Carbonic anhydrase inhibitors: inhibition of the beta-class enzymes from the fungal pathogens Candida albicans and Cryptococcus neoformans with simple anions.
The catalytic activity and inhibition of the beta-carbonic anhydrases (CAs, EC 4.2.1.1) from the pathogenic fungi Candida albicans (Nce103) and Cryptococcus neoformans (Can2) with inorganic anions such as halogenides, pseudohalogenides, bicarbonate, carbonate, nitrate, nitrite, hydrogen sulfide, bisulfite, perchlorate, sulfate were investigated. The two enzymes showed appreciable CO(2) hydrase activity (k(cat) in the range of (3.9-8.0)x10(5)s(-1), and k(cat)/K(m) in the range of (4.3-9.7)x10(7)M(-1)s(-1)). Can2 was weakly inhibited by cyanide and sulfamic acid (K(I)s of 8.22-13.56 mM), while all other anions displayed more potent inhibition. Nce103 was strongly inhibited by cyanide and carbonate (K(I)s of 10-11 microM), and weakly inhibited by sulfate, phenylboronic, and phenyl arsonic acid (K(I)s of 14.15-30.85 mM). These data demonstrate that pathogenic, fungal beta-CAs may be targets for the development of antifungals that have a novel mechanism of action.
Innocenti
Alessio
A
Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Room 188, Via della Lastruccia 3, I-50019 Sesto Fiorentino (Firenze), Italy.
Mühlschlegel
Fritz A
FA
Hall
Rebecca A
RA
Steegborn
Clemens
C
Scozzafava
Andrea
A
Supuran
Claudiu T
CT
D000838:Anions / Q000737:chemistry; D002176:Candida albicans / Q000737:chemistry* / Q000201:enzymology; D002254:Carbonates / Q000494:pharmacology; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D002256:Carbonic Anhydrases / Q000378:metabolism*; D003455:Cryptococcus neoformans / Q000737:chemistry* / Q000201:enzymology; D006219:Halogens / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D015394:Molecular Structure; D009566:Nitrates / Q000494:pharmacology; D013431:Sulfates / Q000494:pharmacology; D013440:Sulfides / Q000494:pharmacology
D000838:Anions; D002254:Carbonates; D002257:Carbonic Anhydrase Inhibitors; D006219:Halogens; D007527:Isoenzymes; D009566:Nitrates; D013431:Sulfates; D013440:Sulfides; D002256:Carbonic Anhydrases