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

Boone, Christopher D.; Tu, Cong; McKenna, Robert

doi:10.1107/s1399004714007457

Cited by 22 publications

(22 citation statements)

References 23 publications

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“…DC 1 contains a bile acid head-group (specifically, a lithocholic acid amide, LAA) since bile acids are known to interact with hCA-II. 54, 55 The LAA head-group was attached to the core ON domain via a short C3 linker. This linker length was specifically utilized since in the single stranded state DC 1 can project the LAA moiety into the conical and deep (15 Å) active site of hCA-II.…”

Section: Resultsmentioning

confidence: 99%

Bile Acid Conjugated DNA Chimera that Conditionally Inhibits Carbonic Anhydrase-II in the Presence of MicroRNA-21

et al. 2015

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In order to tackle the issue of systemic toxicity in chemotherapy, there is a need to develop novel mechanisms for the activation of protein inhibitors using biomarkers over-expressed in cancer cells. Many current strategies focus on using cancer associated enzymes as a triggering agent for prodrugs. Herein, we detail an alternative approach that harnesses a microRNA (miR-21) that is overexpressed in cancers as the trigger that activates an inhibitor of human carbonic anhydrase-II (hCA-II). Specifically, we have developed a DNA-small molecule chimera (DC) composed of an hCA-II binding lithocholic acid amide (LAA) head-group that can transition from a rigid duplex state (that does not bind appreciably to hCA) to a single stranded conformation via a miR-21 trigger. The activated single-stranded DC can project the LAA head-group into the hCA-II active site and is a robust hCA-II inhibitor (Ki of 3.12 μM). This work may spur research into developing new classes of cancer selective protein inhibitors.

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Section: Resultsmentioning

confidence: 99%

Bile Acid Conjugated DNA Chimera that Conditionally Inhibits Carbonic Anhydrase-II in the Presence of MicroRNA-21

et al. 2015

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“…The lengthening of the carboxyalkyl chain of ursodeoxycholic acid (5) by a glycine unit as in 6 does not affect the derivatives efficacy against both considered isoforms. Reduction of the enone system at ring A of testosterone (13) to 5a-steroids androstanolone (16) and androsterone (14) does not interfere with the hCA II and IX inhibitory efficacy.…”

Section: Biological Activitymentioning

confidence: 92%

“…Chenodeoxycholic acid (1), ursodeoxycholic acid (5), hyodeoxycholic acid (8), hyocholic acid (9), coprostan-3-ol (12), trans-dehydroandrosterone (15), progesterone (17), 11a-hydroprogesterone (18), a-estradiol (19), and diosgenin (22) were purchased from Sigma-Aldrich. Cholic acid (2), lithocholic acid (3), deoxycholic acid (4), cholesterol (11), testosterone (13), and oestron (20) were purchased from Fluka. Dehydrocholic acid (10) and hydrocortisone (21) were purchased from Janssen Chimica and BDH Chemicals, respectively.…”

Section: Steroidsmentioning

confidence: 99%

“…According to the X-ray solved structure (PDB code 4PXX) of cholic acid (2) in complex with hCA II 13 , the carboxylic group of the docked hyocholic acid (9) directly coordinates the zinc ion in a bidentate manner, and showing a very good agreement with the positioning of the crystallographic complex ligand. Thorough analogies between cholic acid (2) crystallography and hyocholic acid (9) docking with hCA II were found.…”

Section: Computational Studiesmentioning

confidence: 99%

“…The damage produced mainly by primary bile acids and their conjugates has been related with gastric mucosal CAs inhibition in rats and humans 12 . The structural evidence of the hormonal inhibition mechanism of the bile acid cholate to hCA II has been given in 2014 13 . The carboxylate was found to bind to the zinc ion in a bivalent manner displacing the zinc-bound solvent molecule.…”

Section: Introductionmentioning

confidence: 99%

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Steroids interfere with human carbonic anhydrase activity by using alternative binding mechanisms

Nocentini

Bonardi²,

Gratteri

et al. 2018

Journal of Enzyme Inhibition and Medicinal Chemistry

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Bile acids have been shown to inhibit human (h) carbonic anhydrases (CA, EC 4.2.1.1) along the gastrointestinal tract, including hCA II. The elucidation of the hormonal inhibition mechanism of the bile acid cholate to hCA II was provided in 2014 by X-ray crystallography. Herein, we extend the inhibition study to a wealth of steroids against four relevant hCA isoforms. Steroids displaying pendants and functional groups of the carboxylate, phenolic or sulfonate types appended at the tetracyclic ring were shown to inhibit the cytosolic CA II and the tumor-associated, transmembrane CA IX in a medium micromolar range (38.9-89.9 µM). Docking studies displayed the different chemotypes CA inhibition mechanisms. Molecular dynamics (MD) gave insights on the stability over time of hyocholic acid binding to CA II.

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Coordination Dynamics of Zinc Triggers the Rate Determining Proton Transfer in Human Carbonic Anhydrase II

Paul

Taraphder

2020

ChemPhysChem

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We present, for the first time, how transient changes in the coordination number of zinc ion affects the rate determining step in the enzyme human carbonic anhydrase (HCA) II. The latter involves an intramolecular proton transfer between a zinc‐bound water and a distant histidine residue (His‐64). In the absence of time‐resolved experiments, results from classical and QM‐MM molecular dynamics and transition path sampling simulations are presented. The catalytic zinc ion is found to be present in two possible coordination states; viz. a stable tetra‐coordinated state, T and a less stable penta‐coordinated state, P with tetrahedral and trigonal bipyramidal coordination geometries, respectively. A fast dynamical inter‐conversion occurs between T and P due to reorganization of active site water molecules making the zinc ion more positively charged in state P. When initiated from different coordination environments, the most probable mechanism of proton transfer is found to be deprotonation of the equatorial water molecule from state P and transfer of the excess proton via a short path formed by hydrogen bonded network of active site water molecules. We estimate the rate constant of proton transfer as kP=1.29×106s-1 from P and kT=4.37×104s-1 from T. A quantitative match of estimated kP with the experimental value, (kexp∼0.8×106s-1 ) suggests that dynamics of Zn coordination triggers the rate determining proton transfer step in HCA II.

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

Cited by 22 publications

References 23 publications

Bile Acid Conjugated DNA Chimera that Conditionally Inhibits Carbonic Anhydrase-II in the Presence of MicroRNA-21

Bile Acid Conjugated DNA Chimera that Conditionally Inhibits Carbonic Anhydrase-II in the Presence of MicroRNA-21

Steroids interfere with human carbonic anhydrase activity by using alternative binding mechanisms

Coordination Dynamics of Zinc Triggers the Rate Determining Proton Transfer in Human Carbonic Anhydrase II

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