiter, RJ, Bermoser, K, Glossmann, H, Cho, SY & Paik, Y-K 1998, 'Pharmacological analysis of sterol Δ8=Δ7 isomerase proteins with [3H]fenprodil', Molecular Pharmacology, vol. 54, no. 3, pp. 591-598. https://doi.org/10.1124/mol.54.3.591

Pharmacological analysis of sterol Δ8=Δ7 isomerase proteins with [3H]fenprodil. / Moebius, Fabian F.; Reiter, Raphael J.; Bermoser, Katrin; Glossmann, Hartmut; Cho, Sang Yun; Paik, Young-Ki.

In: Molecular Pharmacology, Vol. 54, No. 3, 01.01.1998, p. 591-598.

Research output: Contribution to journalArticle

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