Carbonic anhydrase inhibitors. Inhibition of the zinc and cobalt γ-class enzyme from the archaeon Methanosarcina thermophila with anions

Alessio Innocenti, Sabrina Zimmerman, James G. Ferry, Andrea Scozzafava, Claudiu T. Supuran

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Abstract

Anions represent the second class of inhibitors of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), in addition to sulfonamides, which possess clinical applications. The first inhibition study of the zinc and cobalt γ-class enzyme from the archaeon Methanosarcina thermophila (Cam) with anions is reported here. Inhibition data of the α-class human isozymes hCA I and hCA II (cytosolic) as well as the membrane-bound isozyme hCA IV with a large number of anionic species such as halides, pseudohalides, bicarbonate, carbonate, nitrate, nitrite, hydrosulfide, bisulfite, and sulfate, etc., are also provided for comparison. The best Zn-Cam anion inhibitors were hydrogen sulfide and cyanate, with inhibition constants in the range of 50-90μM, whereas thiocyanate, azide, carbonate, nitrite, and bisulfite were weaker inhibitors (Kis in the range of 5.8-11.7mM). Fluoride, chloride, and sulfate do not inhibit this enzyme appreciably up to concentrations of 200mM, whereas the substrate bicarbonate behaves as a weak inhibitor (Ki of 42mM). The best Co-Cam inhibitor was carbonate, with an inhibition constant of 9μM, followed by nitrate and bicarbonate (Kis in the range of 90-100μM). The metal poisons were much more ineffective inhibitors of this enzyme, with cyanide possessing an inhibition constant of 51.5mM, whereas cyanate, thiocyanate, azide, iodide, and hydrogen sulfide showed Kis in the range of 2.0-6.1mM. As for Zn-Cam, fluoride, chloride, and sulfate are not inhibitors of Co-Cam. These major differences between the two γ-CAs investigated here can be explained only in part by the different geometries of the metal ions present within their active sites.

Original languageEnglish (US)
Pages (from-to)3327-3331
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume14
Issue number12
DOIs
StatePublished - Jun 21 2004

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All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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