Carbonic anhydrase activators: activation of the human tumor-associated isozymes IX and XII with amino acids and amines.
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.
Pastorekova
Silvia
S
Centre of Molecular Medicine, Institute of Virology, Slovak Academy of Sciences, Dubravska Cesta 9, 84505 Bratislava, Slovak Republic.
Vullo
Daniela
D
Nishimori
Isao
I
Scozzafava
Andrea
A
Pastorek
Jaromir
J
Supuran
Claudiu T
CT
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
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