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Synthesis of Creatine

The primary locations of creatine synthesis in the human body are the liver and the kidneys.  The process involves 3 amino acids that are naturally found in the human body: arginine, methionine, and glycine.  There are also 2 specific enzymes involved AGAT and GAMT.1,2,3  There are two steps to creatine synthesis. 

The first step of synthesis is the formation of guanidinoacetate.  Glycine and arginine react to produce two compounds known as ornithine and guanidinoacetate.1  This formation is catalyzed by an enzyme known as arginine:glycine amidino-transferase, also known as AGAT.  This is considered the rate limiting step of the synthesis reaction.1  AGAT is essential in the first step of synthesis because it is absolutely specific to the amino acids involved in guanidinoacetate and will not bind with any other amino acids.

The second step of creatine synthesis is methylation Guanidinoacetate N-methyltransferase (GAMT) employs S-adenosylmethionine to donate the methyl group from methionine to guanidinoacetate thus producing creatine (Scheme 1).1,2  GAMT binds substrates in a specific order and binds S-adenosylmethionine before binding guanidinoacetate to complete the synthesis of creatine.1

Scheme 1. The synthesis of creatine. Arginine and Glycine forming Guanidinoacetic Acid which is then methylated to form creatine. 

The scheme shows the synthesis of creatine at physiological pH.

 

References

1. Kaddurah-Daouk R.; Wyss M. Creatine and Creatinine Metabolism. Physiol. Rev. [Online] 2000, 80, 1107-1213. American Physiological Society. http://physrev.physiology.org/content/80/3/1107.full.pdf+html (October 4,2012)

2. Brazeau G.; Persky A. Clinical Pharmacology of the Dietary Supplement Creatine Monohydrate. Pharmacol. Rev. [Online] 2001, 53, 161-176. ASPET http://pharmrev.aspetjournals.org/content/53/2/161.full.pdf+html (October 4,2012)

3.Cantoni G.; Vignos P. Enzymatic Mechanism of Creatine Synthesis. Unknown. [Online] 1954,647-659 J. Biol. Chem. http://www.jbc.org/content/209/2/647 (October 7, 2012)