Multiple Binding Modes of Inhibitors to Human Carbonic Anhydrases: An Update on the Design of Isoform-Specific Modulators of Activity.

Human carbonic anhydrases (hCAs) are widespread zinc enzymes that catalyze the hydration of CO to bicarbonate and a proton. Currently, 15 isoforms have been identified, of which only 12 are catalytically active. Given their involvement in numerous physiological and pathological processes, hCAs are recognized therapeutic targets for the development of inhibitors with biomedical applications.

Optimisation of quality features of new wheat beers fermented through sequential inoculation of non- yeasts.

The choice of the starchy ingredients as well as that of the yeasts strongly can represent a useful tool to differentiate the final beers. Our research investigated twelve white beers obtained applying a 2-factor mixed 3-level/4-level experimental design. The first factor was the cereal mixture, with 3 combinations of barley malt (65 %) and unmalted wheat (35 % of common, durum, or emmer).

Discovery of a novel series of potent carbonic anhydrase inhibitors with selective affinity for μ Opioid receptor for Safer and long-lasting analgesia.

In this study, we investigated the development of dual-targeted ligands that bind to both μ-opioid receptor (MOR) and carbonic anhydrase (CA) enzymes, using fentanyl structure as a template. We synthesized and evaluated 21 novel compounds with dual-targeted affinity identifying the lead candidate compound 8, showing selective affinity for MOR and potent inhibition of several cytosolic CA isoforms. By means of repeated treatment of 3 daily administrations for 17 days, fentanyl (0.

Assessment of the impact of unmalted cereals, hops, and yeast strains on volatolomic and olfactory profiles of Blanche craft beers: A chemometric approach.

This study investigated the impact of changes in craft beer formulation, by modifying the unmalted cereal [(durum (Da) and soft (Ri) wheat), emmer (Em)], hops [Cascade (Ca) and Columbus (Co)], and yeast strains [M21 (Wi) - M02 (Ci)], on volatolomic, acidic, and olfactory profiles. Olfactory attributes were evaluated by the trained panel. Volatolomic and acidic profiles were determined by GC-MS.

Functional Bread Produced in a Circular Economy Perspective: The Use of Brewers' Spent Grain.

Brewers' spent grain (BSG) is the main by-product of the brewing industry, corresponding to ~85% of its solid residues. The attention of food technologists towards BSG is due to its content in nutraceutical compounds and its suitability to be dried, ground, and used for bakery products. This work was aimed to investigate the use of BSG as a functional ingredient in bread-making.

Quality control on digital cancer registration.

Population-based cancer registration methods are subject to internationally-established rules. To ensure efficient and effective case recording, population-based cancer registries widely adopt digital processing (DP) methods. At the Veneto Tumor Registry (RTV), about 50% of all digitally-identified (putative) cases of cancer are further profiled by means of registrars' assessments (RAs).

α-CAs from Photosynthetic Organisms.

Carbonic anhydrases (CAs) are ubiquitous enzymes that catalyze the reversible carbon dioxide hydration reaction. Among the eight different CA classes existing in nature, the α-class is the largest one being present in animals, bacteria, protozoa, fungi, and photosynthetic organisms. Although many studies have been reported on these enzymes, few functional, biochemical, and structural data are currently available on α-CAs isolated from photosynthetic organisms.

Biochemical, structural, and computational studies of a γ-carbonic anhydrase from the pathogenic bacterium .

Melioidosis is a severe disease caused by the highly pathogenic gram-negative bacterium . Several studies have highlighted the broad resistance of this pathogen to many antibiotics and pointed out the pivotal importance of improving the pharmacological arsenal against it. Since γ-carbonic anhydrases (γ-CAs) have been recently introduced as potential and novel antibacterial drug targets, in this paper, we report a detailed characterization of BpsγCA, a γ-CA from .

Biochemical and Structural Insights into the Winged Helix Domain of P150, the Largest Subunit of the Chromatin Assembly Factor 1.

The Chromatin Assembly Factor 1 is a heterotrimeric complex responsible for the nucleosome assembly during DNA replication and DNA repair. In humans, the largest subunit P150 is the major actor of this process. It has been recently considered as a tumor-associated protein due to its overexpression in many malignancies.

