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

Activation of carbonic anhydrase II by active-site incorporation of histidine analogs

2004 ◽  
Vol 421 (2) ◽  
pp. 283-289 ◽  
Author(s):  
Ileana Elder ◽  
Shoufa Han ◽  
Chingkuang Tu ◽  
Heather Steele ◽  
Philip J. Laipis ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Active Site ◽  
Carbonic Anhydrase Ii

Out of the active site binding pocket for carbonic anhydrase inhibitors

2015 ◽  
Vol 51 (2) ◽  
pp. 302-305 ◽  
Author(s):  
Katia D'Ambrosio ◽  
Simone Carradori ◽  
Simona M. Monti ◽  
Martina Buonanno ◽  
Daniela Secci ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Active Site ◽  
Binding Pocket ◽  
Carbonic Anhydrase Ii ◽  
Carbonic Anhydrase Inhibitors ◽  
Human Carbonic Anhydrase ◽  
Site Binding

2-Benzylsulfinylbenzoic acid binds to human carbonic anhydrase II in a mode completely different from any other class of carbonic anhydrase inhibitors investigated so far.

scholarly journals Effect of Active-site Mutation at Asn67 on the Proton Transfer Mechanism of Human Carbonic Anhydrase II

Biochemistry ◽  
2009 ◽  
Vol 48 (33) ◽  
pp. 7996-8005 ◽  
Author(s):  
C. Mark Maupin ◽  
Jiayin Zheng ◽  
Chingkuang Tu ◽  
Robert McKenna ◽  
David N. Silverman ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Proton Transfer ◽  
Active Site ◽  
Transfer Mechanism ◽  
Carbonic Anhydrase Ii ◽  
Site Mutation ◽  
Human Carbonic Anhydrase

scholarly journals Importance of C-Terminal Knot Structure in Carbonic Anhydrase II (Part I): Role of C-Terminal Knot Forming GLN253 on Enzymatic Property of Human Carbinic II

1970 ◽  
Vol 14 ◽  
pp. 1-9
Author(s):  
Mohammad Taufiq Alam
Keyword(s):  
Amino Acid ◽  
Carbonic Anhydrase ◽  
Point Mutation ◽  
Amino Acid Residue ◽  
Active Site ◽  
Terminal Region ◽  
Carbonic Anhydrase Ii ◽  
C Terminus ◽  
Human Carbonic Anhydrase

In both, bovine and human carbonic anhydrase II, a conserved glutamine residue occupies the position in the middle of the knot, which is formed by intercrossing of C-terminal end with N-terminal region. Previous studies have indicated that C-terminus is not the part of an active site, but truncation of 7 amino acid residue in this region can have marked effects on stability of the enzyme (data not published). To gain further insight into the role of specific amino acid residue in C-terminal region, site directed mutagenesis was used to introduce point mutation. Substitution of glutamine with cysteine was chosen because the cysteine residue is less hydrophilic as compared with glutamine and thus, may disrupt the hydrophilic environment in this region. Result indicates that Gln253 located within the C-terminus knot topology plays a significant role in normal function of the enzyme. Thus, C-terminal region might mediate cooperativity between the central active site of the enzyme through proper formation of knot. Key words: Human carbonic anhydrase II; knot topology; point mutation J. bio-sci. 14: 1-9, 2006

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 Mechanism of Action of Non-Synonymous Single Nucleotide Variations Associated with α-Carbonic Anhydrase II Deficiency

Molecules ◽  
2019 ◽  
Vol 24 (21) ◽  
pp. 3987 ◽  
Author(s):  
Taremekedzwa Allan Sanyanga ◽  
Bilal Nizami ◽  
Özlem Tastan Bishop
Keyword(s):  
Carbonic Anhydrase ◽  
Mechanism Of Action ◽  
Active Site ◽  
The Body ◽  
Carbonic Anhydrase Ii ◽  
Motif Analysis ◽  
Acid Base Balance ◽  
Compensatory Mechanisms ◽  
Single Nucleotide ◽  
Single Nucleotide Variations

Human carbonic anhydrase II (CA-II) is a Zinc (Zn 2 + ) metalloenzyme responsible for maintenance of acid-base balance within the body through the reversible hydration of CO 2 to produce protons (H + ) and bicarbonate (BCT). Due to its importance, alterations to the amino acid sequence of the protein as a result of single nucleotide variations (nsSNVs) have detrimental effects on homeostasis. Six pathogenic CA-II nsSNVs, K18E, K18Q, H107Y, P236H, P236R and N252D were identified, and variant protein models calculated using homology modeling. The effect of each nsSNV was analyzed using motif analysis, molecular dynamics (MD) simulations, principal component (PCA) and dynamic residue network (DRN) analysis. Motif analysis identified 11 functionally important motifs in CA-II. RMSD data indicated subtle SNV effects, while PCA analysis revealed that the presence of BCT results in greater conformational sampling and free energy in proteins. DRN analysis showed variant allosteric effects, and the average betweenness centrality (BC) calculations identified Glu117 as the most important residue for communication in CA-II. The presence of BCT was associated with a reduction to Glu117 usage in all variants, suggesting implications for Zn 2 + dissociation from the CA-II active site. In addition, reductions to Glu117 usage are associated with increases in the usage of the primary and secondary Zn 2 + ligands; His94, His96, His119 and Asn243 highlighting potential compensatory mechanisms to maintain Zn 2 + within the active site. Compared to traditional MD simulation investigation, DRN analysis provided greater insights into SNV mechanism of action, indicating its importance for the study of missense mutation effects in proteins and, in broader terms, precision medicine related research.

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