Influence of pH on the kinetics of complex formation between aromatic sulfonamides and human carbonic anhydrase

Taylor, Palmer; King, Roy W.; Burgen, A. S. V.

doi:10.1021/bi00822a007

Cited by 84 publications

(94 citation statements)

References 24 publications

(17 reference statements)

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“…The observation that for this isoenzyme pKapp is close to 6.5 (Fig. 2), while pKa is close to 9 (14,17), is thus quite consistent with the mechanism. No data are presently available for the carboxyketoethyl C isoenzyme water-ligand ionization to make such a comparison, but one would predict from the above treatment that pKa should be about 7.9 or greater.…”

Section: Resultssupporting

confidence: 80%

Carbon Dioxide Hydration Activity of Carbonic Anhydrase: Kinetics of Alkylated Anhydrases B and C from Humans

Khalifah

Edsall

1972

Proc. Natl. Acad. Sci. U.S.A.

358

519

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A stop-flow kinetic study was performed on the carbon dioxide hydration activity of the human carbonic anhydrase B isoenzyme carboxymethylated at its histidine20O, and of the human C isoenzyme carboxyketoethylated at its histidinen. The Michaelis-Menten parameters determined between pH 5.6 and 8.7 showed striking differences between the native and the alkylated enzymes, as well as between the modified enzymes themselves. The alkylations caused: (i) a decrease in the kmat values, particularly marked for the carboxymethylated B isoenzyme,(ii) a change in the apparent pK of the kcat curves, and (iii) a dependence of Km on pH, for the alkylated enzymes, in contrast to the pH-independent Km values of the native enzymes. The CO2 hydration and esterase activities of the carboxymethyl B isoenzyme differ markedly in their pH dependence. A kinetic mechanism, which is found to be compatible with all the present observations, is proposed. The results indicate that the modifiable histidine residues do not play an essential role in the catalytic mechanism of the native carbonic anhydrases, but they may well influence the enzyme activity in a secondary role.

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Section: Resultssupporting

confidence: 80%

Carbon Dioxide Hydration Activity of Carbonic Anhydrase: Kinetics of Alkylated Anhydrases B and C from Humans

Khalifah

Edsall

1972

Proc. Natl. Acad. Sci. U.S.A.

358

519

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“…The charges calculations were performed on model systems including the ligand, the zinc ion and the side chains of the three coordinating histidine residues. Since literature data suggest that the sulphamate and sulphamide groups, similarly to sulphonamides 36,37 , bind the zinc ion in a deprotonated form, the total charge for ligands was set at À1 e. A charge of 1.5 e was obtained for the zinc ion, whereas a high negative charge was derived for the deprotonated nitrogen atom N1 ($ À1.7 e) in all the three ligands. A complete list of the partial charges computed for the ligands atoms is reported in Table 2.…”

Section: Systems Preparationmentioning

confidence: 99%

Insights into the binding mode of sulphamates and sulphamides to hCA II: crystallographic studies and binding free energy calculations

Simone

Langella

Esposito

et al. 2017

Journal of Enzyme Inhibition and Medicinal Chemistry

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Sulphamate and sulphamide derivatives have been largely investigated as carbonic anhydrase inhibitors (CAIs) by means of different experimental techniques. However, the structural determinants responsible for their different binding mode to the enzyme active site were not clearly defined so far. In this paper, we report the X-ray crystal structure of hCA II in complex with a sulphamate inhibitor incorporating a nitroimidazole moiety. The comparison with the structure of hCA II in complex with its sulphamide analogue revealed that the two inhibitors adopt a completely different binding mode within the hCA II active site. Starting from these results, we performed a theoretical study on sulphamate and sulphamide derivatives, demonstrating that electrostatic interactions with residues within the enzyme active site play a key role in determining their binding conformation. These findings open new perspectives in the design of effective CAIs using the sulphamate and sulphamide zinc binding groups as lead compounds. ARTICLE HISTORY

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“…[1,26,27] Although an exceptionally simple process in principle, the mechanism of interaction of CA with sulfonamides is still a matter of debate: both displacement of the Zn II -bound water by the sulfonamide anion [Eq. (1)] and displacement of the Zn II -bound hydroxide by the neutral sulfonamide [Eq.…”

Section: Thermodynamic Framework and Backgroundmentioning

confidence: 99%

“…Although King and co-workers suggested that the mechanism involves three states (with an intermediate state that is weakly populated and has only hydrophobic contacts between CA and the ligand), [27,28] the details of the mechanism do not concern us here because we are only interested in the equilibrium between the separated reactants and the end-product complex, and because no intermediate in the pathway has been detected experimentally. [28] We only want to remove the dependence of the equilibrium thermodynam-ic parameters on the fractions of arylsulfonamide and CA that are present in their active, charged forms (see next section).…”

Section: Thermodynamic Framework and Backgroundmentioning

confidence: 99%

Thermodynamic Parameters for the Association of Fluorinated Benzenesulfonamides with Bovine Carbonic Anhydrase II

Krishnamurthy

Bohall

Kim

et al. 2006

Chemistry An Asian Journal

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This paper describes a calorimetric study of the association of a series of seven fluorinated benzenesulfonamide ligands (C6HnF5−nSO2NH2) with bovine carbonic anhydrase II (BCA). Quantitative structure–activity relationships between the free energy, enthalpy, and entropy of binding and pKa and log P of the ligands allowed the evaluation of the thermodynamic parameters in terms of the two independent effects of fluorination on the ligand: its electrostatic potential and its hydrophobicity. The parameters were partitioned to the three different structural interactions between the ligand and BCA: the ZnII cofactor–sulfonamide bond (≈65 % of the free energy of binding), the hydrogen bonds between the ligand and BCA (≈10 %), and the contacts between the phenyl ring of the ligand and BCA (≈25 %). Calorimetry revealed that all of the ligands studied bind in a 1:1 stoichiometry with BCA; this result was confirmed by 19F NMR spectroscopy and X‐ray crystallography (for complexes with human carbonic anhydrase II).

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Influence of pH on the kinetics of complex formation between aromatic sulfonamides and human carbonic anhydrase

Cited by 84 publications

References 24 publications

Carbon Dioxide Hydration Activity of Carbonic Anhydrase: Kinetics of Alkylated Anhydrases B and C from Humans

Carbon Dioxide Hydration Activity of Carbonic Anhydrase: Kinetics of Alkylated Anhydrases B and C from Humans

Insights into the binding mode of sulphamates and sulphamides to hCA II: crystallographic studies and binding free energy calculations

Thermodynamic Parameters for the Association of Fluorinated Benzenesulfonamides with Bovine Carbonic Anhydrase II

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