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

被引:57
作者
Innocenti, A
Zimmerman, S
Ferry, JG
Scozzafava, A
Supuran, CT
机构
[1] Univ Florence, Lab Chim Bioinorgan, I-50019 Florence, Italy
[2] Penn State Univ, Eberly Coll Sci, Dept Biochem & Mol Biol, University Pk, PA 16802 USA
关键词
D O I
10.1016/j.bmcl.2004.03.101
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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 gamma-class enzyme from the archaeon Methanosarcina thermophila (Cam) with anions is reported here. Inhibition data of the alpha-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 50-90 muM, whereas thiocyanate, azide, carbonate, nitrite, and bisulfite were weaker inhibitors (K(1)s in the range of 5.8-11.7 mM). Fluoride, chloride, and sulfate do not inhibit this enzyme appreciably LIP to concentrations of 200 mM, whereas the substrate bicarbonate behaves as a weak inhibitor (K-i of 42 mM). The best Co-Cam inhibitor was carbonate, with an inhibition constant of 9 muM, followed by nitrate and bicarbonate (K(i)s in the range of 90-100 muM). The metal poisons were Much more ineffective inhibitors of this enzyme, with cyanide possessing an inhibition constant of 51,5 mM, whereas cyanate, thiocyanate, azide, iodide, and hydrogen sulfide showed Kis in the range of 2.0-6.1 mM. As for Zn-Cam, fluoride, chloride, and sulfate are not inhibitors of Co-Cam. These major differences between the two gamma-CAs investigated here can be explained only in part by the different geometries of the metal ions present within their active sites. (C) 2004 Elsevier Ltd. All rights reserved.
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页码:3327 / 3331
页数:5
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