|Topic:||Creatine Biosynthesis .|
|Details:|| Creatine synthesis occurs predominantly in the kidneys and the liver. The synthesis of creatine begins in the kidneys using the amino acids arginine and glycine. The formation of guanidinoacetate (GAA) from these two amino acids is catalyzed by the enzyme glycine amidinotransferase, also called L-arginine:glycine amidinotransferase (AGAT). Glycine amidinotransferase is encoded by the GATM gene located on chromosome 15q21.1 and is composed of 12 exons that encode a 423 amino acid protein that localizes to the mitochondria. Guanidinoacetate it transported to the blood and picked up by hepatocytes where it is methylated forming creatine. The methyl donor for this reaction is S-adenosylmethionine (SAM or AdoMet) and the reaction is catalyzed by the enzyme guanidinoacetate N-methyltransferase. This latter enzyme is encoded by the GAMT gene located on chromosome 19p13.3 and is composed of 6 exons that generate two alternatively spliced mRNAs that encode isoform a (236 amino acids) and isoform b (269 amino acids).
Following synthesis creatine is released to the blood where is is picked up, predominantly, by the brain and skeletal muscle cells through the action of the SLC family member transporter, SLC6A8. The SLC6A8 gene is located on the X chromosome (Xq28) and is composed of 14 exons that generate three alternatively spliced mRNAs, each of which encode a distinct protein isoform. Within cells creatine is phosphorylated by creatine kinases (CK; also called creatine phosphokinase, CPK) that generate the high-energy storage compound, creatine phosphate. There are two creatine kinase genes in humans identified as the muscle creatine kinase gene (symbol: CKM) and the brain creatine kinase gene (symbol: CKB). The CKM gene is located on chromosome 19q13.32 and is composed of 9 exons that encode a protein of 381 amino acids. The CKB gene is located on chromosome 14q32 and is composed of 8 exons that encode a protein of 381 amino acids. Different combinations of the proteins encoded by these two genes generate tissue-specific isoforms of the functional enzymes.
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