scholarly journals Structural elucidation of the hormonal inhibition mechanism of the bile acid cholate on human carbonic anhydrase II

2014 ◽  
Vol 70 (6) ◽  
pp. 1758-1763 ◽  
Author(s):  
Christopher D. Boone ◽  
Chingkuang Tu ◽  
Robert McKenna
Keyword(s):  
Bile Acid ◽  
Mucosal Injury ◽  
Inhibition Mechanism ◽  
Crystallographic Structure ◽  
Carbonic Anhydrases ◽  
Hydrogen Bond Interactions ◽  
Zinc Metalloenzymes ◽  
Ordered Water ◽  
Biophysical Interactions ◽  
Reversible Hydration

The carbonic anhydrases (CAs) are a family of mostly zinc metalloenzymes that catalyze the reversible hydration/dehydration of CO2into bicarbonate and a proton. Human isoform CA II (HCA II) is abundant in the surface epithelial cells of the gastric mucosa, where it serves an important role in cytoprotection through bicarbonate secretion. Physiological inhibition of HCA IIviathe bile acids contributes to mucosal injury in ulcerogenic conditions. This study details the weak biophysical interactions associated with the binding of a primary bile acid, cholate, to HCA II. The X-ray crystallographic structure determined to 1.54 Å resolution revealed that cholate does not make any direct hydrogen-bond interactions with HCA II, but instead reconfigures the well ordered water network within the active site to promote indirect binding to the enzyme. Structural knowledge of the binding interactions of this nonsulfur-containing inhibitor with HCA II could provide the template design for high-affinity, isoform-specific therapeutic agents for a variety of diseases/pathological states, including cancer, glaucoma, epilepsy and osteoporosis.

scholarly journals Tracking solvent and protein movement during CO2 release in carbonic anhydrase II crystals

2016 ◽  
Vol 113 (19) ◽  
pp. 5257-5262 ◽  
Author(s):  
Chae Un Kim ◽  
HyoJin Song ◽  
Balendu Sankara Avvaru ◽  
Sol M. Gruner ◽  
SangYoun Park ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Active Site ◽  
Zinc Ion ◽  
Intermediate Water ◽  
Carbonic Anhydrases ◽  
Zinc Metalloenzymes ◽  
Close Proximity ◽  
First Time ◽  
Reversible Hydration ◽  
Co2 Release

Carbonic anhydrases are mostly zinc metalloenzymes that catalyze the reversible hydration/dehydration of CO2/HCO3−. Previously, the X-ray crystal structures of CO2-bound holo (zinc-bound) and apo (zinc-free) human carbonic anhydrase IIs (hCA IIs) were captured at high resolution. Here, we present sequential timeframe structures of holo- [T = 0 s (CO2-bound), 50 s, 3 min, 10 min, 25 min, and 1 h] and apo-hCA IIs [T = 0 s, 50 s, 3 min, and 10 min] during the “slow” release of CO2. Two active site waters, WDW (deep water) and WDW′ (this study), replace the vacated space created on CO2 release, and another water, WI (intermediate water), is seen to translocate to the proton wire position W1. In addition, on the rim of the active site pocket, a water W2′ (this study), in close proximity to residue His64 and W2, gradually exits the active site, whereas His64 concurrently rotates from pointing away (“out”) to pointing toward (“in”) active site rotameric conformation. This study provides for the first time, to our knowledge, structural “snapshots” of hCA II intermediate states during the formation of the His64-mediated proton wire that is induced as CO2 is released. Comparison of the holo- and apo-hCA II structures shows that the solvent network rearrangements require the presence of the zinc ion.

scholarly journals Probing the Surface of Human Carbonic Anhydrase for Clues towards the Design of Isoform Specific Inhibitors

2015 ◽  
Vol 2015 ◽  
pp. 1-15 ◽  
Author(s):  
Melissa A. Pinard ◽  
Brian Mahon ◽  
Robert McKenna
Keyword(s):  
Active Site ◽  
Expression Patterns ◽  
Carbonic Anhydrases ◽  
Zinc Metalloenzymes ◽  
High Amino Acid ◽  
Catalytically Active ◽  
Reversible Hydration ◽  
High Amino Acid Conservation ◽  
Specific Inhibitors ◽  
Amino Acid Conservation

