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Olfactory receptor neurons in Atlantic salmon (Salmo salar) appear to use a phosphoinositide-directed phospholipase C (PLC) in odorant signal transduction. The consequences of odor-activated PLC depend on its product, inositol 1,4,5-trisphosphate (IP3). Therefore, a plasma membrane rich (PMR) fraction, previously characterized from salmon olfactory rosettes, was used to study binding sites for IP3 and its phosphorylation product, inositol 1,3,4,5-tetrakisphosphate (IP4). Binding sites for IP3 were present at the lower limit for detection in the PMR fraction but were abundant in a microsomal fraction. Binding sites for IP4 were abundant in the PMR fraction and thus colocalized in the same subcellular fraction with odorant receptors for amino acids and bile acids. Binding of IP4 was saturable and high affinity (K d = 83 nM). The rank order for potency of inhibition of IP4 by other inositol polyphosphates (InsP x ) followed the phosphorylation number with InsP6 > InsP5 > other InsP4 isomers > InsP3 isomers > InsP2 isomers, with the latter showing no activity. The consequences of PLC activity in this system may be dictated in part by a putative receptor for IP4.
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The search for selective anticholinergic agents stems from varying cholinesterase levels as Alzheimer’s Disease progresses from the mid-to-late stage and from butyrylcholinesterase’s (BChE) role in β-amyloid plaque formation. While structure-based and pharmacophore-based virtual screening could search from large libraries in a short time, these methods do not consider dynamic features that result from a ligand’s inhibition of the enzyme and consequently may under- or overexaggerate enzyme selectivity of a given ligand. In this computational study, we probed the selectivity of representative secondary metabolite compounds against acetylcholinesterase and BChE through molecular dynamics simulations. The results were evaluated by analysis of the root mean squared deviation of ligand heavy atoms, the radius of gyration of each inhibited and uninhibited enzyme, root mean squared fluctuation of residues, intermolecular interaction energy, and linear interaction energy approximation of the Gibbs free energy of binding. These considerations further reveal the induced-fit characteristics contributing to ChE selectivity that are predominantly due to the greater flexibility of BChE’s active site gorge. © 2025 by the authors.
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Acetylcholinesterase (AChE) inhibitors are the primary target for single-molecule anti-Alzheimer’s disease (AD) therapeutics. Though AChE has historically been the focus of investigation for small-molecule inhibitors, interest in another cholinergic enzyme, butyrylcholinesterase (BChE), has grown in recent years. Attention stems from BChE’s role in β-amyloid (Aβ) protein aggregation and an increase in BChE concentration during the late stages of AD, where a decrease in AChE concentration is also observed. Currently, five FDA-approved drugs are on the market for inhibiting AChE, though no BChE-selective drugs have been approved so far. In this review, we focus on newly identified BChE selective inhibitors and present the ideas behind these discoveries. © 2025 by the authors.
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