Characterization of human carbonic anhydrase XII stability and inhibitor binding

Jogaite, Vaida; Zubrienė, Asta; Michailovienė, Vilma; Gylytė, Joana; Morkūnaitė, Vaida; Matulis, Daumantas

doi:10.1016/j.bmc.2012.10.016

Cited by 49 publications

(50 citation statements)

References 32 publications

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“…The pK a and enthalpies of active site hydroxide protonation could be compared to other CA isoforms ( Table 2). The CA I had a pKa 8.4, CA II-7.1 [53], CA XIII-8.3 [50], CA XII-7.0 [51], and for CA VB the pK a was 7.2. The increase in pK a for CA I and CA XIII was largely due to the more exothermic enthalpy of protonation (-41 and -44 kJ mol -1 , respectively) as compared to other CAs (* -30 kJ mol -1 ).…”

Section: Discussionmentioning

confidence: 99%

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Thermodynamic characterization of human carbonic anhydrase VB stability and intrinsic binding of compounds

Kasiliauskaitė

Časaitė

Juozapaitienė

et al. 2015

J Therm Anal Calorim

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The thermodynamics of low molecular weight synthetic sulfonamide inhibitor binding to carbonic anhydrase (CA) VB was determined by the isothermal titration calorimetry (ITC) and the fluorescent thermal shift assay (FTSA). ITC provided the enthalpic and entropic contributions to the binding affinity of ethoxzolamide to CA VB. FTSA is a high-throughput assay that measures protein thermal stabilization by added ligands. FTSA enabled determination of extremely high affinity of several compounds binding to CA VB. CA VB is one of two isoforms that are expressed in mitochondria, participate in carbon metabolism and pH homeostasis and are implicated in diseases such as obesity. Therefore CA VB is a drug target. Here a series of para-substituted tetrafluoro benzenesulfonamides were investigated as high affinity inhibitors of CA VB. Thermodynamic equilibrium binding measurements such as ITC and FTSA provide only the observed parameters. Dissection of binding-linked reactions is necessary to obtain the intrinsic parameters that in turn could be correlated with the chemical structure of the inhibitors. Intrinsic dissociation constants of the inhibitors were estimated and they reached 1 pM, one of the strongest binding reactions observed between any protein-ligand binding.

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Section: Discussionmentioning

confidence: 99%

“…The standard error of the K d measurements is approximately 1.69 of the K d value isoforms [50][51][52][53][54] and are explained by the binding-linked protonation equilibria. First, a sulfonamide compound has to undergo deprotonation in order to bind to the Zn in the active center of the enzyme.…”

Section: Inhibitor Binding To Ca Vb By Itcmentioning

confidence: 98%

Thermodynamic characterization of human carbonic anhydrase VB stability and intrinsic binding of compounds

Kasiliauskaitė

Časaitė

Juozapaitienė

et al. 2015

J Therm Anal Calorim

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“…Expression and purification of CA I, II, VII, XII and XIII has been previously described: CA I by Baranauskiene et al 28 , CA II by Cimmperman et al 29 , CA VII and XIII by Sudzius et al 21 and CA XII by Jogaite et al 30 .…”

Section: Protein Preparationmentioning

confidence: 99%

Benzenesulfonamides with benzimidazole moieties as inhibitors of carbonic anhydrases I, II, VII, XII and XIII

Zubrienė

Čapkauskaitė

Gylytė

et al. 2013

Journal of Enzyme Inhibition and Medicinal Chemistry

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A series of benzenesulfonamide derivatives, bearing benzimidazole moieties, were designed and synthesized as inhibitors of carbonic anhydrases (CAs). Their binding affinities to recombinant human CA isozymes I, II, VII, XII and XIII were determined by the thermal shift assay. A group of compounds containing a benzimidazole substituent in the para position of the benzenesulfonamide ring was found to exhibit higher binding potency toward tested CAs than meta-substituted benzenesulfonamides. Some of these compounds exhibited nanomolar affinities and selectivity toward the CA isozymes tested.

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“…However, it should be kept in mind that the diagrams in Figure 5 and the values in Tables 1 and 2 represent only the observed K d s that are valid exclusively for pH 7.0 and 37°C. These values depend on pH because there are linked protonation reactions observed upon compound binding to CA [26, 27]. In order to better understand the structure-thermodynamics correlations, it would be important to obtain the intrinsic values of binding by subtracting the contributing protonation reactions.…”

Section: Discussionmentioning

confidence: 99%

Saccharin Sulfonamides as Inhibitors of Carbonic Anhydrases I, II, VII, XII, and XIII

Morkūnaitė

Baranauskienė

Zubrienė

et al. 2014

BioMed Research International

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A series of modified saccharin sulfonamides have been designed as carbonic anhydrase (CA) inhibitors and synthesized. Their binding to CA isoforms I, II, VII, XII, and XIII was measured by the fluorescent thermal shift assay (FTSA) and isothermal titration calorimetry (ITC). Saccharin bound the CAs weakly, exhibiting the affinities of 1–10 mM for four CAs except CA I where binding could not be detected. Several sulfonamide-bearing saccharines exhibited strong affinities of 1–10 nM towards particular CA isoforms. The functional group binding Gibbs free energy additivity maps are presented which may provide insights into the design of compounds with increased affinity towards selected CAs.

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Characterization of human carbonic anhydrase XII stability and inhibitor binding

Cited by 49 publications

References 32 publications

Thermodynamic characterization of human carbonic anhydrase VB stability and intrinsic binding of compounds

Thermodynamic characterization of human carbonic anhydrase VB stability and intrinsic binding of compounds

Benzenesulfonamides with benzimidazole moieties as inhibitors of carbonic anhydrases I, II, VII, XII and XIII

Saccharin Sulfonamides as Inhibitors of Carbonic Anhydrases I, II, VII, XII, and XIII

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