Gatm Inhibitors

Chemical inhibitors of guanidinoacetate methyltransferase (Gatm) encompass a diverse array of molecules that engage in competitive inhibition by mimicking the natural substrates of the enzyme. Methionine sulfoximine and guanidinoacetate, for instance, vie for the active site on Gatm, which is also the binding region for L-arginine, Gatm's usual substrate in creatine synthesis. By occupying this site, these inhibitors prevent Gatm from catalyzing the conversion of arginine and glycine into creatine. Cyclocreatine and creatine sulfate share a similar mode of action, presenting themselves as structural analogs to creatine and, as a result, compete with the natural substrates for the active site, leading to a reduction in enzyme activity.

Further inhibitory action is seen with chemicals such as beta-guanidinopropionic acid and hydroxyguanidine, which again exhibit their effects by competing with L-arginine. Creatinine, a metabolite found in creatine phosphate, also binds to Gatm's active site, diminishing the enzyme's capacity to interact with its natural substrates. Other inhibitors like 1-methylguanidine and arginine methyl ester share this competitive behavior, binding to the same site as L-arginine, thereby decreasing Gatm's activity. Homocysteine thiolactone, by resembling the substrates of Gatm, disrupts the enzymatic process that leads to creatine formation. Similarly, creatinol O-phosphate acts as a competitive inhibitor, engaging the active site of Gatm and impeding its function in the creatine biosynthesis pathway. These inhibitors collectively function by structural mimicry, binding to the enzyme's active site, and effectively reducing its ability to synthesize creatine.