Introduction:
L-arginine/glycine transamidinase (AGAT) is a 48.5 kilodalton enzyme composed of 423 amino acid residues. It catalyzes the production of glycocyamine guanidoacetate, which is the first, and rate-limiting step in creatine synthesis. The enzyme you can now see in the neighboring frame, assuming you have Chime, is from the pdb file, 3jdw, and was produced using X-ray diffraction after cloning and isolation from Escherichia coli B121 (De3) Plyss. It is, however, a human gene that was engineered and incorporated into the bacteria by the Pr3et plasmid.
AGAT is found mainly in the kidney and pancreas of vertebrates, but has also been found in some echinoderms. It also is 37% similar to a 38 kilodalton transamidinase found in streptomyces griseus, which is called inosamine-phosphate aminidotransferase. This bacterial protein can actually carry out most of the reaction that AGAT does. However, it cannot bind glycine, and so cannot form glycocyamine guanidoacetate. The native human protein is transcribed from a 2330 nucleotide mRNA transcript from the gene locus at38h of the short arm of chromosome 15. Upon translation, it is released into the cytosol, where it may remain for its whole "lifetime." The average turnover rate for AGAT is about twenty minutes. AGAT is typically transported into the mitochondria, where a 37 amino acid amino terminus sequence tag is cleaved in order to transport the protein into the intermembrane space and consequently attach it to the outside of the inner membrane of the mitochondria.
Creatine is important because it is used in muscle to regenerate ATP very quickly. It is typically found in the cell as creatine phosphate, which can donate its phosphoryl group to ADP quite readily and is the main source of energy for quick bursts of activity, like sprinting, weightlifting, or playing American football.
Creatine also has a function in regards to the control of AGAT. When creatine levels rise to abnormal concentrations, as happens with creatine supplements, creatine and growth hormone interact with the gene locus for AGAT and reduce transcription of its mRNA. They also interfere with the translation of the AGAT mRNA. The overall activity of AGAT can be reduced to a mere 26% of normal with only 0.3% creatine supplements in rats.
However, a more important inhibition of the enzyme occurs when ornithine is in excess, as happens with hyperornithinemia. Ornithine competitively inhibits AGAT, and, if severe inhibition occurs, pathogenesis of choroidal, retinal, and muscle fiber tissues may occur. This happens in the autosomal recessive disease called gyrate atrophy. This leads to blindness later in adulthood, and also contributes to age-related muscle atrophy.
Other names for AGAT are glycine amidinotransferase (enzymatic name) and AT38 (genomic protein name), and its enzyme classification number is 2.1.4.1.