Post-translational modifications in tumor-associated carbonic anhydrases.

Human carbonic anhydrases IX (hCA IX) and XII (hCA XII) are two proteins associated with tumor formation and development. These enzymes have been largely investigated both from a biochemical and a functional point of view. However, limited data are currently available on the characterization of their post-translational modifications (PTMs) and the functional implication of these structural changes in the tumor environment.

Design, synthesis and biochemical evaluation of novel carbonic anhydrase inhibitors triggered by structural knowledge on hCA VII.

To tackle the challenge of isoform selectivity, we explored the entrance of the cavity for selected druggable human Carbonic Anhydrases (hCAs). Based on X-ray crystallographic studies on the 4-(4-(2-chlorobenzoyl)piperazine-1-carbonyl)benzenesulfonamide in complex with the brain expressed hCA VII (PDB code: 7NC4), a series of 4-(4(hetero)aroylpiperazine-1-carbonyl)benzene-1-sulfonamides has been developed. To evaluate their capability to fit the hCA VII catalytic cavity, the newer benzenesulfonamides were preliminary investigated by means of docking simulations.

Colorectal cancer incidence and mortality after negative fecal immunochemical tests by age 70: A prospective observational study.

Limited endoscopy capacity usually represents the main barrier to the extension of screening to subjects older than 70, given the high positivity rate in this age group. We assessed CRC incidence and mortality by number of previous negative fecal immunochemical tests (FIT) among subjects turning 70. We selected persons aged 70 years who had received their last screening invitation when they were 68 or 69 years old within the population-based screening program in the Veneto region of Italy.

Inhibition of the β-carbonic anhydrase from the protozoan pathogen with sulphonamides.

Sulphonamides and their isosteres are classical inhibitors of the carbonic anhydrase (CAs, EC 4.2.1.

Inhibition of the newly discovered β‑carbonic anhydrase from the protozoan pathogen Trichomonas vaginalis with inorganic anions and small molecules.

The protozoan pathogen Trichomonas vaginalis encodes two carbonic anhydrases (CAs, EC 4.2.1.

Human carbonic anhydrases and post-translational modifications: a hidden world possibly affecting protein properties and functions.

Human carbonic anhydrases (CAs) have become a well-recognized target for the design of inhibitors and activators with biomedical applications. Accordingly, an enormous amount of literature is available on their biochemical, functional and structural aspects. Nevertheless post-translational modifications (PTMs) occurring on these enzymes and their functional implications have been poorly investigated so far.

Biochemical and structural characterisation of a protozoan beta-carbonic anhydrase from .

We report the biochemical and structural characterisation of a beta-carbonic anhydrase (β-CA) from , a unicellular parasite responsible for one of the world's leading sexually transmitted infections, trichomoniasis. CAs are ubiquitous metalloenzymes belonging to eight evolutionarily divergent groups (α, β, γ, δ, ζ, η, θ, and ι); humans express only α-CAs, whereas many clinically significant pathogens express only β- and/or γ-CAs. For this reason, the latter two groups of CAs are promising biomedical targets for novel antiinfective agents.

Looking toward the Rim of the Active Site Cavity of Druggable Human Carbonic Anhydrase Isoforms.

We report the synthesis and biochemical evaluation of a series of substituted 4-(4-aroylpiperazine-1-carbonyl)benzenesulfonamides (-) developed as inhibitors of druggable carbonic anhydrase (CA) isoforms, as tools for the identification of new therapeutics. X-ray crystallography confirmed that this class of benzenesulfonamides binds CAs through the canonical anchoring of the benzenesulfonamide moiety to the metal ion and a recognition of the middle/top area of the active site cavity. Compound (R = 2-Cl) demonstrated relevant selectivity toward brain-expressed hCA VII.

Exploration of the residues modulating the catalytic features of human carbonic anhydrase XIII by a site-specific mutagenesis approach.

