title: Carbonic anhydrase activators: activation of the human tumor-associated isozymes IX and XII with amino acids and amines.
abstract: The first activation study of the human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms associated to tumors, hCA IX and XII, with a small library of natural and non-natural amino acids as well as aromatic/heterocyclic amines is reported. hCA IX was activated efficiently by dopamine, adrenaline and heterocyclic amines possessing aminoethyl-/aminomethyl-moieties (K(A)s of 9 nM-1.07 microM), whereas the best hCA XII activators were serotonin, L-adrenaline, 4-(2-aminoethyl)-morpholine and d-Phe (K(A) of 0.24-0.41 microM). Precise steric and electronic requirements are needed to be present in the molecules of effective hCA IX/hCA XII activators, in order to assure an adequate fit within the enzyme active site cavity for the formation of the enzyme-activator complex, and for an efficient proton transfer process within this complex, leading to the release of a proton and formation of the catalytically active, zinc-hydroxide species of the enzyme. Selective activation of these CA isoforms might be useful to develop pharmacologic tools or to understand whether some of these biogenic amines/amino acids may influence the progression of tumors overexpressing CA IX and/or CA XII.
authors.affiliation: Centre of Molecular Medicine, Institute of Virology, Slovak Academy of Sciences, Dubravska Cesta 9, 84505 Bratislava, Slovak Republic.
authors.forename: Silvia
authors.initials: S
authors.lastname: Pastorekova
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: Jaromir
authors.initials: J
authors.lastname: Pastorek
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D000588:Amines / Q000737:chemistry / Q000494:pharmacology*; D000596:Amino Acids / Q000737:chemistry / Q000494:pharmacology*; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000378:metabolism*; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000737:chemistry / Q000378:metabolism*; D017124:Conserved Sequence; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009369:Neoplasms / Q000201:enzymology*; D016415:Sequence Alignment; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D000596:Amino Acids; D000951:Antigens, Neoplasm; D007527:Isoenzymes; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; C477378:carbonic anhydrase XII