title: Synthesis and accumulation of an extremely stable high-energy phosphate compound by muscle, heart, and brain of animals fed the creatine analog, 1-carboxyethyl-2-iminoimidazolidine (homocyclocreatine).
abstract: A new creatine analog, 1-carboxyethyl-2-iminoimidazolidine (homocyclocreatine), has been synthesized and compared with other synthetic analogs of creatine as a substrate for creatine kinase under both in vitro and in vivo conditions. Reactivity with rabbit muscle creatine kinase at 2 mM and pH 7.0 occurred in the order: creatine greater than cyclocreatine (1-carboxymethyl-2-iminoimidazolidine) greater than N-ethylguanidinoacetate greater than N-propylguanidinoacetate greater than guanidinoacetate greater than N-methyl-3-guanidinopropionate greater than 3-guanidinopropionate greater than homocyclocreatine. Homocyclocreatine was 10,000-fold less active than creatine. In the reverse direction at 0.2 mM and pH 7.0: creatine-P greater than N-ethylguanidinoacetate-P greater than cyclocreatine-P much greater than homocyclocreatine-P. Homocyclocreatine-P was 200,000-fold less active than creatine-P. The phosphoryl group transfer potential of homocyclocreatine-P was estimated to be 2 kcal/mol lower than that of creatine-P. Chicks fed 5% homocyclocreatine for 16 days synthesized and accumulated homocyclocreatine-P in breast muscle (32 mumol/g wet wt), leg muscle (24 mumol/g), heart (7 mumol/g), intestine (8.5 mumol/g), and brain (2.4 mumol/g). During ischemia homocyclocreatine-P was utilized by muscle much more slowly for the regeneration of ATP than was creatine-P or cyclocreatine-P. Our results suggest that in tissues of homocyclocreatine-fed animals subjected to a sudden large increase in work load or to ischemia, the residual creatine-P system would rapidly equilibrate with the adenylate system at the new lower cytosolic phosphorylation potential, whereas in the same cytosol the (homocyclocreatine-P)/(homocyclocreatine) ratio would exhibit a hysteresis or memory effect and reflect for a considerable period of time the earlier higher (ATP)/(free ADP) ratio rather than the actual lower (ATP)/(free ADP) ratio.
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D002645:Chickens; D003402:Creatine Kinase / Q000378:metabolism; D003404:Creatinine / Q000031:analogs & derivatives* / Q000378:metabolism; D004032:Diet; D004734:Energy Metabolism; D005260:Female; D048289:Imidazolidines; D007700:Kinetics; D008297:Male; D051379:Mice; D009132:Muscles / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D010725:Phosphocreatine / Q000031:analogs & derivatives* / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D013816:Thermodynamics
chemical_list: D048289:Imidazolidines; D010725:Phosphocreatine; C037182:homocyclocreatine; C037183:phosphohomocyclocreatine; D003404:Creatinine; D003402:Creatine Kinase