The alpha carbonic anhydrases (α-CAs) are a group of structurally related zinc metalloenzymes that catalyze the reversible hydration of CO2toHCO3-. Humans have 15 differentα-CAs with numerous physiological roles and expression patterns. Of these, 12 are catalytically active, and abnormal expression and activities are linked with various diseases, including glaucoma and cancer. Hence there is a need for CA isoform specific inhibitors to avoid off-target CA inhibition, but due to the high amino acid conservation of the active site and surrounding regions between each enzyme, this has proven difficult. However, residues towards the exit of the active site are variable and can be exploited to design isoform selective inhibitors. Here we discuss and characterize this region of “selective drug targetability” and how these observations can be utilized to develop isoform selective CA inhibitors.

scholarly journals Effect of Sulfonamides and Their Structurally Related Derivatives on the Activity of ι-Carbonic Anhydrase from Burkholderia territorii

2021 ◽  
Vol 22 (2) ◽  
pp. 571
Author(s):  
Viviana De Luca ◽  
Andrea Petreni ◽  
Alessio Nocentini ◽  
Andrea Scaloni ◽  
Claudiu T. Supuran ◽  
...  
Keyword(s):  
Carbon Dioxide ◽  
Antibiotic Resistance ◽  
Pathogenic Bacteria ◽  
Selective Inhibition ◽  
Extensive Study ◽  
Protein Isoforms ◽  
Carbonic Anhydrases ◽  
Physiological Processes ◽  
Microbial Survival ◽  
Reversible Hydration

Carbonic anhydrases (CAs) are essential metalloenzymes in nature, catalyzing the carbon dioxide reversible hydration into bicarbonate and proton. In humans, breathing and many other critical physiological processes depend on this enzymatic activity. The CA superfamily function and inhibition in pathogenic bacteria has recently been the object of significant advances, being demonstrated to affect microbial survival/virulence. Targeting bacterial CAs may thus be a valid alternative to expand the pharmacological arsenal against the emergence of widespread antibiotic resistance. Here, we report an extensive study on the inhibition profile of the recently discovered ι-CA class present in some bacteria, including Burkholderia territorii, namely BteCAι, using substituted benzene-sulfonamides and clinically licensed sulfonamide-, sulfamate- and sulfamide-type drugs. The BteCAι inhibition profile showed: (i) several benzene-sulfonamides with an inhibition constant lower than 100 nM; (ii) a different behavior with respect to other α, β and γ-CAs; (iii) clinically used drugs having a micromolar affinity. This prototype study contributes to the initial recognition of compounds which efficiently and selectively inhibit a bacterial member of the ι-CA class, for which such a selective inhibition with respect to other protein isoforms present in the host is highly desired and may contribute to the development of novel antimicrobials.

Cyanobacterial carbonic anhydrases

2005 ◽  
Vol 83 (7) ◽  
pp. 721-734 ◽  
Author(s):  
Anthony K-C So ◽  
George S Espie
Keyword(s):  
Carbonic Anhydrase ◽  
Gene Families ◽  
Marine Cyanobacteria ◽  
Carbonic Anhydrases ◽  
Catalytic Function ◽  
Concentrating Mechanism ◽  
Number Distribution ◽  
Zinc Metalloenzymes

Carbonic anhydrases (CAs) are ubiquitous zinc metalloenzymes that catalyze the reversible dehydration of HCO3–. These enzymes are encoded by at least five distinct, evolutionarily unrelated gene families, four of which have been found among the cyanobacteria examined to date. However, the distribution and expression of these cyanobacterial α-, β-, γ-, and ∈-CAs and their homologues among species have not yet been investigated in great detail. In this study, the number, distribution, and catalytic function of known and putative CAs and CA-like proteins from a variety of freshwater and marine cyanobacteria are examined.Key words: carbonic anhydrase, carboxysome, CO2-concentrating mechanism, cyanobacteria, Prochlorococcus, Synechococcus, Synechocystis.

Dissecting the Inhibition Mechanism of Cytosolic versus Transmembrane Carbonic Anhydrases by ESR

2009 ◽  
Vol 113 (42) ◽  
pp. 13998-14005 ◽  
Author(s):  
Laura Ciani ◽  
Alessandro Cecchi ◽  
Claudia Temperini ◽  
Claudiu T. Supuran ◽  
Sandra Ristori
Keyword(s):  
Inhibition Mechanism ◽  
Carbonic Anhydrases

Effect of capsaicin on gastric mucosal injury and blood flow following bile acid exposure

