Screening of substrate analogs as potential enzyme inhibitors for the arginine kinase of Trypanosoma cruzi.
Arginine kinase catalyzes the transphosphorylation between phosphoarginine and ADP. Phosphoarginine is involved in temporal ATP buffering and inorganic phosphate regulation. Trypanosoma cruzi arginine kinase phosphorylates only L-arginine (specific activity 398.9 x mUE-min(-1) x mg(-1)), and is inhibited by the arginine analogs, agmatine, canavanine, nitroarginine, and homoarginine. Canavanine and homoarginine also produce a significant inhibition of the epimastigote culture growth (79.7% and 55.8%, respectively). Inhibition constants were calculated for canavanine and homoarginine (7.55 and 6.02 mM, respectively). In addition, two novel guanidino kinase activities were detected in the epimastigote soluble extract. The development of the arginine kinase inhibitors of T. cruzi could be an important feature because the phosphagens biosynthetic pathway in trypanosomatids is different from the one in their mammalian hosts.
Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina.
Claudio A
CA
Pereira
Guillermo D
GD
Alonso
Soledad
S
Ivaldi
León A
LA
Bouvier
Héctor N
HN
Torres
Mirtha M
MM
Flawiá
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D001122:Arginine Kinase / Q000037:antagonists & inhibitors*; D002172:Canavanine / Q000494:pharmacology; D003470:Culture Media; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006146:Guanidines / Q000378:metabolism; D006709:Homoarginine / Q000494:pharmacology; D010766:Phosphorylation; D010770:Phosphotransferases / Q000378:metabolism; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology* / Q000254:growth & development
D003470:Culture Media; D004791:Enzyme Inhibitors; D006146:Guanidines; D006709:Homoarginine; D002172:Canavanine; D001120:Arginine; D010770:Phosphotransferases; D001122:Arginine Kinase