GATM

GATM (AGAT; L-arginine:glycine amidinotransferase, EC 2.1.4.1) is the first and rate-limiting enzyme of creatine biosynthesis. It catalyzes the transfer of the amidino group of L-arginine onto the amino group of glycine to yield guanidinoacetate and L-ornithine; guanidinoacetate is subsequently methylated by GAMT to form creatine. The mature enzyme is a homodimer with a five-fold pseudosymmetric basket fold and a buried active site that uses a Cys-His-Asp catalytic triad and an amidino-cysteine covalent intermediate (ping-pong mechanism). Although glycine is the strongly preferred acceptor, the enzyme is promiscuous and can also amidinate GABA, beta-alanine and taurine to produce guanidinobutyrate, guanidinopropionate and taurocyamine. The canonical mitochondrial isoform carries a cleavable N-terminal transit peptide and localizes to the mitochondrial intermembrane space, attached to the intermembrane side of the inner membrane; an alternatively spliced isoform is cytoplasmic. GATM is expressed broadly with highest levels in kidney, and is also abundant in liver, pancreas (exocrine acinar cells), heart, brain and skeletal muscle, supplying creatine to high-energy-demand tissues for ATP buffering. Loss-of-function variants cause autosomal-recessive cerebral creatine deficiency syndrome 3 (AGAT deficiency), a treatable disorder of brain creatine depletion presenting with intellectual disability, speech delay and myopathy, whereas distinct dominant aggregation-prone variants cause Fanconi renotubular syndrome 1.

Disorders

Relationship is the entry's genetic[].relationship_type. untyped means the entry has a genetic record for the gene but does not type it; its free-text association is shown instead.

An entry matches when ClinGen's MONDO disease is the entry's own disease term, a subtype term, or an exact-match mapping. An amber status marks an entry ClinGen supports the gene for (Definitive, Strong or Moderate) whose own record does not type it. A Limited, Disputed or Refuted tier on such an entry is not a gap.