Carbonic anhydrase inhibitors. Inhibition of the newly isolated murine isozyme XIII with anions

• Published in: Bioorganic & medicinal chemistry letters Vol. 14; no. 21; pp. 5435 - 5439
• Main Authors: INNOCENTI, Alessio, LEHTONEN, Jonna M, PARKKILA, Seppo, SCOZZAFAVA, Andrea, SUPURAN, Claudiu T
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier 01.11.2004
• Subjects: Analytical, structural and metabolic biochemistry; Animals; Anions - chemistry; Biological and medical sciences; Carbonic Anhydrase Inhibitors - chemistry; Carbonic Anhydrases - chemistry; Cytosol - enzymology; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Isoenzymes - antagonists & inhibitors; Isoenzymes - chemistry; Lyases; Medical sciences; Mice; Miscellaneous; Pharmacology. Drug treatments; Structure-Activity Relationship; Enzyme; Isozyme; Rodentia; Enzyme inhibitor; Lyases; In vitro; Vertebrata; Mammalia; Inorganic anion; Mouse; Animal; Carbonate dehydratase; Carbon-oxygen lyases; Hydro-lyases
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2004.07.086

The inhibition of the newly discovered cytosolic carbonic anhydrase (CA, EC 4.2.1.1) isozyme XIII of murine origin (mCA XIII) has been investigated with a series of anions, such as the physiological ones (bicarbonate, chloride), or the metal complexing anions (cyanate, cyanide, azide, hydrogen sulfide, etc), nitrate, nitrite, sulfate, sulfamate, sulfamide as well as with phenylboronic and phenylarsonic acids. The best mCA XIII inhibitors were cyanate, thiocyanate, cyanide and sulfamide, with K(I)-s in the range of 0.25microM-0.74 mM, whereas fluoride, iodide, azide, carbonate and hydrogen sulfide were less effective (K(I)-s in the range of 3.0-5.5mM). The least effective inhibitors were sulfate, chloride and bicarbonate (K(I)-s in the range of 138-267 mM). The affinity of mCA XIII for anions is very different from that of the other cytosolic isozymes (hCA I and II) or the mitochondrial isozyme hCA V. This resistance to inhibition by the physiological anions bicarbonate and chloride suggests an evolutionary adaptation of CA XIII to the presence of high concentrations of such anions (e.g., in the reproductive tract of both female and male), and the possible participation of this isozyme (similarly to CA II, CA IV and CA V) in metabolons with proteins involved in the anion exchange and transport, such as the anion exchangers (AE1-3) or the sodium bicarbonate co-transporter (NBC1 and NBC3) proteins, which remain to be identified.