scholarly journals Carbonic Anhydrase Activators. Part 191 Spectroscopic and Kinetic Investigations for the Interaction of Isozymes I and II With Primary Amines

1997 ◽  
Vol 4 (4) ◽  
pp. 221-227 ◽  
Author(s):  
Fabrizio Briganti ◽  
Andrea Scozzafava ◽  
Claudiu T. Supuran
Keyword(s):  
Carbonic Anhydrase ◽  
Active Site ◽  
Metal Ion ◽  
Competitive Inhibitor ◽  
The Other ◽  
Primary Amines ◽  
Hydrophobic Pocket ◽  
X Ray ◽  
Active Site Cavity ◽  
Kinetic Investigations

The interactions of Zn(II)- and Co(II)-substituted carbonic anhydrase (CA) isozymes I and II with amine type activators such as histamine, serotonin, phenetylamine dopamine and benzylhydrazine have been investigated kinetically, and spectroscopically. All of such activators are of the non-competitive type towards CO2 hydration and 4-nitrophenylacetate hydrolysis for both human isozymes (HCA I and HCA II). The electronic spectra of the adducts of Co(II)CA with amine activators are similar to the spectrum of the previously reported Co(II)CAII-phenol adduct, the only known competitive inhibitor towards CO2 hydration, where the phenol molecule binds into the hydrophobic pocket of the active site. This is a direct spectroscopic evidence that the activator molecules bind within the active site, but not directly to the metal ion. Recent X-ray crystallographic data for the adduct of HCA II with histamine show that the activator molecule is bound at the entrance of the active site cavity, near to residues His 64, Asn 62 and Gln 92, where actively aids in shuttling protons between the active site and the environment. Similar arrangements probably occur for the other activators reported in the present paper.

scholarly journals Synthesis, Molecular Docking Analysis, and Carbonic Anhydrase Inhibitory Evaluations of Benzenesulfonamide Derivatives Containing Thiazolidinone

Molecules ◽  
2019 ◽  
Vol 24 (13) ◽  
pp. 2418
Author(s):  
Zuo-Peng Zhang ◽  
Ze-Fa Yin ◽  
Jia-Yue Li ◽  
Zhi-Peng Wang ◽  
Qian-Jie Wu ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Active Site ◽  
Docking Studies ◽  
Active Site Residues ◽  
Single Crystal Diffraction ◽  
Docking Analysis ◽  
X Ray ◽  
Active Site Cavity ◽  
Molecular Docking Analysis ◽  
Positive Controls

To find novel human carbonic anhydrase (hCA) inhibitors, we synthesized thirteen compounds by combining thiazolidinone with benzenesulfonamide. The result of the X-ray single-crystal diffraction experiment confirmed the configuration of this class of compounds. The enzyme inhibition assays against hCA II and IX showed desirable potency profiles, as effective as the positive controls. The docking studies revealed that compounds (2) and (7) efficiently bound in the active site cavity of hCA IX by forming sufficient interactions with active site residues. The fragment of thiazolidinone played an important role in the binding of the molecules to the active site.

scholarly journals Photolabelling of Salmonella typhimurium LT2 sialidase. Identification of a peptide with a predicted structural similarity to the active sites of influenza-virus sialidases

1992 ◽  
Vol 285 (3) ◽  
pp. 957-964 ◽  
Author(s):  
T G Warner ◽  
R Harris ◽  
R McDowell ◽  
E R Vimr
Keyword(s):  
Salmonella Typhimurium ◽  
Active Site ◽  
Influenza A ◽  
Active Sites ◽  
Enzyme Inhibitors ◽  
Structural Similarity ◽  
Competitive Inhibitor ◽  
Beta Sheets ◽  
Sialidase Inhibitor ◽  
Active Site Cavity

The sialidase from Salmonella typhimurium LT2 was characterized by using photoaffinity-labelling techniques. The well-known sialidase inhibitor 5-acetamido-2,6-anhydro-3,5-dideoxy-D-glycero-D-galacto-non- 2-enonic acid (Neu5Ac2en) was modified to contain an amino group at C-9, which permitted the incorporation of 4-azidosalicylic acid in amide linkage at this position. Labelling of the purified protein with the radioactive (125I) photoprobe was determined to be highly specific for a region within the active-site cavity. This conclusion was based on the observation that the competitive inhibitor Neu5Ac2en in the photolysis mixture prevented labelling of the protein. In contrast, compounds with structural and chemical features similar to the probe and Neu5Ac2en, but which were not competitive enzyme inhibitors, did not affect the photolabelling of the protein. The peptide interacting with the probe was identified by CNBr treatment of the labelled protein, followed by N-terminal sequence analysis. Inspection of the primary structure of the protein, predicted from the cloned structural gene for the sialidase [Hoyer, Hamilton, Steenbergen & Vimr (1992) Mol. Microbiol. 6, 873-884] revealed that the label was incorporated into a 9.6 kDa fragment situated within the terminal third of the molecule near the C-terminal end. Secondary-structural predictions using the Garnier-Robson algorithm [Garnier, Osguthorpe & Robson (1978) J. Mol. Biol. 120, 97-120] of the labelled peptide revealed a structural similarity to the active site of influenza-A- and Sendai-HN-virus sialidases with a repetitive series of alternating beta-sheets connected with loops.

scholarly journals GMP and IMP Are Competitive Inhibitors of CMY-10, an Extended-Spectrum Class C β-Lactamase

2017 ◽  
Vol 61 (5) ◽  
Author(s):  
Jung-Hyun Na ◽  
Young Jun An ◽  
Sun-Shin Cha
Keyword(s):  
Crystal Structure ◽  
Active Site ◽  
Binding Mode ◽  
Competitive Inhibitor ◽  
Phosphate Group ◽  
The Other ◽  
Extended Spectrum ◽  
Competitive Inhibitors ◽  
Class C

ABSTRACT Nucleotides were effective in inhibiting the class C β-lactamase CMY-10. IMP was the most potent competitive inhibitor, with a Ki value of 16.2 μM. The crystal structure of CMY-10 complexed with GMP or IMP revealed that nucleotides fit into the R2 subsite of the active site with a unique vertical binding mode where the phosphate group at one terminus is deeply bound in the subsite and the base at the other terminus faces the solvent.

