Carbonic anhydrase activators: activation of the beta-carbonic anhydrases from the pathogenic fungi Candida albicans and Cryptococcus neoformans with amines and amino acids.
The proteins encoded by the Nce103 genes of Candida albicans and Cryptococcus neoformans are catalytically active beta-carbonic anhydrases (CAs, EC 4.2.1.1) playing various roles in the life cycle of these fungal pathogens, such as CO(2) sensing, regulation of capsule biosynthesis, filamentation, and adaptation of the organism to various pH and CO(2) conditions in various niches where the fungi grow. Here, we report the first activation study of these two enzymes, CaNce103 and Can2, respectively, with amines and amino acids. The C. albicans enzyme, CaNce103 was activated by amino acids such as L-/D-His, L-D-Trp, L-Tyr with K(A)s in the range of 19.5-46 microM. More effective activators were some amines such as histamine, dopamine, 2-aminoethyl-piperazine, and L-adrenaline (K(A)s of 13.2-18.5 microM). The best CaNce103 activators were L- and D-Dopa, with K(A)s of 0.96-2.5 microM. The C. neoformans enzyme, Can2, showed much lower propensity to be activated by all these amino acids and amines, which had activation constants in the range of 28.7-47.2 microM. The best Can2 activator was L-Trp. This study may help to better understand the catalytic/activation mechanisms of the beta-CAs and eventually to design CA activity modulators of such widespread enzymes in pathogenic fungi.
Innocenti
Alessio
A
Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, I-50019 Sesto Fiorentino (Firenze), Italy.
Hall
Rebecca A
RA
Scozzafava
Andrea
A
Mühlschlegel
Fritz A
FA
Supuran
Claudiu T
CT
D000588:Amines / Q000494:pharmacology*; D000596:Amino Acids / Q000494:pharmacology*; D002176:Candida albicans / Q000201:enzymology*; D024401:Carbonic Anhydrase I / Q000378:metabolism*; D002256:Carbonic Anhydrases / Q000378:metabolism; D003455:Cryptococcus neoformans / Q000201:enzymology*; D004789:Enzyme Activation / Q000187:drug effects*; D013329:Structure-Activity Relationship
D000588:Amines; D000596:Amino Acids; D024401:Carbonic Anhydrase I; D002256:Carbonic Anhydrases