L-arginine:glycine amidinotransferase (AGAT)

L-arginine:glycine amidinotransferase (AGAT) is a mitochondrial enzyme that catalyzes the first and committed step of creatine biosynthesis — the transfer of an amidino group from L-arginine to glycine to form guanidinoacetate and ornithine[1][2][3][5][6][9][10]. The guanidinoacetate produced is then methylated to creatine, a molecule essential for storing and buffering cellular energy, chiefly in muscle and brain. AGAT belongs to the amidinotransferase enzyme family, is encoded by the GATM gene on chromosome 15q15.3, and is critical for normal brain and muscle function through its central role in energy homeostasis. Deficiency of AGAT due to genetic mutations leads to cerebral creatine deficiency syndrome, characterized by intellectual disability, developmental delay, and sometimes muscle weakness, all of which can often be alleviated or reversed by oral creatine supplementation[2][4][7]. AGAT is not a direct drug target for inhibition or modulation but is of clinical importance because its deficiency causes a well-defined metabolic disease with available therapy. The structure of AGAT is notable for fivefold pseudosymmetry, a basket-like overall fold, and a catalytic triad (Cys-His-Asp) at the active site[1][3][5][9].

Other names

AGATglycine amidinotransferaseglycine amidinotransferase (mitochondrial)GATM (gene)transamidinaseAT

Drugs (e.g. creatine supplementation) do not inhibit or bind AGAT but bypass the metabolic block caused by its deficiency, providing exogenous creatine to restore cellular function