Carbonic anhydrase inhibitors: the membrane-associated isoform XV is highly inhibited by inorganic anions.
The membrane-associated mouse isozyme of carbonic anhydrase XV (mCA XV), has been investigated for its interaction with anion inhibitors. mCA XV is an isoforms possessing a very particular inhibition profile by anions, dissimilar to that of all other mammalian CAs investigated earlier. Many simple inorganic anions (thiocyanate, cyanide, azide, bicarbonate, hydrogen sulfide, bisulfite and sulfate) showed low micromolar inhibition constants against mCA XV (K(I)s of 8.2-10.1 microM), whereas they acted as much weaker (usually millimolar) inhibitors of other isoforms. Halides, nitrate, nitrite, carbonate, sulfamate, sulfamide and phenylboronic/arsonic acid were weaker inhibitors, with inhibition constants in the range of 27.6-288 microM. Our data may be useful for the design of more potent inhibitors of mCA XV (considering various zinc binding groups present in the anions investigated here, e.g., the sulfonate one) and for understanding some physiologic/pharmacologic consequences of mCA XV inhibition by anions such as bicarbonate or sulfate which show quite high affinity for it.
Innocenti
Alessio
A
Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Room 188, Via della Lastruccia 3, Sesto Fiorentino, I-50019 Firenze, Italy.
Hilvo
Mika
M
Parkkila
Seppo
S
Scozzafava
Andrea
A
Supuran
Claudiu T
CT
D000818:Animals; D000838:Anions; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000187:drug effects*; D002462:Cell Membrane / Q000201:enzymology*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D015394:Molecular Structure; D012689:Sequence Homology, Nucleic Acid
D000838:Anions; D002257:Carbonic Anhydrase Inhibitors; D007527:Isoenzymes; D002256:Carbonic Anhydrases; C507974:carbonic anhydrase XV, mouse