Abstract
It has been proven that specific isoforms of human carbonic anhydrase (hCA) are able to fine-tune physiological pathways connected to signal processing, and that decreased CAs expression negatively influences cognition, leading to mental retardation, Alzheimer’s disease, and aging-related cognitive dysfunctions. For this reason, a small library of natural and synthetic nitrogen containing cyclic derivatives was assayed as activators of four human isoforms of carbonic anhydrase (hCA I, II, IV and VII). Most of the compounds activated hCA I, IV and VII in the micromolar range, with KAs ranging between 3.46 and 80.5 μM, whereas they were not active towards hCA II (KAs > 100 μM). Two natural compounds, namely l-(+)-ergothioneine (1) and melatonin (2), displayed KAs towards hCA VII in the nanomolar range after evaluation by a CO2 hydration method in vitro, showing a rather efficient and selective activation profile with respect to histamine, used as a reference compound. Corroborated with the above in vitro findings, a molecular modelling in silico approach has been performed to correlate these biological data, and to elucidate the binding interaction of these activators within the enzyme active site.
Highlights
Carbonic anhydrases (CAs, EC 4.2.1.1) are a large family of zinc-containing metalloenzymes found in prokaryotes and eukaryotes, involved in the reversible conversion of carbon dioxide into bicarbonate and a proton
On the basis of the enzyme-activator adducts and keeping in mind the central nervous system (CNS) distribution of human carbonic anhydrase (hCA) I, II, IV, and VII isozymes, we propose novel chemotypes incorporating all the above mentioned characteristics in five- or six-membered nitrogen containing structures to elicit this peculiar biological activity and to explore the chemical space around these positions
The abundant and cytosolic hCA I isozyme was moderately activated by compounds 3–9 to histamine, whereas compounds 1 and 2 did not affect its enzymatic activity up to 100 μM; (ii) As histamine, all compounds reported in this work were totally inactive against hCA II isozyme, usually abundant in the choroid plexus, oligodendrocytes, astrocytes, myelinated tracts, and myelin sheets; (iii) With regards to the membrane-bound hCA IV isoform located on the luminal surface of cerebral capillaries and within the cortex, the hippocampus and thalamus, compounds 2–9 were poor activators (KA s = 53.4–80.5 μM) and with the same activation profile of histamine in the micromolar range
Summary
Carbonic anhydrases (CAs, EC 4.2.1.1) are a large family of zinc-containing metalloenzymes found in prokaryotes and eukaryotes, involved in the reversible conversion of carbon dioxide into bicarbonate and a proton. The specific activation of this enzyme has been explored in animal models of neurodegenerative or age-related diseases with the aim of proposing new innovative pathways able to contrast cognitive impairment and brain functional loss [1,2,3,4] As evidence of this concept, the management of such pathological conditions in which learning and memory are altered relies on a large plethora of studies demonstrating how neuronal responses, especially in the hippocampus, were strictly modulated by an increased bicarbonate conductance through synaptic GABAA receptor channels and by extracellular signal-regulated kinase (ERK) phosphorylation in the amygdala [5,6].
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