Creatine biosynthesis (vertebrate, two-step AGAT to GAMT)

De novo biosynthesis of creatine, the two-step pathway that supplies the phosphocreatine/creatine system used for cellular energy buffering in tissues with high and fluctuating ATP demand (skeletal and cardiac muscle, brain). The pathway is short and committed: L-arginine and glycine are first condensed by L-arginine:glycine amidinotransferase (AGAT/GATM) to give guanidinoacetate (GAA) and L-ornithine, then guanidinoacetate is methylated by guanidinoacetate N-methyltransferase (GAMT) using S-adenosyl-L-methionine (SAM) as the methyl donor to yield creatine and S-adenosyl-L-homocysteine (SAH). The two activities are characteristically split both by subcellular compartment and, in mammals, by organ: AGAT/GATM is a mitochondrial intermembrane-space enzyme and catalyses the first, committed, feedback- regulated step (creatine represses GATM), whereas GAMT is a cytosolic enzyme and is the second, methylation step. The first step is most active in kidney and pancreas and the second predominates in liver, so guanidinoacetate is an inter-organ intermediate that is exported and taken up before methylation; finished creatine is distributed in the blood and imported into target tissues by the creatine transporter SLC6A8. GAMT is also the largest single consumer of SAM-derived methyl groups in the body, tying creatine synthesis to one-carbon / methionine-cycle metabolism. Inherited deficiency of either enzyme (and of the SLC6A8 transporter) causes cerebral creatine-deficiency syndromes. Creatine utilization by the creatine kinases (the phosphocreatine shuttle and the "futile creatine cycle") is downstream of this module and is not part of the biosynthetic pathway itself.