Selective hydrophobic pocket binding observed within the carbonic anhydrase II active site accommodate different 4-substituted-ureido-benzenesulfonamides and correlate to inhibitor potency

2010 ◽  
Vol 46 (44) ◽  
pp. 8371 ◽  
Author(s):  
Fabio Pacchiano ◽  
Mayank Aggarwal ◽  
Balendu Sankara Avvaru ◽  
Arthur H. Robbins ◽  
Andrea Scozzafava ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Active Site ◽  
Carbonic Anhydrase Ii ◽  
Hydrophobic Pocket

Proton transfer within the active-site cavity of carbonic anhydrase III

2002 ◽  
Vol 1599 (1-2) ◽  
pp. 21-27 ◽  
Author(s):  
Haiqian An ◽  
Chingkuang Tu ◽  
Ke Ren ◽  
Philip J. Laipis ◽  
David N. Silverman
Keyword(s):  
Carbonic Anhydrase ◽  
Proton Transfer ◽  
Active Site ◽  
Carbonic Anhydrase Iii ◽  
Active Site Cavity

Dual Human Carbonic Anhydrase/Cyclooxygenase-2 Inhibitors: A Promising Approach for Cancer Treatment

2021 ◽  
Vol 21 ◽  
Author(s):  
Mohammad Mahboubi-Rabbani ◽  
Afshin Zarghi
Keyword(s):  
Carbonic Anhydrase ◽  
Combination Therapy ◽  
Active Site ◽  
Inhibitory Action ◽  
Cyclooxygenase 2 ◽  
X Ray ◽  
Cox 2 ◽  
Human Carbonic Anhydrase ◽  
Cancer Chemoresistance ◽  
Cyclooxygenase 2 Inhibitors

: Human carbonic anhydrase (hCA) and cyclooxygenase-2 (COX-2) have been known for a long to be chiefly involved in both the pathogenesis and progression of cancer and cancer chemoresistance. Interestingly, there is emerging evidence that the sulfonamide-type COX-2 selective inhibitors (coxibs) demonstrate inhibitory action against the cancer-related hCA isoforms, confirmed by X-ray crystal structures for celecoxib and valdecoxib complexes with the hCA active site. Consequently, the antineoplastic activity of the sulfonamide coxibs may be justified by the contribution of hCA inhibition to such processes in addition to COX-2 inhibition. Accordingly, these compounds' anti-tumoral activity should be further explored for their possible use in cancer prevention and combination therapy; however, few papers deal with this issue. Beginning with a brief description of the main molecular and catalytic features of both enzymes and their roles in tumor physiology, this review covers a survey of the most recent evidence regarding the molecules targeting one or both of hCA and COX-2, also providing insights into their mechanism of action and efficacy in preventing cancer.

Intermolecular proton transfer in catalysis by carbonic anhydrase V

1999 ◽  
Vol 77 (5-6) ◽  
pp. 726-732 ◽  
Author(s):  
J Nicole Earnhardt ◽  
Chingkuang Tu ◽  
David N Silverman
Keyword(s):  
Carbonic Anhydrase ◽  
Proton Transfer ◽  
Active Site ◽  
Rate Constants ◽  
Intramolecular Proton Transfer ◽  
Proton Donor ◽  
Marcus Theory ◽  
Intermolecular Proton Transfer ◽  
Donor And Acceptor ◽  
Active Site Cavity

The dehydration of bicarbonate catalyzed by carbonic anhydrase is accompanied by the transfer of a proton from solution to the zinc-bound hydroxide. We have investigated the properties of proton transfer from donors in solution, mostly derivatives of imidazole and pyridine, to a truncated mutant of carbonic anhydrase V with replacements that render the active site cavity less sterically constrained, Tyr 64 →> Ala and Phe 65 →> Ala. Catalysis was measured by determining the rate of exchange of 18O between the CO2-HCO3- system and water, and rate constants for proton transfer were estimated as the rate-limiting step in the release of H218O from the enzyme to solution. Each proton donor enhanced catalytic activity in a saturable manner. The resulting rate constants for proton transfer when compared with the values of pKa of the donor and acceptor gave a Brønsted plot of high curvature. These data could also be described by Marcus theory which showed an intrinsic barrier for intermolecular proton transfer near 0.8 kcal/mol and a work term or thermodynamic contribution to the free energy of reaction near 10 kcal/mol. This low intrinsic kinetic barrier for proton transfer is very similar to nonenzymic bimolecular proton transfer between nitrogen and oxygen acids and bases in solution. However, the significant thermodynamic contribution suggests appreciable involvement of solvent and active-site organization prior to proton transfer. These Marcus parameters are very similar to those describing intramolecular proton transfer from His 64 in carbonic anhydrase, suggesting similarities in the intra- and intermolecular proton transfer processes.Key words: carbonic anhydrase, proton transfer, Marcus theory, carbon dioxide.

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