Enzymatic mechanism of creatine synthesis.

It is well established that the last step in the biosynthesis of creatine involves the methylation of guanidinoacetic acid.’ This conclusion is based upon experimental evidence derived from two independent lines of investigation. By application of the isotopic tracer technique, du Vigneaud et al. (2) have demonstrated that the methyl group in creatine is derived from L-methionine; furthermore, these authors obtained conclusive evidence that, in wivo, the methyl group of L-methionine is transferred to the methyl acceptor as a unit. In an independent study of this transmethylation reaction in vitro, Borsook and Dubnoff (3) reached similar conclusions using guinea pig liver slices. Subsequently (4), these authors have shown that cell-free liver homogenates fortified with adenylic acid and an oxidizable substrate such as a-ketoglutaric acid are able to form creatine under aerobic conditions. It was assumed by these authors and by others (5, 6) that these requirements were a reflection of the endergonic nature of this transmethylation reaction and an indication of the ability of ATP to serve as an energy source in this system. These conclusions appeared to have been borne out by the findings of Cohen (5) that the methylation of guanidinoacetic acid proceeds anaerobically in the presence of ATP and Mg++. The biosyntheses of creatine and W-methylnicotinamide are similar. In both cases the methyl group is derived from L-methionine and, furthermore, ATP and Mg++ are required. Recent investigations (6, 7) have