Carbonic anhydrase inhibitors.: Inhibition of the zinc and cobalt γ-class enzyme from the archaeon Methanosarcina thermophila with anions
Carbonic anhydrase inhibitors.: Inhibition of the zinc and cobalt γ-class enzyme from the archaeon Methanosarcina thermophila with anions
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DOI：
10.1016/j.bmcl.2004.03.101
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发表时间：
2004-06-21
影响因子：
2.7
通讯作者：
Supuran, CT
中科院分区：
文献类型：
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作者：
Innocenti, A;Zimmerman, S;Supuran, CT
除了磺胺类化合物外，阴离子是锌酶碳酸酐酶(CA，EC 4.2.1.1)的第二类抑制剂，具有临床应用价值。本文首次报道了阴离子对嗜热甲烷单胞菌(CaM)产生的锌钴伽马类酶的抑制作用。还提供了人α类同工酶Hca I和Hca II(胞液)以及Hca IV与大量阴离子物种如卤化物、假卤化物、碳酸氢盐、碳酸盐、硝酸盐、亚硝酸盐、硫化氢、亚硫酸盐和硫酸盐等的抑制数据，以供比较。硫氰酸盐、叠氮化物、碳酸盐、亚硝酸盐和亚硫酸盐的抑制作用较弱(K(1)S在5.8~11.7 mM范围内)。氟化物、氯化物和硫酸盐在200 mM的浓度下对该酶没有明显的抑制作用，而底物碳酸氢盐则表现为微弱的抑制作用(K-I为42 mM)。抑制效果最好的是碳酸盐，抑制常数为9um，其次是硝酸盐和小苏打(K(I)S，在90~100um范围内)。金属毒物对该酶的抑制作用较弱，氰化物的抑制常数为51.5 mM，而氰酸盐、硫氰酸盐、叠氮化物、碘化物和硫化氢的抑制常数为2.0-6.1 mM。对于锌钙调素，氟化物、氯化物和硫酸盐不是钴钙调素的抑制剂。这里所研究的两个伽马-CA之间的这些主要差异只能部分地解释其活性中心内存在的金属离子的不同几何形状。(C)2004爱思唯尔有限公司。保留所有权利。
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.