SYNTHETIC ANALOGUES OF CREATINE-P AS RESERVOIRS OF HIGH-ENERGY PHOSPHATE WITH UNUSUAL KINETIC AND THERMODYNAMIC PROPERTIES IN MUSCLE, HEART, BRAIN, AND TUMOR CELLS; PRESERVATION OF MYOCARDIAL ADENOSINE-5'-TRIPHOSPHATE LEVELS DURING ISCHEMIA

[摘要] Several analogues of creatine have been synthesized, characterized, and fed to animals, and the accumulation and utilization by tissues of their high energy phosphorylated derivatives have been studied. Chicks fed 1-carboxyethy1-2-iminoimidazolidine(homocyclocreatine) accumulated the extremely stable synthetic phosphagen, 1-carboxyethyl-2-imino-3-phosphonoimidazolidine (homocyclocreatine-P) in breast muscle (32 (mu)mol/g wet wt), heart (7 (mu)mol/g), and brain (2.4 (mu)mol/g). Homocyclocreatine-P reacted with creatine kinase (EC 2.7.3.2) to regenerate ATP up to 200,000-fold more slowly than creatine-P, and its Gibbs standard free energy of hydrolysis was approximately 2 kcal/mol lower than that of creatine-P. Muscle, heart, and brain of chicks and mice fed N-ethylguanidinoacetate accumulated N-ethylguanidinoacetate-P, which was found to be the most reactive known analogue of creatine-P, with a similar Gibbs standard free energy of hydrolysis. Mouse Ehrlich ascites tumor cells incubated in vitro accumulated up to 8 (mu)mol/g packed cells of N-ethylguanid-inoacetate-P, which was shown to be utilized for the regeneration of ATP more rapidly and completely than another coexisting synthetic phosphagen, 1-carboxymethyl-2-imino-3-phosphonoimidazolidine(cyclocreatine-P). Dietary N-ethylguanidinoacetate reduced the level of arginine:glycine amidinotransferase (EC 2.1.4.1), the first enzyme of creatine biosynthesis, in liver of chicks. On the basis of V(,max)/K(,m), N-ethylgunidinoacetate was more active than creatine as substrate for bacterial creatinine amidohydrolase (EC 3.5.2.10), and was cyclized to a greater extent than creatine. Hearts of rats fed cyclocreatine accumulated 12 (mu)mol/g of cyclocreatine-P, higher levels of glycogen, and during subsequent ischemia demonstrated a nearly 2-fold delay in development of rigor-contracture, prolonged glycolysis, and a marked delay in depletion of ATP levels. During ischemia cyclocreatine-P continued to be utilized for ATP regeneration long after creatine-P stores had been exhausted.

[发布机构] Rice University