High affinity of sigma₁‐binding sites for sterol isomerization inhibitors: evidence for a pharmacological relationship with the yeast sterol C₈–C₇ isomerase

Abstract

1 The sigma-drug binding site of guinea-pig liver is carried by a protein which shares signi®cant amino acid sequence similarities with the yeast sterol C 8 ± C 7 isomerase (ERG2 protein). Pharmacologicallybut not structurally -the sigma 1 -site is also related to the emopamil binding protein, the mammalian sterol C 8 ± C 7 isomerase. We therefore investigated if sterol C 8 ± C 7 isomerase inhibitors are high anity ligands for the (+)-[3 H]-pentazocine labelled sigma 1 -binding site. 2 Among the compounds which bound with high anity to native hepatic and cerebral as well as to yeast expressed sigma 1 -binding sites were the agricultural fungicide fenpropimorph (K i 0.005 nM), the antihypocholesterinaemic drugs triparanol (K i 7.0 nM), AY-9944 (K i 0.46 nM) and MDL28,815 (K i 0.16 nM), the enantiomers of the ovulation inducer clomiphene (K i 5.5 and 12 nM, respectively) and the antioestrogene tamoxifen (K i 26 nM). 3 Except for tamoxifen these anities are essentially identical with those for the [ 3 H]-ifenprodil labelled sterol C 8 ± C 7 isomerase of S. cerevisiae. This demonstrates that sigma 1 -binding protein and yeast isomerase are not only structurally but also pharmacologically related. Because of its aliations with yeast and mammalian sterol isomerases we propose that the sigma 1 -binding site is localized on a sterol isomerase related protein, involved in postsqualene sterol biosynthesis.

Identification of Regions of the σ-1 Receptor Ligand Binding Site Using a Novel Photoprobe

“…Fenpropimorph, a yeast sterol isomerase inhibitor, has been found previously to bind with high affinity to the guinea pig -1 receptor (K i ϭ 0.005 nM) (Moebius et al, 1997). This is perhaps not surprising, because the -1 receptor shows sequence homology with the C8 -C7 yeast sterol isomerase Jbilo et al, 1997;Moebius et al, 1997).…”

“…This is perhaps not surprising, because the -1 receptor shows sequence homology with the C8 -C7 yeast sterol isomerase Jbilo et al, 1997;Moebius et al, 1997).…”

“…The -2 receptor, however, has yet to be cloned. The -1 receptor has 223 amino acids and shares 30% identity and 67% similarity with a yeast sterol C8 -C7 isomerase, which is involved in cholesterol synthesis (Moebius et al, 1997). Unlike this yeast sterol isomerase, however, the -1 receptor does not have any sterol isomerase activity , and it shares no sequence homology with any known mammalian proteins, including the mammalian C8 -C7 sterol isomerase.…”

Biochemical Pharmacology of the Sigma-1 Receptor

“…The S1R shares 60% amino acid identity to a yeast sterol isomerase, ERG2, however, the mammalian S1R does not possess sterol isomerase activity, nor can it rescue the growth of sterol isomerase-deficient yeast (Moebius et al, , 1997. The S1R is a ligand-regulated non-ATP-binding membrane bound chaperone protein (Hayashi and Su, 2007).…”

Intracellular Dynamics of σ-1 Receptors (σ1Binding Sites) in NG108-15 Cells

“…); and 2) what are the translocated -1 receptors doing at the periphery of cells? Because -1 receptors have a high homology to a fungal sterol C8-C7 isomerase (Hanner et al, 1996), some reports speculate that -1 receptors act as an enzyme in cholesterol metabolism (Moebius et al, 1997;Labit-Le Bouteiller et al, 1998). Indeed, a number of enzymes involved in lipid metabolisms are located on the smooth endoplasmic reticulum similar to -1 receptors (Koning et al, 1996;Khelef et al, 1998).…”