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Understanding the role of GCAT and glycine-to-aminoacetone conversion in physiology and in cancer

Understanding the role of GCAT and glycine-to-aminoacetone conversion in physiology and in cancer

Glycine C-acetyltransferase (GCAT) and threonine dehydrogenase (TDH) mediate the bidirectional interconversion of glycine and threonine in mitochondria. This involves an unstable intermediate, 2-amino-3-ketobutyrate, which can be spontaneously decarboxylated to form the toxic metabolite aminoacetone, but this ‘leak’ is minimized by the physical association of GCAT and TDH. Surprisingly, in humans TDH is a pseudogene and no significant threonine dehydrogenase activity is observed. Thus, in contrast to other metazoans, it appears that human metabolism is unidirectionally wired so that any glycine metabolized by GCAT can only can only be converted to aminoacetone instead of threonine (Figure 1). Demonstrating this notion, we found that when cells accumulate excess glycine such as due to GLDC inhibition, GCAT activity forms toxic levels of aminoacetone. But what is the raison d’etre of this metabolic route? We are exploring both the physiological and pathological roles for this pathway.