1992 ◽  
Vol 52 (6) ◽  
pp. 596-600 ◽  
Author(s):  
Theodore R. Sullivan ◽  
Richard Milner ◽  
Daniel T. Dempsey ◽  
Wallace P. Ritchie
Keyword(s):  
Blood Flow ◽  
Bile Acid ◽  
Mucosal Injury ◽  
Gastric Mucosal Injury ◽  
Acid Exposure

scholarly journals Inhibitory Effects of Sulfonamide Derivatives on the β-Carbonic Anhydrase (MpaCA) from Malassezia pachydermatis, a Commensal, Pathogenic Fungus Present in Domestic Animals

2021 ◽  
Vol 22 (22) ◽  
pp. 12601
Author(s):  
Viviana De Luca ◽  
Andrea Angeli ◽  
Valeria Mazzone ◽  
Claudia Adelfio ◽  
Fabrizio Carta ◽  
...  
Keyword(s):  
Pathogenic Fungus ◽  
Seborrheic Dermatitis ◽  
Co2 Concentration ◽  
Carbonic Anhydrases ◽  
Medical Sciences ◽  
Inhibitory Effects ◽  
Malassezia Pachydermatis ◽  
Sensing Systems ◽  
Promising Target ◽  
Reversible Hydration

Fungi are exposed to various environmental variables during their life cycle, including changes in CO2 concentration. CO2 has the potential to act as an activator of several cell signaling pathways. In fungi, the sensing of CO2 triggers cell differentiation and the biosynthesis of proteins involved in the metabolism and pathogenicity of these microorganisms. The molecular machineries involved in CO2 sensing constitute a promising target for the development of antifungals. Carbonic anhydrases (CAs, EC 4.2.1.1) are crucial enzymes in the CO2 sensing systems of fungi, because they catalyze the reversible hydration of CO2 to proton and HCO3-. Bicarbonate in turn boots a cascade of reactions triggering fungal pathogenicity and metabolism. Accordingly, CAs affect microorganism proliferation and may represent a potential therapeutic target against fungal infection. Here, the inhibition of the unique β-CA (MpaCA) encoded in the genome of Malassezia pachydermatis, a fungus with substantial relevance in veterinary and medical sciences, was investigated using a series of conventional CA inhibitors (CAIs), namely aromatic and heterocyclic sulfonamides. This study aimed to describe novel candidates that can kill this harmful fungus by inhibiting their CA, and thus lead to effective anti-dandruff and anti-seborrheic dermatitis agents. In this context, current antifungal compounds, such as the azoles and their derivatives, have been demonstrated to induce the selection of resistant fungal strains and lose therapeutic efficacy, which might be restored by the concomitant use of alternative compounds, such as the fungal CA inhibitors.

scholarly journals Carbonic Anhydrase Inhibitors and Epilepsy: State of the Art and Future Perspectives

Molecules ◽  
2021 ◽  
Vol 26 (21) ◽  
pp. 6380
Author(s):  
Lidia Ciccone ◽  
Chiara Cerri ◽  
Susanna Nencetti ◽  
Elisabetta Orlandini
Keyword(s):  
Ionic Composition ◽  
Rapid Change ◽  
Carbonic Anhydrases ◽  
Brain Disorder ◽  
Ph Buffering ◽  
Treatment Of Epilepsy ◽  
Relevant Role ◽  
Spontaneous Recurrent Seizures ◽  
Reversible Hydration ◽  
Intracellular Potassium Concentration

Carbonic anhydrases (CAs) are a group of ubiquitously expressed metalloenzymes that catalyze the reversible hydration/dehydration of CO2/HCO3. Thus, they are involved in those physiological and pathological processes in which cellular pH buffering plays a relevant role. The inhibition of CAs has pharmacologic applications for several diseases. In addition to the well-known employment of CA inhibitors (CAIs) as diuretics and antiglaucoma drugs, it has recently been demonstrated that CAIs could be considered as valid therapeutic agents against obesity, cancer, kidney dysfunction, migraine, Alzheimer’s disease and epilepsy. Epilepsy is a chronic brain disorder that dramatically affects people of all ages. It is characterized by spontaneous recurrent seizures that are related to a rapid change in ionic composition, including an increase in intracellular potassium concentration and pH shifts. It has been reported that CAs II, VII and XIV are implicated in epilepsy. In this context, selective CAIs towards the mentioned isoforms (CAs II, VII and XIV) have been proposed and actually exploited as anticonvulsants agents in the treatment of epilepsy. Here, we describe the research achievements published on CAIs, focusing on those clinically used as anticonvulsants. In particular, we examine the new CAIs currently under development that might represent novel therapeutic options for the treatment of epilepsy.

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