Grayanotoxin III (GTX3) was investigated for inhibition of all catalytically active mammalian carbonic anhydrase (CA, EC 4.2.1.1) isoforms, i.e. CA I to CA XIV. It showed micromolar inhibition (KIs of 8.01 and 6.13 µM) for cytosolic isoforms CA I and II, respectively. GTX3 showed a submicromolar inhibition (KIs in the range of 0.51-2.15 µM) for the remaining cytosolic (CA III, VII and XIII), membrane-associated/transmembrane (CA IV, IX, XII and XIV), mitochondrial (CA VA and CA VB) and secreted (CA VI) isoforms. This inhibition profile is very different from that of the sulfonamide CA inhibitors (CAIs), which possess different clinical applications. A molecular docking study for GTX3 within the active sites of CA I and II assisted to the understanding of molecular mechanism of the ligand. The interesting inhibition profile, coupled with various possibilities of interacting with the enzyme active site make this family of natural compounds attractive leads for designing novel chemotypes acting as CAIs.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.3109/14756366.2013.804072 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Basic Science and Pathogenesis.
Alzheimers Dement
December 2024
Alzheimer's Center at Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA.
Background: FDA-approved carbonic anhydrase inhibitors (CAIs) have been shown to attenuate Aβ pathology, neurodegeneration, and cerebrovascular dysfunction in models of Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA), suggesting a key role for CAs as a novel and previously unexplored target for AD therapy. Amyloid β accumulation severely impairs the cerebral neuro-signaling pathway with a progressive loss in neurotrophic factors (NTFs, i.e.
View Article and Find Full Text PDFBasic Science and Pathogenesis.
Alzheimers Dement
December 2024
Alzheimer's Center at Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA.
Background: Brain endothelial cell (EC) stress, including that induced by vascular amyloid β (Aβ) deposits in cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD), contributes to cerebral blood flow impairment, blood brain barrier (BBB) damage, neurovascular unit dysfunction, microhemorrhages and hypoperfusion, precipitating neurodegeneration and neuroinflammation processes. Epidemiological and experimental evidence suggests that hyperhomocysteinemia (Hhcy) contributes to increasing AD risk as well as CAA pathology. However, the cellular and molecular mechanisms through which Aβ and Hhcy drive EC and BBB dysfunction, whether the molecular effects of these challenges are additive or independent, and possible therapeutic strategies, remain to be determined.
View Article and Find Full Text PDFBasic Science and Pathogenesis.
Alzheimers Dement
December 2024
Alzheimer's Center at Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA.
Background: Alzheimer's disease (AD) is characterized- at both early and late stages- by neurovascular impairment. In AD, dysfunctional cerebral microvasculature is accompanied by an inflammatory response, contributing to Aβ and tau accumulation, brain cell stress and death, impaired clearance of metabolic waste, BBB permeability, and ultimately leading to neuronal demise and cognitive impairment. We previously showed that Aβ peptides induce mitochondrial dysregulation and caspase-mediated apoptosis in brain cells, including endothelial, glial, and smooth muscle cells.
View Article and Find Full Text PDFBasic Science and Pathogenesis.
Alzheimers Dement
December 2024
Alzheimer's Center at Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA.
Background: Over the years, Alzheimer's Disease (AD) has been identified as a multifactorial disease, with cerebral vascular dysfunction being one of the most common and early pathological features. Vascular risk factors (VRF) are thought to further increase AD risk and pathology. Cerebral Amyloid Angiopathy (CAA) is defined as the accumulation of amyloid-beta (Aβ) on the vascular wall.
View Article and Find Full Text PDFDepsides from Origanum dictamnus and Satureja pilosa as selective inhibitors of carbonic anhydrases: Isolation, structure elucidation, X-ray crystallography.
Arch Pharm (Weinheim)
January 2025
Laboratory of Pharmacognosy, Department of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki, Greece.
In this study, four depsides were isolated from Origanum dictamnus L. and Satureja pilosa Velen. medicinal plants and their structures were assessed by means of one-dimensional (1D)- and two-dimensional (2D)-nuclear magnetic resonance, high resolution mass spectrometry, and electronic circular dichroism analyses.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!