title: Carbonic anhydrase activators: Activation of the human cytosolic isozyme III and membrane-associated isoform IV with amino acids and amines.
abstract: An activation study of the human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms hCA III (cytosolic) and IV (membrane-associated) with a series of natural and non-natural amino acids and aromatic/heterocyclic amines is reported. hCA III was efficiently activated by d-His, serotonin, pyridyl-alkylamines, and aminoethyl-piperazine/morpholine (K(A)s of 91nM-1.12microM), whereas the best hCA IV activators were 4-amino-phenylalanine, serotonin, and 4-(2-aminoethyl)-morpholine (K(A)s of 79nM-3.14microM). Precise steric and electronic requirements are needed to be present in the molecules of effective CA III/IV activators, in order to assure an adequate fit within the enzyme active site for the formation of the enzyme-activator complex, and for efficient proton transfer processes between the active site and the reaction medium. The activation profiles of CA III and IV are distinct from those of all other mammalian CA isoforms investigated so far for their interaction with amino acids and amines.
authors.affiliation: Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, I-50019 Sesto Fiorentino, Firenze, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Vullo
authors.forename: Isao
authors.initials: I
authors.lastname: Nishimori
authors.forename: Andrea
authors.initials: A
authors.lastname: Scozzafava
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D000588:Amines / Q000494:pharmacology*; D000596:Amino Acids / Q000494:pharmacology*; D001665:Binding Sites; D024403:Carbonic Anhydrase III / Q000187:drug effects* / Q000378:metabolism*; D030741:Carbonic Anhydrase IV / Q000187:drug effects* / Q000378:metabolism*; D002462:Cell Membrane / Q000201:enzymology*; D003600:Cytosol / Q000201:enzymology*; D004789:Enzyme Activation / Q000187:drug effects; D006639:Histidine / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes; D015394:Molecular Structure; D009025:Morpholines / Q000493:pharmacokinetics / Q000494:pharmacology; D012701:Serotonin / Q000493:pharmacokinetics / Q000494:pharmacology; D013237:Stereoisomerism
chemical_list: D000588:Amines; D000596:Amino Acids; D007527:Isoenzymes; D009025:Morpholines; D012701:Serotonin; D006639:Histidine; D024403:Carbonic Anhydrase III; D030741:Carbonic Anhydrase IV