Carbonic anhydrases (CAs) are ubiquitous metallo-enzymes that catalyse the reversible hydration of carbon dioxide to bicarbonate and proton. In humans there are 15 isoforms among which only 12 are catalytically active. Since active human (h) CAs show different efficiency, the understanding of the molecular determinants affecting it is a matter of debate.

Exploring benzoxaborole derivatives as carbonic anhydrase inhibitors: a structural and computational analysis reveals their conformational variability as a tool to increase enzyme selectivity.

Recent studies identified the benzoxaborole moiety as a new zinc-binding group able to interact with carbonic anhydrase (CA) active site. Here, we report a structural analysis of benzoxaboroles containing urea/thiourea groups, showing that these molecules are very versatile since they can bind the enzyme assuming different binding conformations and coordination geometries of the catalytic zinc ion. In addition, theoretical calculations of binding free energy were performed highlighting the key role of specific residues for protein-inhibitor recognition.

Exploring structural properties of potent human carbonic anhydrase inhibitors bearing a 4-(cycloalkylamino-1-carbonyl)benzenesulfonamide moiety.

Guided by the crystal structure of 4-(3,4-dihydroquinolin-1(2H)-ylcarbonyl)benzenesulfonamide 3 in complex with hCA II (PDB code 4Z0Q), a novel series of cycloalkylamino-1-carbonylbenzenesulfonamides was designed and synthesized. Thus, we replaced the quinoline ring with an azepine/piperidine/piperazine nucleus and introduced further modifications on cycloalkylamine nucleus by means the installation of hydrophobic/hydrophilic functionalities able to establish additional contacts in the middle area of the enzyme cavity. Among the synthesized compounds, the derivatives 7a, 7b, 8b exhibited a remarkable inhibition for hCA II and the brain-expressed hCA VII in subnanomolar range.

Protective Role of Carbonic Anhydrases III and VII in Cellular Defense Mechanisms upon Redox Unbalance.

Under oxidative stress conditions, several constitutive cellular defense systems are activated, which involve both enzymatic systems and molecules with antioxidant properties such as glutathione and vitamins. In addition, proteins containing reactive sulfhydryl groups may eventually undergo reversible redox modifications whose products act as protective shields able to avoid further permanent molecular oxidative damage either in stressful conditions or under pathological circumstances. After the recovery of normal redox conditions, the reduced state of protein sulfhydryl groups is restored.

The Crystal Structure of a hCA VII Variant Provides Insights into the Molecular Determinants Responsible for Its Catalytic Behavior.

Although important progress has been achieved in understanding the catalytic mechanism of Carbonic Anhydrases, a detailed picture of all factors influencing the catalytic efficiency of the various human isoforms is still missing. In this paper we report a detailed structural study and theoretical pKa calculations on a hCA VII variant. The obtained data were compared with those already known for another thoroughly investigated cytosolic isoform, hCA II.

Inhibition of carbonic anhydrase IX targets primary tumors, metastases, and cancer stem cells: Three for the price of one.

Human carbonic anhydrase (CA) IX is a tumor-associated protein, since it is scarcely present in normal tissues, but highly overexpressed in a large number of solid tumors, where it actively contributes to survival and metastatic spread of tumor cells. Due to these features, the characterization of its biochemical, structural, and functional features for drug design purposes has been extensively carried out, with consequent development of several highly selective small molecule inhibitors and monoclonal antibodies to be used for different purposes. Aim of this review is to provide a comprehensive state-of-the-art of studies performed on this enzyme, regarding structural, functional, and biomedical aspects, as well as the development of molecules with diagnostic and therapeutic applications for cancer treatment.

How grinding level and brewing method (Espresso, American, Turkish) could affect the antioxidant activity and bioactive compounds in a coffee cup.

Background: Depending on geographical origin and cultural traditions, different brewing procedures are used all over the world to prepare a cup of coffee. In this work, we explored how three grinding levels of coffee powder and three coffee preparation methods - filtration (American), boiling (Turkish) and extraction under pressure (Espresso) - affect healthy compounds and physicochemical attributes in coffee served to consumers.

Results: Grinding level slightly affected the quality of coffee, whereas the preparation method significantly influenced all in-cup attributes.