Carbonic anhydrase inhibitors: inhibition of the beta-class enzyme from the yeast Saccharomyces cerevisiae with sulfonamides and sulfamates.
The protein encoded by the Nce103 gene of Saccharomyces cerevisiae, a beta-carbonic anhydrase (CA, EC 4.2.1.1) designated as scCA, has been cloned, purified, characterized kinetically and investigated for its inhibition with a series of sulfonamides and one sulfamate. The enzyme showed high CO(2) hydrase activity, with a k(cat) of 9.4x10(5)s(-1), and k(cat)/K(M) of 9.8x10(7)M(-1)s(-1). Simple benzenesulfonamides substituted in 2-, 4- and 3,4-positions of the benzene ring with amino, alkyl, halogeno and hydroxyalkyl moieties were weak scCA inhibitors with K(I)s in the range of 0.976-18.45 microM. Better inhibition (K(I)s in the range of 154-654 nM) was observed for benzenesulfonamides incorporating aminoalkyl/carboxyalkyl moieties or halogenosulfanilamides; benzene-1,3-disulfonamides; simple heterocyclic sulfonamides and sulfanilyl-sulfonamides. The clinically used sulfonamides/sulfamate (acetazolamide, ethoxzolamide, methazolamide, dorzolamide, topiramate, celecoxib, etc.) generally showed effective scCA inhibitory activity, with K(I)s in the range of 82.6-133 nM. The best inhibitor (K(I) of 15.1 nM) was 4-(2-amino-pyrimidin-4-yl)-benzenesulfonamide. These inhibitors may be useful to better understand the physiological role of beta-CAs in yeast and some pathogenic fungi which encode orthologues of the yeast enzyme and eventually for designing novel antifungal therapies.
Isik
Semra
S
Balikesir University, Science and Art Faculty, Department of Chemistry, Balikesir, Turkey.
Kockar
Feray
F
Aydin
Meltem
M
Arslan
Oktay
O
Guler
Ozen Ozensoy
OO
Innocenti
Alessio
A
Scozzafava
Andrea
A
Supuran
Claudiu T
CT
D000595:Amino Acid Sequence; D000935:Antifungal Agents / Q000737:chemistry* / Q000494:pharmacology; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D002256:Carbonic Anhydrases / Q000378:metabolism; D007700:Kinetics; D008969:Molecular Sequence Data; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology*; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology*; D013451:Sulfonic Acids / Q000737:chemistry / Q000494:pharmacology
D000935:Antifungal Agents; D002257:Carbonic Anhydrase Inhibitors; D029701:Saccharomyces cerevisiae Proteins; D013449:Sulfonamides; D013451:Sulfonic Acids; C005741:sulfamic acid; D002256:Carbonic Anhydrases