Structural Basis for the Inhibition of Helicobacter pylori α-Carbonic Anhydrase by Sulfonamides.
Periplasmic α-carbonic anhydrase of Helicobacter pylori (HpαCA), an oncogenic bacterium in the human stomach, is essential for its acclimation to low pH. It catalyses the conversion of carbon dioxide to bicarbonate using Zn(II) as the cofactor. In H. pylori, Neisseria spp., Brucella suis and Strepto...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2015-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4444264?pdf=render |
| _version_ | 1818031446689841152 |
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| author | Joyanta K Modak Yu C Liu Mayra A Machuca Claudiu T Supuran Anna Roujeinikova |
| author_facet | Joyanta K Modak Yu C Liu Mayra A Machuca Claudiu T Supuran Anna Roujeinikova |
| author_sort | Joyanta K Modak |
| collection | DOAJ |
| description | Periplasmic α-carbonic anhydrase of Helicobacter pylori (HpαCA), an oncogenic bacterium in the human stomach, is essential for its acclimation to low pH. It catalyses the conversion of carbon dioxide to bicarbonate using Zn(II) as the cofactor. In H. pylori, Neisseria spp., Brucella suis and Streptococcus pneumoniae this enzyme is the target for sulfonamide antibacterial agents. We present structural analysis correlated with inhibition data, on the complexes of HpαCA with two pharmacological inhibitors of human carbonic anhydrases, acetazolamide and methazolamide. This analysis reveals that two sulfonamide oxygen atoms of the inhibitors are positioned proximal to the putative location of the oxygens of the CO2 substrate in the Michaelis complex, whilst the zinc-coordinating sulfonamide nitrogen occupies the position of the catalytic water molecule. The structures are consistent with acetazolamide acting as site-directed, nanomolar inhibitors of the enzyme by mimicking its reaction transition state. Additionally, inhibitor binding provides insights into the channel for substrate entry and product exit. This analysis has implications for the structure-based design of inhibitors of bacterial carbonic anhydrases. |
| first_indexed | 2024-12-10T05:51:37Z |
| format | Article |
| id | doaj.art-e7539f85b80f4042a1b828b342d189cf |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-10T05:51:37Z |
| publishDate | 2015-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-e7539f85b80f4042a1b828b342d189cf2022-12-22T02:00:02ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-01105e012714910.1371/journal.pone.0127149Structural Basis for the Inhibition of Helicobacter pylori α-Carbonic Anhydrase by Sulfonamides.Joyanta K ModakYu C LiuMayra A MachucaClaudiu T SupuranAnna RoujeinikovaPeriplasmic α-carbonic anhydrase of Helicobacter pylori (HpαCA), an oncogenic bacterium in the human stomach, is essential for its acclimation to low pH. It catalyses the conversion of carbon dioxide to bicarbonate using Zn(II) as the cofactor. In H. pylori, Neisseria spp., Brucella suis and Streptococcus pneumoniae this enzyme is the target for sulfonamide antibacterial agents. We present structural analysis correlated with inhibition data, on the complexes of HpαCA with two pharmacological inhibitors of human carbonic anhydrases, acetazolamide and methazolamide. This analysis reveals that two sulfonamide oxygen atoms of the inhibitors are positioned proximal to the putative location of the oxygens of the CO2 substrate in the Michaelis complex, whilst the zinc-coordinating sulfonamide nitrogen occupies the position of the catalytic water molecule. The structures are consistent with acetazolamide acting as site-directed, nanomolar inhibitors of the enzyme by mimicking its reaction transition state. Additionally, inhibitor binding provides insights into the channel for substrate entry and product exit. This analysis has implications for the structure-based design of inhibitors of bacterial carbonic anhydrases.http://europepmc.org/articles/PMC4444264?pdf=render |
| spellingShingle | Joyanta K Modak Yu C Liu Mayra A Machuca Claudiu T Supuran Anna Roujeinikova Structural Basis for the Inhibition of Helicobacter pylori α-Carbonic Anhydrase by Sulfonamides. PLoS ONE |
| title | Structural Basis for the Inhibition of Helicobacter pylori α-Carbonic Anhydrase by Sulfonamides. |
| title_full | Structural Basis for the Inhibition of Helicobacter pylori α-Carbonic Anhydrase by Sulfonamides. |
| title_fullStr | Structural Basis for the Inhibition of Helicobacter pylori α-Carbonic Anhydrase by Sulfonamides. |
| title_full_unstemmed | Structural Basis for the Inhibition of Helicobacter pylori α-Carbonic Anhydrase by Sulfonamides. |
| title_short | Structural Basis for the Inhibition of Helicobacter pylori α-Carbonic Anhydrase by Sulfonamides. |
| title_sort | structural basis for the inhibition of helicobacter pylori α carbonic anhydrase by sulfonamides |
| url | http://europepmc.org/articles/PMC4444264?pdf=render |
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