Anion inhibition profiles of α-, β- and γ-carbonic anhydrases from the pathogenic bacterium Vibrio cholerae

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• 作者：Sonia Del Prete^a ; ^b ; Daniela Vullo^b ; Viviana De Luca^a ; Vincenzo Carginale^a ; Pietro di Fonzo^a ; Sameh M. Osman^c ; Zeid AlOthman^c ; ^d ; Claudiu T. Supuran^c ; ^e ; ^{claudiu.supuran@unifi.it" class="auth_mail" title="E-mail the corresponding author} ; Clemente Capasso^a ; ^{clemente.capasso@ibbr.cnr.it" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Carbonic anhydrase ; Metalloenzymes ; Inhibitors ; Anions ; Hydratase activity ; Pathogenic bacteria
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：15 August 2016
• 年：2016
• 卷：24
• 期：16
• 页码：3413-3417
• 全文大小：390 K

文摘

Among the numerous metalloenzymes known to date, carbonic anhydrase (CA, EC 4.2.1.1) was the first zinc containing one, being discovered decades ago. CA is a hydro-lyase, which catalyzes the following hydration–dehydration reaction: CO₂ + H₂O ⇋ HCO₃⁻ + H⁺. Several CA classes are presently known, including the α-, β-, γ-, δ-, ζ- and η-CAs. In prokaryotes, the existence of genes encoding CAs from at least three classes (α-, β- and γ-class) suggests that these enzymes play a key role in the physiology of these organisms. In many bacteria CAs are essential for the life cycle of microbes and their inhibition leads to growth impairment or growth defects of the pathogen. CAs thus started to be investigated in detail in bacteria, fungi and protozoa with the aim to identify antiinfectives with a novel mechanism of action. Here, we investigated the catalytic activity, biochemical properties and anion inhibition profiles of the three CAs from the bacterial pathogen Vibrio cholera, VchCA, VchCAβ and VchCAγ. The three enzymes are efficient catalysts for CO₂ hydration, with k_cat values ranging between (3.4 − 8.23) × 10⁵ s⁻¹ and k_cat/K_M of (4.1 − 7.0) × 10⁷ M⁻¹ s⁻¹. A set of inorganic anions and small molecules was investigated for inhibition of these enzymes. The most potent VchCAγ inhibitors were N,N-diethyldithiocarbamate, sulfamate, sulfamide, phenylboronic acid and phenylarsonic acid, with K_I values ranging between 44 and 91 μM.